Cosmetic Formulationof Skin Care Products

COSMETIC SCIENCE AND TECHNOLOGY Series Editor ERIC JUNGERMANN Jungermann Associates, Inc. Phoenix, Arizona1. Cosmetic and Drug Preservation: Principles and Practice, edited by Jon J. Kabara2. The Cosmetic Industry: Scientific and Regulatory Foundations, edited by Norman F. Estrin3. Cosmetic Product Testing: A Modern Psychophysical Approach, Howard R. Moskowitz4. Cosmetic Analysis: Selective Methods and Techniques, edited by P. Boré5. Cosmetic Safety: A Primer for Cosmetic Scientists, edited by James H. Whittam6. Oral Hygiene Products and Practice, Morton Pader7. Antiperspirants and Deodorants, edited by Karl Laden and Carl B. Felger8. Clinical Safety and Efficacy Testing of Cosmetics, edited by William C. Waggoner9. Methods for Cutaneous Investigation, edited by Robert L. Rietschel and Thomas S. Spencer10. Sunscreens: Development, Evaluation, and Regulatory Aspects, edited by Nicholas J. Lowe and Nadim A. Shaath11. Glycerine: A Key Cosmetic Ingredient, edited by Eric Jungermann and Norman O. V. Sonntag12. Handbook of Cosmetic Microbiology, Donald S. Orth13. Rheological Properties of Cosmetics and Toiletries, edited by Dennis Laba14. Consumer Testing and Evaluation of Personal Care Products, Howard R. Moskowitz15. Sunscreens: Development, Evaluation, and Regulatory Aspects. Second Edition, Revised and Expanded, edited by Nicholas J. Lowe, Nadim A. Shaath, and Madhu A. Pathak

16. Preservative-Free and Self-Preserving Cosmetics and Drugs: Principles and Practice, edited by Jon J. Kabara and Donald S. Orth17. Hair and Hair Care, edited by Dale H. Johnson18. Cosmetic Claims Substantiation, edited by Louise B. Aust19. Novel Cosmetic Delivery Systems, edited by Shlomo Magdassi and Elka Touitou20. Antiperspirants and Deodorants: Second Edition, Revised and Expanded, edited by Karl Laden21. Conditioning Agents for Hair and Skin, edited by Randy Schueller and Perry Romanowski22. Principles of Polymer Science and Technology in Cosmetics and Personal Care, edited by E. Desmond Goddard and James V. Gruber23. Cosmeceuticals: Drugs vs. Cosmetics, edited by Peter Elsner and Howard I. Maibach24. Cosmetic Lipids and the Skin Barrier, edited by Thomas Förster25. Skin Moisturization, edited by James J. Leyden and Anthony V. Rawlings26. Multifunctional Cosmetics, edited by Randy Schueller and Perry Romanowski27. Cosmeceuticals and Active Cosmetics: Drugs Versus Cosmetics, Second Edition, edited by Peter Elsner and Howard I. Maibach28. Sunscreens: Regulations and Commercial Development, Third Edition, edited by Nadim A. Shaath29. Biotechnology in Personal Care, edited by Raj Lad30. Cosmetic Formulation of Skin Care Products, edited by Zoe Diana Draelos and Lauren A. Thaman

Cosmetic Formulationof Skin Care Products edited by Zoe Diana Draelos Wake Forest University School of Medicine Winston-Salem, North Carolina, U.S.A. Lauren A. Thaman P&G Beauty Cincinnati, Ohio, U.S.A. New York London Taylor & Francis is an imprint of the Taylor & Francis Group, an informa business

Taylor & Francis Group270 Madison AvenueNew York, NY 10016© 2006 by Taylor and Francis Group, LLCTaylor & Francis is an Informa businessNo claim to original U.S. Government worksPrinted in the United States of America on acid-free paper10 9 8 7 6 5 4 3 2 1International Standard Book Number-10: 0-8493-3968-5 (Hardcover)International Standard Book Number-13: 978-0-8493-3968-4 (Hardcover)Library of Congress Card Number 2006040471This book contains information obtained from authentic and highly regarded sources. Reprinted material is quotedwith permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been madeto publish reliable data and information, but the author and the publisher cannot assume responsibility for the valid-ity of all materials or for the consequences of their use.No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical,or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in anyinformation storage or retrieval system, without written permission from the publishers.For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety ofusers. For organizations that have been granted a photocopy license by the CCC, a separate system of payment hasbeen arranged.Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only foridentification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication DataCosmetic formulation of skin care products / edited by Zoe Diana Draelos, Lauren A. Thaman. p. cm. -- (Cosmetic science and technology ; v. 30) Includes bibliographical references and index. ISBN-13: 978-0-8493-3968-4 (acid-free paper) ISBN-10: 0-8493-3968-5 (acid-free paper) 1. Cosmetic delivery systems. 2. Skin--Care and hygiene. 3. Cosmetics. I. Draelos, Zoe Diana. II.Thaman, Lauren. III. Cosmetic science and technology series ; v. 30.TP983.3.C67 2006 2006040471668’.55--dc22 Taylor & Francis Group is the Academic Division of Infomra plc. Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com

About the SeriesThe Cosmetic Science and Technology series was conceived to permit discussion of abroad range of current knowledge and theories of cosmetic science and technology. Theseries is composed of books written by either one or two authors or edited volumes with anumber of contributors. Authorities from industry, academia, and the governmentparticipate in writing these books. The aim of the series is to cover the many facets of cosmetic science and technology.Topics are drawn from a wide spectrum of disciplines ranging from chemistry, physics,biochemistry and dermatology to consumer evaluations, safety issues, efficacy, toxicityand regulatory questions. Organic, inorganic, physical, analytical and polymer chemistry,microbiology, emulsion and lipid technology all play important roles in cosmetic science. There is little commonality in the scientific methods, processes and formulationsrequired for the wide variety of toiletries and cosmetics in the market. Products range fromhair, skin, and oral care products to lipsticks, nail polishes, deodorants, body powders andaerosols, to cosmeceuticals which are quasi-pharmaceutical over-the-counter productssuch as antiperspirants, dandruff shampoos, wrinkle reducers, antimicrobial soaps, acnetreatments, or sun screen products. Emphasis in the Cosmetic Science and Technology series is placed on reporting thecurrent status of cosmetic science and technology, the ever-changing regulatory climate,and historical reviews. The series has now grown to 30 books dealing with the constantlychanging trends in the cosmetic industry, including globalization. Several of the bookshave been translated into Japanese and Chinese. Contributions range from highlysophisticated and scientific treaties to primers and presentations of practical applications.Authors are encouraged to present their own concepts as well as established theories.Contributors have been asked not to shy away from fields that are in a state of transition orsomewhat controversial, and not to hesitate to present detailed discussions of their ownwork. Altogether, we intend to develop in this series a collection of critical surveys andideas covering the diverse phases of the cosmetic industry. The thirtieth book in this series, Cosmetic Formulation of Skin Care Products editedby Zoe Diana Draelos, MD and Lauren Thaman, MS comprises 22 chapters authored orco-authored by over 30 experts in the field. The development of cosmetics and toiletriesrepresents a highly diversified field involving many subsections of science and “art.” Itcovers the discovery of novel raw materials, development and manufacture of uniqueformulations, ever more sophisticated testing methods particularly in the areas of safety,clinical and performance efficacy evaluations, and claim substantiation. But even in thesedays of high technology and ever increasing scientific sophistication, art and intuitioncontinue to play an important part in the development of formulations, their evaluation, iii

iv About the Seriesselection of raw materials, and, perhaps most importantly, the successful marketing of newproducts. Aesthetic considerations, such as fragrance, color, packaging and productpositioning often can be as important to the success of a new cosmetic product asdelivering the promised (implied) performance or the use of a new magic ingredient. The application of more sophisticated methodologies to the evaluation of cosmeticsthat began in the 1980s has continued and has greatly impacted such areas as claimsubstantiation, safety and efficacy testing, product evaluations and testing, development ofnew raw materials, such as biotechnology products, for example products produced bymicroorganisms where genes are modified by recombinant DNA technologies. Butregardless how great the science and the medical proofs behind a new product, bad or justindifferent aesthetics can hurt the performance in the marketplace. New cosmetic formulations usually are the result of systematic developmentprograms sponsored by corporations and carried out either in their own laboratories or bysponsored programs in cooperation with consulting laboratories. Their developmentinvolves individuals with diverse backgrounds, experience, and objectives. Thoughmulti-tasking has become a favorite buzzword, there are obvious limitations. Topmanagement and marketing and advertising executives identify areas of new productdevelopment that were either developed internally or brought to their attention byvarious outsides sources. This sometimes leads to a push for extravagant claims thatmight require the repeal of one or more laws of nature. The product developmentchemists (formulators) in the laboratory are then charged with meeting the performanceobjectives and product parameters set by management. In addition, they have to beconcerned with a host of considerations, ranging from safety issues, global regulations,raw material cost and availability, awareness of the competitive climate, patent status,adequate preservation, stability and compatibility issues, product scale-up and productionproblems, to cosmetic elegance considerations, such as fragrance selection, color, andpackaging. Finally, there is the medical fraternity, often dermatologists, devising andsupervising efficacy and safety tests concerned with the performance of the products.This can be a key activity particularly with cosmeceuticals and other products makingclinical claims that need substantiation and scientific credibility. When looking at the total process of developing and commercializing a newcosmetic product, there are a number of stakeholders: top management, marketing andsales, R&D and operations, academic support groups, and consultants. These groups mayhave quite different philosophical approaches and goals. While all share a common goal ofcoming up with a commercially successful product, there are often real differences in howthe various groups view or perceive the project. Some are clearly business-driven; othersare science-driven. This book tries to bridge some of these differences. Business-driven activitiesinclude top management’s desire to have the product in the market place with goodcustomer acceptance, a strong business plan and strategy, and good profit margins;involvement in the details on how this is achieved is secondary. To quote a speaker(Harvey Gedeon, Estee Lauder Companies) at the 2005 Annual meeting of Society ofCosmetic Chemists, “Management expects us to create low-cost breakthrough productsthat are the best-in-category.” Marketing and sales are concerned with developing themarketing strategies and coordinating and directing the management of the new productor brand. Science-driven activities predominate in the laboratory. The formulators andthe clinical workers attacking the various technical problems will be intrigued by theuse of new chemicals, clever processing techniques, patentability and new testingtechniques, often involving expensive new and intriguing new technical tools to solvethe technical challenges presented by the project. Sometimes too many technical

About the Series vtangents can delay the timely resolution of new product development projects. Buildinga good communication bridge between the business and different science-driven groupsis the key to the success of a new cosmetic product. I want to thank all the contributors and the editors, Zoe Diana Draelos, MD andLauren Thaman, MS for participating in the Cosmetic Science and Technology series andthe Informa Healthcare organization, particularly Sandra Beberman, with whom I haveworked since the inception of this series twenty-five years ago, for their support and help. Eric Jungermann, PhD

I dedicate this book to my two sons, Mark and Matthew,who constantly challenge me to see the world in new fresh ways! Zoe Diana Draelos I dedicate this book to my many P&G colleagues who consistently demand and force me to think what’s next. Lauren Thaman

PrefaceCosmetic formulation is becoming increasingly complex given the challenges offormulating for a technologically sophisticated consumer. This text is designed to meetthe needs of the cosmetic chemist, scientist, dermatologist and formulator who mustunderstand a wide range of issues to create successful, novel skin care products for adiverse population. To accomplish this end, the text is divided into the key knowledgeareas of cutaneous formulation issues, formulation development, raw materials and activeingredients, and product testing, efficacy, and clinical assessment. The section oncutaneous formulation deals with the unique aspects of formulating for specific body areas,such as the face, eyelids, lips, hands, underarms, etc., while discussing the needs of specialpopulations, such as individuals with sensitive skin, rosacea, atopic dermatitis, etc. Issuesspecific to both genders and all skin color types are presented. This initial section presentsthe framework necessary to design products that successfully perform in body areas withunique anatomic considerations while considering gender and ethnic differences. The text continues by delving into formulation development by product category:cleansers, moisturizers, toners, antiperspirants, and sunscreens. This allows the reader totake the information learned in section one regarding unique anatomic needs and createskin care products by employing state-of-the-art formulation chemistry. However, the skincare industry has moved beyond basic skin maintenance product categories into activesdesigned to deliver skin-enhancing benefits. These areas of skin treatment include therealms of acne, photoaging, dyspigmentation, and inflammation. Actives that are importantin these areas include salicylic acid, benzoyl peroxide, hydroxy acids, retinoids, vitamins,hydroquinone, antioxidants, botanicals, etc. Understanding the mechanism of action andformulation issues regarding these actives allows the creation of skin care products thatdeliver benefits into the treatment realm beyond maintenance. In summary, the text presents diverse knowledge sets from dermatology, cosmeticchemistry, and product formulation. It synthesizes the information into one cohesive unitfor practical application by the dermatologist, cosmetic chemist, formulator, or testingfacility. Only by understanding all aspects of cosmetic formulation can technology expandthe skin care marketplace. Zoe Diana Draelos Lauren A. Thaman ix

ContentsAbout the Series Eric Jungermann : : : : iiiPreface : : : : ixContributors : : : : xix 1. Cosmetic Formulation of Skin Care Products . . . . . . . . . . . . . . . . . . 1 Zoe Diana Draelos Introduction: How to Utilize This Text : : : : 1PART I: CUTANEOUS FORMULATION ISSUES 2. Cutaneous Formulation Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Zoe Diana Draelos Site-Specific Cutaneous Needs : : : : 3 Suggested Readings : : : : 26 3. Formulation for Special Populations . . . . . . . . . . . . . . . . . . . . . . . . 27 Zoe Diana Draelos Gender : : : : 27 Age Issues : : : : 28 Skin Color : : : : 29 Hair Shaft Architecture : : : : 30 Sensitive Skin : : : : 31 Contact Dermatitis Issues : : : : 32 Acne Issues : : : : 34 Summary : : : : 34 References : : : : 34PART II: FORMULATION DEVELOPMENT AND APPLICATION 4. Personal Cleansing Products: Properties and Use . . . . . . . . . . . . . . 35 Keith Ertel Introduction : : : : 35 xi

xii Contents Skin Cleansing : : : : 35 Personal Cleanser Effects on Skin : : : : 40 Some Practical Considerations When Choosing a Personal Cleanser : : : : 54 References : : : : 59 5. Toners and Astringents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Melanie Smith Introduction : : : : 67 Product Nomenclature : : : : 67 Function and Order of Application Within a Skin Care Regimen : : : : 68 Formulation Considerations : : : : 68 Product Claims : : : : 73 Claims Testing Methods : : : : 74 Uses in Dermatology : : : : 74 Adverse Reactions : : : : 75 Summary : : : : 75 References : : : : 76 6. The Dry Skin Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 Paul J. Matts and Anthony V. Rawlings Introduction : : : : 79 Stratum Corneum and Epidermal Structure : : : : 80 Stratum Corneum Lipid Chemistry and Biophysics : : : : 81 Stratum Corneum Corneodesmosomes and Corneodesmolysis : : : : 84 Corneocyte Envelope Maturation and the Role of Transglutaminases : : : : 87 Stratum Corneum Natural Moisturizing Factors (NMF) : : : : 89 The Effect of Humidity on Epidermal Differentiation and Stratum Corneum Quality : : : : 92 The Pathophysiology of Winter- and Soap-Induced Dry Skin : : : : 93 The “Dry Skin Cycle” Model: A New Way to Describe Induction and Propagation of the Xerosis : : : : 96 Management of Dry Skin : : : : 99 Summary and Conclusions : : : : 106 References : : : : 107 7. Factors Influencing Optimal Skin Care and Product Selection . . . 115 James Q. Del Rosso Basic Skin Care Processes : : : : 115 The Epidermal Barrier and Water Content : : : : 116 Epidermal Barrier Integrity, Function, and Repair : : : : 117 Impact of Exogenous Moisturization on Barrier Repair : : : : 117 Clinical Implications of Exogenous Moisturization : : : : 117

Contents xiiiComponents of Moisturizer Formulations : : : : 118Balancing Effects and Cosmetic Elegance of Product Components : : : : 118Formulation Characteristics : : : : 119Special Additives and Ingredients : : : : 119The Significance of Gentle Skin Cleansing : : : : 120Basic Cleanser Formulations : : : : 120Conclusion : : : : 120References : : : : 1218. Antiperspirants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 John E. Wild, A. C. Lanzalaco, and D. F. Swaile Introduction : : : : 123 Antiperspirants : : : : 124 Antiperspirant Efficacy : : : : 126 Formulation : : : : 128 Formulating for the Consumer : : : : 131 Introducing New Antiperspirant Active Formulations : : : : 131 Medical Approaches to Hyperhidrosis : : : : 131 References : : : : 134PART III: ACTIVE INGREDIENTS FOR SKIN TREATMENT 9. Sunscreens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 J. F. Nash and Paul R. Tanner Introduction : : : : 135 Sunscreens : : : : 136 Self-Tanning Products : : : : 141 Formulation Challenges : : : : 143 Regulatory Issues : : : : 144 Safe Sun Strategy : : : : 145 Conclusions : : : : 148 References : : : : 14910. Photoprotection and the Prevention of Photocarcinogenesis . . . . . 153 Nathalie Nguyen and Darrell S. Rigel Overview : : : : 153 Relationship of UV Exposure to Skin Cancer Development : : : : 154 Spectral Differences Related to UV Photocarcinogenesis : : : : 155 Photocarcinogenesis-Decreasing Photoprotection Modalities : : : : 155 Sunscreens : : : : 156 Types of Sunscreens and Mechanisms of Action : : : : 156 Chemical Sunscreens : : : : 157 Physical Sunscreens : : : : 159 Photocarcinogenesis Reduction by Wearing Clothing : : : : 159

xiv ContentsBehavior Modification : : : : 160Effectiveness of Photoprotection : : : : 160Photoprotection and Vitamin D : : : : 160Patient Recommendations and Future Directions : : : : 161References : : : : 16211. Anti-aging Skin Care Formulations . . . . . . . . . . . . . . . . . . . . . . . 167 Donald L. Bissett Introduction : : : : 167 Vitamin A : : : : 167 Vitamin B3 : : : : 170 Vitamin C : : : : 174 Peptides : : : : 176 Dimethylaminoethanol (DMAE) : : : : 178 Kinetin (N6-Furfuryladenine) : : : : 179 Triterpenoids : : : : 180 Ubiquinone (Co-Enzyme Q10) : : : : 181 Other Technologies : : : : 181 Discussion : : : : 181 References : : : : 18312. The Role of Cosmeceuticals in Dermatology . . . . . . . . . . . . . . . . . 187 David H. McDaniel, Joseph DiNardo, and Joseph Lewis What Are “Cosmeceuticals”—Cosmetics vs. RX Drugs : : : : 187 Domestic and International Regulatory Guidelines Impacting Cosmetics : : : : 191 Categories of Currently Popular Cosmeceuticals in Dermatology : : : : 192 How to Select the “Best” Formulation of a Cosmeceutical : : : : 199 The Future of Cosmeceuticals : : : : 200 References : : : : 20213. Skin Lightening Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 Wen-Yuan Zhu and Ru-Zhi Zhang Tyrosinase Inhibition : : : : 205 Product Reduction and Reactive Oxygen Species : : : : 209 Inhibition of Melanosome Transfer : : : : 211 Skin Turnover Acceleration : : : : 212 Traditional Chinese Medicine : : : : 213 References : : : : 21514. Medical and Surgical Approaches to Skin Lightening . . . . . . . . . 219 Marta I. Rendon and Jorge I. Gaviria Introduction : : : : 219 Topical Depigmenting Agents : : : : 221 Phenolic Depigmenting Agents : : : : 221 Non-Phenolic Agents : : : : 224

Contents xv Topical Cosmeceuticals : : : : 225 Botanicals : : : : 226 Physical Therapies : : : : 226 Chemical Peels : : : : 227 Microdermabrasion : : : : 228 Dermabrasion : : : : 228 Lasers : : : : 228 Our Therapeutic Approach : : : : 230 Conclusions : : : : 231 References : : : : 23215. Topical Exfoliation—Clinical Effects and Formulating Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 M. Elizabeth Briden and Barbara A. Green Exfoliation : : : : 237 Physical Exfoliants: Scratching the Surface : : : : 238 Chemical Exfoliation : : : : 239 Conclusion : : : : 247 References : : : : 24716. Over-the-Counter Acne Medications . . . . . . . . . . . . . . . . . . . . . . . 251 Theresa Chen and Yohini Appa Introduction : : : : 251 Clinical Considerations : : : : 252 Highlights of Over-the-Counter Acne Monograph : : : : 253 Formulation of Over-the-Counter Acne Products : : : : 253 Trends in Over-the-Counter Acne Formulations : : : : 254 Advances in Over-the-Counter Acne Formulations : : : : 255 Summary : : : : 267 References : : : : 26817. Acne Treatment Methodologies . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Emmy M. Fernandez, Andrea L. Zaenglein, and Diane M. Thiboutot Introduction : : : : 273 Morphology : : : : 276 Topical Retinoid : : : : 276 Cleansers : : : : 279 Hydroxy Acids : : : : 279 Benzoyl Peroxide : : : : 281 Other Topical Treatments : : : : 281 Oral Antibiotics : : : : 281 Hormonal Therapy : : : : 286 Isotretinoin : : : : 287 Manual Treatments : : : : 290 Phototherapy : : : : 291 References : : : : 292

xvi Contents18. Topical Botanicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Tracy Cornuelle and Jan Lephart Introduction : : : : 297 Selecting Plant Species : : : : 298 Sourcing Plant Material : : : : 298 Accurate Identification of Plant Species : : : : 299 Harvesting Plant Material : : : : 299 Cosmetic Extracts : : : : 300 Standardization of Extracts : : : : 302 Quality Issues : : : : 303 Safety and Toxicology : : : : 304 Conclusions : : : : 305 References : : : : 30519. Herbs in Cosmeceuticals: Are They Safe and Effective? . . . . . . . . 309 Carl Thornfeldt Background : : : : 309 Processing Botanicals : : : : 310 Regulatory Climate : : : : 311 Adverse Reactions : : : : 311 Specific Herbs : : : : 328 Summary : : : : 347 References : : : : 34720. Topical Anti-inflammatories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351 Bryan B. Fuller and Dustin R. Smith Introduction : : : : 351 Biology of Skin Inflammation : : : : 351 Prescription and Over-the-Counter Treatments for Inflammation and Mechanism of Action : : : : 353 Anti-inflammatory Cosmeceutical “Actives” : : : : 361 Biological Screening Assays to Identify Novel Anti-inflammatory Compounds : : : : 363 Development of Effective Topical Formulations : : : : 368 Conclusions : : : : 373 References : : : : 37321. Topical Nutritional Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . 377 Karen E. Burke Introduction : : : : 377 Vitamin C : : : : 377 Vitamin E : : : : 379 Selenium : : : : 384 New Combinations of Antioxidants : : : : 386 Soy Extract: Genistein : : : : 387 Alpha-Lipoic Acid : : : : 390

Contents xvii Ubiquinone : : : : 394 Summary : : : : 395 References : : : : 39622. What Is Next in Skin Care Cosmetic Products? .............. 403 Lauren A. Thaman Cosmeceuticals : : : : 403 Nutraceuticals : : : : 405 Medical Mimics : : : : 405 Customized Products : : : : 406 Skin Tone Alteration : : : : 406 Delivery Systems : : : : 407 New Users : : : : 407 The Skin Care Market : : : : 407 References : : : : 408Index : : : : 409

ContributorsYohini Appa Neutrogena Skincare Institute, Los Angeles, California, U.S.A.Donald L. Bissett P&G Beauty, Miami Valley Innovation Center, Cincinnati, Ohio,U.S.A.M. Elizabeth Briden Advanced Dermatology and Cosmetic Institute, Edina,Minnesota, U.S.A.Karen E. Burke Department of Dermatology, Mount Sinai Medical Centerand Department of Medicine, Cabrini Medical Center, New York, New York, U.S.A.Theresa Chen Neutrogena Skincare Institute, Los Angeles, California, U.S.A.Tracy Cornuelle Research and Development, Nu Skin Enterprises, Provo, Utah,U.S.A.James Q. Del Rosso Department of Dermatology, University of Nevada School ofMedicine, Las Vegas, Nevada, U.S.A.Joseph DiNardo Pharma Cosmetix Research, LLC, Richmond, Virginia, U.S.A.Zoe Diana Draelos Department of Dermatology, Wake Forest University School ofMedicine, Winston-Salem, and Dermatology Consulting Services, High Point, NorthCarolina, U.S.A.Keith Ertel P&G Beauty, Sharon Woods Technical Center, Cincinnati, Ohio, U.S.A.Emmy M. Fernandez Department of Dermatology, Pennsylvania State UniversityMilton S. Hershey Medical Center, Hershey, Pennsylvania, U.S.A.Bryan B. Fuller Department of Biochemistry and Molecular Biology, University ofOklahoma Health Sciences Center, Oklahoma City, Oklahoma, U.S.A.Jorge I. Gaviria Medical Hair Research Group, Inc. and Clinical Research, Skin CareResearch, Inc., Boca Raton, Florida, U.S.A.Barbara A. Green NeoStrata Company, Inc., Princeton, New Jersey, U.S.A.A. C. Lanzalaco P&G Beauty, Sharon Woods Technical Center, Cincinnati,Ohio, U.S.A. xix

xx ContributorsJan Lephart Research and Development, Nu Skin Enterprises, Provo, Utah, U.S.A.Joseph Lewis Pharma Cosmetix Research, LLC, Richmond, Virginia, U.S.A.Paul J. Matts P&G Beauty, Rusham Park Technical Center, Egham, Surrey, U.K.David H. McDaniel The Institute of Anti-Aging Research, Virginia Beach, Virginia,U.S.A.J. F. Nash P&G Beauty, Sharon Woods Technical Center, Cincinnati, Ohio, U.S.A.Nathalie Nguyen Department of Dermatology, New York University School ofMedicine, New York, New York, U.S.A.Anthony V. Rawlings AVR Consulting Ltd., Northwich, Cheshire, U.K.Marta I. Rendon Dermatology and Aesthetic Center and University of Miami,Miami, and Florida Atlantic University, Boca Raton, Florida, U.S.A.Darrell S. Rigel Department of Dermatology, New York University School ofMedicine, New York, New York, U.S.A.Dustin R. Smith Department of Biochemistry and Molecular Biology,University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, U.S.A.Melanie Smith Mary Kay Inc., Dallas, Texas, U.S.A.D. F. Swaile P&G Beauty, Sharon Woods Technical Center, Cincinnati, Ohio, U.S.A.Paul R. Tanner P&G Beauty, Sharon Woods Technical Center, Cincinnati, Ohio,U.S.A.Lauren A. Thaman P&G Beauty, Sharon Woods Technical Center, Cincinnati, Ohio,U.S.A.Diane M. Thiboutot Department of Dermatology, Pennsylvania State UniversityMilton S. Hershey Medical Center, Hershey, Pennsylvania, U.S.A.Carl Thornfeldt Episciences, Inc., Boise, and CT Derm, Fruitland, Idaho, and OregonHealth Sciences University, Portland, Oregon, U.S.A.John E. Wild Hill Top Research, Miamiville, Ohio, U.S.A.Andrea L. Zaenglein Department of Dermatology, Pennsylvania State UniversityMilton S. Hershey Medical Center, Hershey, Pennsylvania, U.S.A.Ru-Zhi Zhang Department of Dermatology, The Affiliated Hospital, BangBuMedical College, BangBu, P.R. ChinaWen-Yuan Zhu Department of Dermatology, The First Affiliated Hospital, NanjingMedical University, Nanjing, P.R. China

1Cosmetic Formulation of SkinCare ProductsZoe Diana DraelosDepartment of Dermatology, Wake Forest University School of Medicine,Winston-Salem, and Dermatology Consulting Services, High Point,North Carolina, U.S.A.INTRODUCTION: HOW TO UTILIZE THIS TEXTThe formulation of skin care products requires a cross-disciplinary knowledge base, whichcan be difficult to obtain. How can any individual obtain the knowledge of a dermatologist,the expertise of a PhD biochemist, the experience of a cosmetic chemist, and the insight ofa research and development scientist? There is not enough time in one lifetime to masterall of these disciplines. It takes eight years after college to become a dermatologist, at leastfive years to obtain a PhD, 10 years to become an experienced cosmetic chemist, and10 years to mature into a research and development scientist. Thus, after 33 years of workexperience and schooling the cross-disciplinary knowledge base would be complete! Thistext aims to condense 33 years into 400 pages, allowing mastery of the field of skin careformulation by the exchange of knowledge. In order to accomplish this goal, the text contains chapters written bydermatologists, PhD basic scientists, cosmetic chemists, and industry research and design(R&D) applied scientists. The book is organized sequentially in three sections: cutaneousformulation issues, formulation development and application, and active ingredients forskin treatment. Cutaneous formulation issues deals with the unique skin needs of each areaof the body and the differences in skin response in various populations. This knowledgebase comes from dermatology. For example, the skin care needs of the face and the handsare quite different. There are numerous sebaceous glands and small vellus hairs on theface, but none on the palms of the hands. This means that reactions to products and productdesign must be different for these two areas. Furthermore, a product that might performwell in fair skin might not meet the needs of persons of color. Titanium dioxide sunscreensare a good example. The titanium dioxide is not perceptible on the skin of a Caucasianindividual, but causes unacceptable whitening in an African American individual. Thesefirst two chapters of the text are designed to offer specific ideas for skin care needs. Thechapters can be read either in their entirety or by using the outline format to select on thosebody areas or special populations of interest. 1

2 Draelos The next section of the book discusses formulation development and application inthe basic skin care areas: cleansers, toners, moisturizers, and antiperspirants. Thesechapters are all written by research and development scientists in industry with anunderstanding of how these products function. The chapters present the basic anatomyand physiology of the skin impacted by the product, ingredients, key considerations, andmethods for product evaluation and testing. The dermatologic perspective on the use andselection of these skin care products is also presented. Lastly, the book presents an up-to-date look at many of the active products that formthe cosmeceutical arena to include: sunscreens, skin lightening agents, exfoliants, andanti-aging skin care products. The dermatologic perspective on each of these areas followswith a discussion of sunscreens in relation to skin cancer prevention, the impact ofcosmeceuticals on the skin, medical therapies for skin lightening, and acne treatmentmethodologies. This approach allows the dermatologist to better understand how theseproducts are constructed, but also helps the industry researcher to view products from amedical perspective that bridges the over-the-counter and prescription worlds. The textthen looks at the world of botanicals, anti-inflammatories, and antioxidants. Specific rawmaterials are discussed by both industry researchers and dermatologists with anencyclopedic review of botanicals that are relevant to skin care. Thus, the text presents skin care, formulation, and raw material selection issuespursuing a unique multidisciplinary approach to the topic. As part of the Marcel DekkerCosmetic Science and Technology series, this text can serve as an introduction to some ofthe more product specific texts in the series that deal solely with moisturizers, cleansers,antiperspirants, etc. This text can provide the 33 years of knowledge necessary tounderstand skin care formulation.

PART I: CUTANEOUS FORMULATION ISSUES2Cutaneous Formulation IssuesZoe Diana DraelosDepartment of Dermatology, Wake Forest University School of Medicine,Winston-Salem, and Dermatology Consulting Services, High Point,North Carolina, U.S.A.An important consideration in formulation technology is the target site for productapplication. Should a skin care product be formulated for the entire body or are thereunique needs for specific body sites? As a dermatologist, I am keenly aware of the need tolook at each anatomic area individually to achieve optimal product functioning. Failureto do so leads to development of a product that works everywhere and nowhere. The goalof this section of the text is to explore the uniqueness of the skin in various body locationsto provide a foundation for anatomic formulation considerations. To understand formulation needs of each body area, several basic concepts must beelucidated. First, the anatomy and physiology of the body site must be identified. Forexample, is the skin in the area bearing hair, sebaceous gland rich, transitional between dryand moist, marked by the presence of sweat glands, hormonally mediated, acne prone, agerelated, etc. The second basic consideration is a discussion of the dermatologic diseasesthat may afflict the given skin area. Good skin care products should supplementprescription medications when disease is present, but also maintain the health of the skinand prevent disease recurrence once resolution of the dermatologic problem has occurred.Third, the hygiene needs of the skin should be considered. Is there natural bacterialcolonization of the site? Is the site a mucous membrane with little resistance to viralparticle penetration? Lastly, thought should be given what constitutes skin health in thearea and what skin care needs should be met to allow maintenance of this health. Only after all of these particular formulation issues have been considered can a trulyquality product begin the development process. Failure to give the necessary forethoughtwill result in a product that is met with initial enthusiasm, due to well-constructedmarketing claims, but poor long-term product performance, due to lack of efficacy. Thisformulation textbook begins with this chapter, since these ideas form the next logical stepin product development following product conception.SITE-SPECIFIC CUTANEOUS NEEDSMany unique body areas require consideration. The face can be considered as a whole;however, the eyelids and the lips represent unique facial areas that demand separate 3

4 Draelosevaluation. The thicker skin of the hands and feet is different from anywhere on the bodywith a transitional area occurring between the rigid nails and the surrounding cuticle andsoft tissue. The abundant sebaceous glands and terminal hair follicles on the scalp makethis a separate skin environment, along with skin that expands and contracts withmovement in intertrigenous areas such as the neck and the underarms. The female andmale genitalia are also unique with numerous glandular and follicular structures thatpresent a hygiene challenge. Everything else that is covered by skin can be simply labeledas the body. Let us begin by examining each of these skin environment areas separately.FaceThe face begins at the anterior hairline, stops at the ears, and is bounded by the lateraljawline and chin. It is the most complex and challenging area of the body for theformulator, yet more products are designed for facial use than any other. Why? Becausethe face is the purveyor of our image, our personality, our health, and our age. It identifieswho we are, how we are, where we are, and sometimes what we hope to be. From adermatologic standpoint, the face possesses unique medical attributes. It contains all of theglandular structures of the body, including hair, and is characterized by dry skin andtransitional skin. The transitional skin is found around the eyes, nose, and mouth. It is alsofrequently afflicted by a variety of skin diseases that complicate product development.Anatomy and PhysiologyLet us begin by considering the anatomy and physiology of the face. The facial skin is thethinnest on the body, except for that around the eyelids. This means that the skin is easy toinjure, but also readily healed. It is for this reason that skin surgeons prefer to operate onfacial skin. Incisions heal imperceptibly due to the minimal movement of skin on the faceand the fact that the face is not weight bearing. Compare the facial skin to that of the upperchest, which heals extremely poorly. The chest skin is constantly subject to pulling andpushing as the arms move, which predisposes any chest incision to healing with athickened hypertrophic scar. Compare the facial skin to that of the lower ankles, which issome of the slowest healing skin on the body, because it must bear a load with walkingaccompanied by constant movement. Indeed, the facial skin is some of the most forgivingon the body when it comes to surgical manipulation. On the other hand, the facial skin is some of the least forgiving when it comes toirritation and allergy. The thinness of the facial skin that is so desirable for healingpurposes allows the ready penetration of irritants and allergens, making productformulation more challenging. The face is also characterized by numerous follicularstructures in the form of pigmented terminal or full thickness hairs in the eyebrows,eyelashes, and male beard combined with white fine downy vellus hairs over the rest of theface. These follicular structures are the transition between the skin on the surface of theface and the ostia, or openings, that lead down into the follicle itself and the associatedsebaceous or oil glands. The follicular ostia forms the structure that is commonly referredto as a pore. The follicle creates the interesting topography of the facial skin withmountains occurring around each follicular structure and intervening valleys in between.This unique topography is known as dermatoglyphics, which forms the pattern and textureof the skin. Prominent dermatoglyphics lead to what is termed coarse skin while a moreeven skin surface with smaller pores leads to fine skin and better texture. At the base of the pore lies the hair follicle just below the oily sebaceous gland. Theskin lining of the pore connecting the surface to the depth of the follicle is an important

Cutaneous Formulation Issues 5transitional area. This is the skin that sloughs improperly creating the environmentappropriate for acne. It is also the skin that is easily irritated resulting in the “breakouts”experienced following the use of products that cause the formation of red bumps, known aspapules, and pus bumps, known as pustules. This skin cannot be reached by traditionalcosmetics and skin care products, but irritant or allergic reactions that occur at the skinsurface can impact this follicular lining. The pore is not only connected to the hair, but also to the sebaceous gland. Thesebaceous gland is the structure that produces sebum. Sebum is the oil of the body thatlubricates the skin surface, but also provides a food supply for bacteria, such as Propioni-bacterium acnes, and fungal elements, such as pityrosporum species. The bacteriapropionibacterium acnes digests the sebum releasing free fatty acids that initiateinflammation characterized by the influx of white blood cells. These white blood cells formthe pus that is seen with acne. Pityrosporum species are responsible for the initiation of theinflammation, also due to the release of free fatty acids, which is associated with the onset ofdandruff of the scalp and face. Dandruff of the face is medically termed seborrheic dermatitis. The facial skin also contains two types of sweat glands, known as eccrine andapocrine glands. Eccrine glands are the sweat glands that produce a sterile watery liquidassociated with the maintenance of body temperature. It is the evaporation of the sweatfrom the skin surface that allows excess heat to be rapidly removed from the body.However, on the face sweating can occur in response to emotion and the ingestion of spicyfood. This type of sweating is under a different neural control than that associated withthermoregulation. The other type of sweat gland, known as an apocrine gland, produces ascented sweat that is unique to each individual. This apocrine sweat contributes to bodyodor and allows certain perfumes to smell differently on each individual. The apocrinesweat glands are uniquely located around the eyes. Our discussion to this point has focused on the anatomic structures present on thefacial skin to include pores (follicular ostia), terminal hairs, vellus hairs, sebaceous glands,eccrine glands, and apocrine glands. The face possesses a larger variety of these structuresthan any other skin on the body, which makes it unique. But, the skin on the face isstructurally identical to any other skin on the body in that it is composed of two layers, toinclude the epidermis and the dermis. The epidermis is the outer layer of skin, which iscovered by a thin layer of nonliving skin cells, known as the stratum corneum. The stratumcorneum is the layer of skin with which all skin care products interact. It is this structurethat is impacted by the majority of formulations concocted by the cosmetic chemist.Beneath the epidermis lies the dermis. The dermis is the collagen-rich, structurally stronglayer of skin. It is the dermis of cow hides that is turned into leather. The dermis activelyparticipates in the immunologic surveillance of the body and produces a scar if injured. Forall practical purposes, the cosmetic chemist is not concerned with the dermis as this is therealm of prescription drugs. The stratum corneum represents the skin barrier and is integral in differentiatingthose substances that must remain outside the body from those that are allowed to enterthrough the skin. It accomplishes this end by a unique arrangement of dehydrated skincells, known as corneocytes, interspersed between a combination of oily substances,known as intercellular lipids. The intercellular lipids implicated in epidermal barrierfunction include sphingolipids, free sterols, and free fatty acidsa. This organization hasbeen likened to a brick wall where the bricks are represented by the nonliving corneocytesa Elias PM: Lipids and the epidermal permeability barrier. Arch Dermatol Res 270:95–117, 1981.

6 Draelosand the mortar is represented by the intercellular lipids. Any disruption in thisorganization, either through removal of the coreneocytes or intercellular lipids, resultsin a barrier defect that can ultimately result in skin disease, our next topic of discussion.Common Dermatologic Disease ConsiderationsThe causes of most facial skin diseases that can be impacted by skin care products are dueto barrier defects. The barrier defects are mostly due to removal of the intercellular lipidsresulting in excessive water loss from the skin surface, a phenomenon known astransepidermal water loss. This loss of water from the skin produces dryness, knownas xerosis, with the onset of flaking of the facial skin later accompanied by redness andswelling. These physical findings are associated with the subjective findings of tightness,itching, stinging, burning, and pain, in order of increasing skin disease severity. It is theonset of this transepidermal water loss that is necessary to initiate synthesis of intercellularlipids to allow barrier repairb,c. The skin disease that results from dryness is known as eczema. Eczema is treated bycreating an environment suitable for barrier repair to occur. Most dermatologistsrecommend decreased bathing and use of a mild detergent to prevent further undesirableremoval of the intercellular lipids. They also recommend the use of oily moisturizers tocreate an artificial barrier soothing irritated nerve endings, thus preventing itching and pain,and to decrease transepidermal water loss. Moisturizers are used not to hydrate the skin, butrather to minimize further damage while the skin is healing the barrier endogenously. It is worth mentioning that some individuals are more susceptible to barrier damagethan others. For unknown reasons, some persons may have defective intercellular lipids,insufficient secretion of intercellular lipids, or corneocytes that are less resistant to structuraldamage. These persons will demonstrate barrier defects more readily than others and will haveeczema that is harder to control and sometimes impossible to cure. These individuals areclassified as possessing sensitive skin and are used in cosmetic testing panels for this reason. The other common facial skin conditions of acne, acne rosacea, and seborrheicdermatitis are due to a completely different mechanism of action. They may ultimatelyresult in a facial skin barrier defect, but can be considered diseases of the facial skinbiofilm. The biofilm is that thin layer of sebum, eccrine sweat, apocrine sweat, skin careproducts, cosmetics, medications, environmental dirt, bacteria, and fungus that is presenton the skin surface. A healthy biofilm will lead to skin health while biofilm abnormalitieswill ultimately lead to disease. For example, as has been mentioned previously, anovergrowth in the facial flora of propionibacterium acnes will lead to acne. Withoutpropionibacterium acnes there can be no acne. Thus, skin care products can impact facialacne by minimizing the growth of this organism on the face. Propionibacterium acnes isalso felt to be operative in an adult acne condition associated with facial redness andpapules and pustules known as acne rosacea. Seborrheic dermatitis is different from acne in that it is caused by a fungus, known aspityrosporum. This fungus is normally found on the facial skin in small numbers with itsgrowth kept in check by the immune system. Seborrheic dermatitis, characterized asdandruff of the face, is more common in the elderly, persons with AIDS, after severeb Jass HE, Elias PM: The living stratum corneum: implications for cosmetic formulation. Cosmet Toilet 106 October 1991:47–53.c Holleran W, Feingold K, Man MQ, Gao W, Lee J, Elias PM: Regulation of epidermal sphingolipid synthesis by permeability barrier function. J Lipid Res 32:1151–1158, 1991.

Cutaneous Formulation Issues 7medical illnesses, and following chemotherapy. Sometimes severe untreatable seborrheicdermatitis is the first indication that an immune problem may be present. Skin careproducts can dramatically affect the presence of fungal elements on the facial skin, thusminimizing or maximizing the chances of developing seborrheic dermatitis through properhygiene, discussed next.Hygiene NeedsThe hygiene needs of the face are more complex than any body area, except forperhaps the genitalia. This is due to the interplay between the skin, the hair, the sebaceousglands, the eccrine glands, and the transitional skin around the eyes, nose, and mouth. Themoist skin of the nasal mucosa and the oral mucosa is an environment perfect for bacterialcolonization and growth. Bacteria from these sites can easily move onto the facial skincovered with a mixture of sebum and sweat perfect for encouraging bacterial growth andspreading infection. The presence of hair also provides added surface area for bacterialgrowth to occur, thus the facial skin is a common site of infection. Good facial hygiene is a careful balance between maintaining a healthy biofilmwhile preserving the integrity of the barrier by leaving the intercellular lipids intact. Thiscan be challenging in light of the fact that cleansers cannot accurately differentiatebetween sebum and intercellular lipids. It is further challenged by the ever changingsebum production of the facial glands, which varies by both age and climate, and thedifferent bacteria with which the body comes in contact. Many dry complected individualsfail to clean the face due to the fear that dryness will result. Ultimately, disease results.Thus, facial skin must be kept clean, but not too clean.Skin Care NeedsIn many cases, barrier damage from meeting the hygiene needs of the skin must bebalanced by the use of additional skin care products. Thus, the skin care needs of the faceare influenced not only by the unique attributes of the facial skin, but also by the needscreated through the use of other skin care products. What are the skin care needs of theface? They are the maintenance of skin health and the enhancement of skin beauty. Theseare two very different goals. The maintenance of skin health has already been discussed asoptimization of the biofilm, which is a careful balance between cleansing (Chapter 4) andmoisturizing (Chapters 6, 7). Yet, there are other skin needs. These include the creation ofan even skin surface and the prevention and reversal of skin damage. The image of healthy facial skin is shiny skin due to abundant light reflection. Thislight reflection is due to an even surface. Causes of uneven facial skin include scars, facialgrowths such as moles, skin disease such as acne, and retained dead skin cells from thestratum corneum, known as corneocytes. Little can be done cosmetically to affect facialscars and moles, while acne issues have already been discussed. One area that deservesfurther mention is the issue of retained corneocytes. During youth the corneocytes slougheasily as the cellular message for cell disadhesion is well transmitted. With advancing age,the cells do not disadhese or desquamate as readily leading to retained dead skin scale.This skin scale, or dander, creates an uneven skin surface. This has led to the concept ofexfoliation, which uses chemical or mechanical means to encourage the removal of thedead skin scale. Exfoliants (Chapter 15) are the product category addressing this need.Exfoliation through the use of mild acids in astringent formulations (Chapter 5), such asglycolic or lactic acid, or the use of abrasive scrubs or textured cleansing cloths removesthe skin scale improving skin texture and skin shine.

8 Draelos The other major skin need is the prevention and reversal of skin damage from sunexposure. Sun contains UVB and UVA radiation, both of which damage the skin. Thisdamage can be seen in the form of collagen loss resulting in premature skin wrinkling orabnormal pigmentation resulting in uneven skin color. Facial skin care products have beendeveloped to meet these needs. Sunscreens (Chapter 9) are themost important anti-agingfacial skin care products currently available for their ability to absorb, scatter, or reflectUVB and/or UVA radiation. After cleansing for good facial skin hygiene, sunscreen is themost important facial skin care product to maintain skin health. Unfortunately, sunscreenis not completely effective in preventing UV damage and compliance, especially duringyouth, is not 100%. Thus, skin lightening preparations (Chapters 13, 14) are available toeven irregular pigmentation and antiaging products (Chapters 9, 10, 11, 12) attemptto reverse facial skin damage once it has occurred.EyelidsFrom the face, we will now move to a discussion of the eyelids. The eyelid skin is some ofthe most interesting on the body. It moves constantly as the eyes open and close; thus, itmust possess unique mechanical properties. It must be thin enough for rapid movement,yet strong enough to protect the tender eye tissues. Eyelid tissue shows the state of healthand age of an individual more rapidly than any other skin of the body. When otherscomment on a tired appearance, they are usually assessing the appearance of the eyes andthe eyelid tissue. When others comment on a sickly appearance, they are also assessing theappearance of the eyes and the eyelid tissue. The eyelid skin appears to age quicklyresulting in the presence of redundant upper eyelid tissue and lower eyelid bags. Theredundant upper eyelid tissue is due to loss of facial fat, cumulative collagen loss in theeyelid skin from UV exposure, and the effect of gravity pulling down the upper eyelid skin.Lower eyelid bags are also due to the effect UV damage and gravity, but edema or swellingmay also contribute. This edema may be due to retained body fluids or the release ofhistamine from inhaled allergens. All of these factors contribute to the complexity of theeyelid skin.Anatomy and PhysiologyThe eyelids are indeed composed of unique skin. It is the thinnest skin on the body,accounting for the eyelids as the most common site of irritant contact dermatitis andallergic contact dermatitis, either from products that are directly applied to the eyelids orfrom products transferred to the eyelids by the hands. The eyelid skin also has a paucity ofsebaceous glands, making it a common area of skin dryness. While there are no hairson the eyelids themselves, the eyelashes form an interesting transition between thekeratinized eyelid skin and the cartilage of the tarsal plate giving structure to the edge ofthe eyelid. Tearing from the eye impacts the skin of the eyelid, since wetting and dryingof the eyelid tissues can predispose to dermatitis. The eyelids are also a common source of symptoms induced by allergies. Thesesymptoms can be itching, stinging, and/or burning. Most persons with these symptomsrespond by vigorously rubbing the eyelids. This can cause mechanical damage to theeyelid skin, from minor trauma resulting in sloughing of portions of the protective stratumcorneum to major trauma resulting in small tears in the skin. Most of the skin on the bodyresponds by thickening or callousing when rubbed. Eyelid skin will also thicken, but thispredisposes to decreased functioning and worsening of the symptoms.

Cutaneous Formulation Issues 9 Eyelids are also a common site for cosmetic adornment. There are more individualcolored cosmetics for the eyelid area than any other body area to include mascara,eyeliner, eye shadow, and eyebrow pencil. These cosmetics and the products used toremove them can be a source of both allergic and irritant contact dermatitis, the next topicof discussion.Common Dermatologic Disease ConsiderationsAs mentioned previously, the eyelid skin is the most common body site afflicted withirritant and allergic contact dermatitis. Some of this predisposition is due to the thinness ofthe eyelid skin, but the transitional nature of the tissue is also important. The eyelid bridgesthe transitional area between the well-keratinized skin of the face and the moist tissue of theconjunctiva that lines the inner eyelid and the eyeball. The moisture from tearing wetsthe eyelid skin and enhances irritant and allergen penetration. It can also help dissolve anyallergen or irritant, possibly enhancing the adverse reaction. The eyes are also uniquelydesigned to sense substances that might cause vision damage, and thus the eyelids have aheightened immune response. Swelling induced by topical, inhaled, or ingested allergensare frequently seen initially in the eyelids. The thin nature of the skin also allows theswelling, due to tissue edema, to appear more dramatic than on other body areas wherethe skin is thicker and less mobile. In addition to irritant and allergic contact dermatitis involving the eyelid skin, thereare also eyelid diseases involving the eyelid sebaceous glands found at the base of theeyelash follicular unit. This condition is basically acne of the eyelashes and is found bothin adolescents and the elderly. It is treated with oral antibiotics, much like traditional facialacne, but superb eyelid hygiene is necessary to prevent recurrence and the avoidance ofoily substances in the eye area that might block the sebaceous gland orifice is mandatory. A type of dandruff, known as seborrheic blepharitis, can also affect the eyelids. Thisrepresents the eyelash equivalent of the seborrheic dermatitis, mentioned earlier, that canaffect primarily the scalp and sometimes the folds of the face, such as the skin around thenose and mouth. Seborrheic blepharitis is also caused by fungus; thus, proper eyelashhygiene is the key to control. Most individuals with scaling in the eyelash area will alsopresent with facial and scalp scaling as well, thus necessitating treatment of the entirescalp and face. The eyelid skin is also uniquely affected by the immune status of the individual.Most persons with inhaled allergies to pollen, fragrance, dust, etc. will complain not onlyof a runny nose, but also of itchy eyes. The eyelids and the nose both represent areaspossessing transitional skin bridging the wet mucosa with the traditional dry keratinizedskin. Since the wet mucosa is devoid of a skin barrier to allergens and infection, theimmune system is particularly fortified in these locations. For this reason, hyperimmunestates that affect the overall body skin are keenly present in the eyelid area. The mostcommon of these conditions is known as atopic dermatitis. Atopic dermatitis is acombination of dry skin, asthma, and hay fever. Thus, these individuals have chronic itchyskin, problems breathing, and bad inhaled allergies. One of the most common sites for thiscondition to manifest is the eyelid. These atopic persons have chronically itchy eyelids thatbecome red, swollen, and tender. They represent a unique population of sensitive eyelidpersons that have problems with many eye area cosmetics and skin care products.Treatment of these individuals usually involves the use of high-potency topicalcorticosteroids and oral antihistamines. By far the most common dermatologic disease to afflict the eyelid is eczema, morecommonly known as bad dry skin. Since the eyelid is relatively poor in oil glands, dry

10 Draeloseyelid skin is frequently seen due to over-aggressive removal of lipids. This may be due tothe use of a strong cleanser or products designed to solubulize oil-based waterproofcosmetics, such as mascara and eyeliner. Anything that damages the intercellular lipids orthe corneocytes will result in eyelid eczema. Thus, eyelid hygiene must achieve a carefulbalance between the removal of excess sebum and old cosmetics to prevent eyelashinfections and seborrheic blepharitis, while preventing damage to the intercellular lipidsand ensuing eyelid eczema.Hygiene NeedsCleansing of the eyelid tissue is indeed a delicate task. Typically, the skin should behandled very gently, due to its thin nature, and cleansing should remove excess sebumwhile preserving the intercellular lipids. If more aggressive cleansing is required, anappropriate moisturizer must be selected that will provide an environment for healingwhile the intercellular lipids are resynthesized. The typical cleanser used in the eye area bydermatologists is baby shampoo. This non-stinging shampoo formula allows cleansing ofthe eyelashes to prevent seborrheic blepharitis, while minimizing further eyelid irritation.Typically, the cleanser is applied with the fingertips and not a washcloth or other cleansingimplement, since the fingers can easily sense if too much pressure or force is being used toclean the thin eyelid tissue. Most of the diseases of the eyelid and the eye itself are relatedto poor eye area hygiene and the onset of infection. Thus, appropriate eyelid hygiene ismedically and cosmetically important.Skin Care NeedsAfter maintaining good eyelid hygiene through proper cleansing, the issues ofmoisturization and sun protection must be addressed. These are the skin care needs ofthe eyelid skin. The recurring theme throughout this discussion of the eyelid has been theunique thinness of the skin. This consideration becomes extremely important whenformulating eyelid moisturizers and sunscreens. Any eyelid moisturizer selected mustspread easily to prevent bruising or tearing. Thus, highly lubricious emollient formulationsare best. They should occlude the eyelid skin enough to allow the skin barrier to repair, butshould not be too oily such that they interfere with vision if accidentally introduced intothe eye. The thinness of the eyelid skin also makes the use of sunscreens important. UVAradiation can easily penetrate to the dermis of the thin eyelid skin, causing prematurewrinkling. The eyelids are also a common site for UVB-induced sunburn. This makes UVAand UVB broad spectrum sun protection vital, a topic more fully discussed in Chapter 9. Itshould come as no surprise that most men and women notice aging first in the upper andlower eyelid tissue. This thin skin quickly looses elasticity from photodamage, which can beexaggerated by familial tendencies toward eyelid skin laxity, a condition known asblepharochalasis. Eyelid sunscreens must be carefully formulated to avoid allergic andirritant contact dermatitis, stinging, and burning should the product enter the eye, andlimited photoprotection. In addition to sunscreens, excellent eyelid skin protection canobtained through the use of sunglasses and hats.LipsThe lips present many of the same challenges as discussed previously for the eyes. Theyboth represent transitional skin between traditional keratinized dry skin and moistmucosal skin and they both are portals of entry for foreign invaders, such as bacteria and

Cutaneous Formulation Issues 11viruses, and other substances entering the body, such as medications. However, the lipsare much more complex in terms of the substances they contact, since the lips areinstrumental in eating. They contact many different foods, chemicals, and cosmetics.They are also in constant motion, much more so than any other part of the body, due totheir participation in the phonation associated with speech. Yet, their cosmetic valuecannot be minimized. They are an instrument of affection as delivered by a kiss and thefocal point of the face. Much poetry has been written about beautiful ruby red lipsthrough the ages.Anatomy and PhysiologyThe lips must sustain pulling, twisting, and contracting forces in many different directionsin order to eat and speak. To accomplish this engineering feat, they contain a transitionalskin surface, known as the vermillion, overlying a complex array of muscles withsupporting fat. The vermillion is the portion of the lip that is visible and adorned by lipcosmetics. It has a rich vascular supply that is visible through the thin overlying skin. Thelip skin is unique in that it does not have a well-developed stratum corneum making itdifferent than the rest of opaque facial skin. Damage to the lip tissue, from sun or cigaretteheat, results in formation of a dysfunctional stratum corneum that causes the lips to losetheir characteristic red color. This causes a whitening of the lips, medically known asleukoplakia, literally translated as white plaque. As the lips age, they begin to thin and lose their characteristic shape. This is due toloss of the fat that gives the lip substance. A profile view of a child will reveal lips thatprotrude from the face, while the profile of a 70-year-old woman will reveal lips that areflat and even depressed from the facial surface. Many of the new cosmetic fillers, such ashyaluronic acid, are designed to replace this lost fat. The loss of lip shape is alsoaccentuated by loss of teeth and bony gum structures that give the lips their characteristicCupid’s bow shape. The lip muscles remain intact throughout life, but cannot make up forthe loss of the underlying fat suspended over a bony frame.Common Dermatologic Disease ConditionsThe lips not only are subject to the effects of aging, but also to the insults of dermatologicdisease. Infection is probably the most common serious lip problem. This is typically dueto the herpes simplex type 1 virus that is responsible for fever blisters. This infection isseen as a group of clustered tiny blisters, known as vesicles, at the margin of the redvermillion. The herpes simplex virus is usually contracted during youth and remainsdormant under the watchful eye of the immune system until reactivated and allowed tomigrate from the nerve root to the skin surface. The virus reactivates when the immunesystem is overburdened. This most commonly occurs when the body is sick with anotherinfection, hence the name “fever blister” for the herpes infection. When the body is busyfighting an infection war at another location, the herpes virus takes the opportunity toreproduce and migrate to the lip causing further pain and misery. The fever blister iscontagious during the time when the blisters are filled with liquid. Once a scab has formedover the blister, the infection is no longer transmissible. This is important to the cosmeticindustry, since shared lip balms and lipsticks can transmit the virus as long as the blisterfluid remains moist. Herpes simplex infections are usually treated with antiviral drugs,such as acyclovir, that stop the virus from reproducing, but unfortunately cannot eradicatethe virus from the body. For this reason, fever blisters are recurrent. The lip is also the site of other infections, such as those caused by yeast. Yeastorganisms may be present in the mouth and can migrate to the lips under certain

12 Draelosconditions. Yeast most commonly infects the corners of the mouth, a condition known asperleche. The corners of the mouth are a frequent site of saliva collection, especially inchildren who drool, adolescents with braces, and the elderly with poor dentition. Themoisture remains in the mouth corners overnight, creating a condition known asmaceration, and provides a perfect environment for the growth of yeast. Yeast typically isnot transferred person to person like the herpes virus previously discussed, but can be asource of pain when cosmetics are applied or a complication of chapped-appearing lips.Perleche is usually treated with a combination of topical low potency corticosteroids andtopical antifungal/antiyeast creams. The last common lip disease to be discussed is chelitis, which simply meansinflammation of the lips. Chelitis can be due to chapped lips, a condition akin to dry skin.This can result from insufficient oil being produced by the tiny yellow oil glands lining theedge of the vermillion border, as seen in elderly individuals, or due to chronic wetting anddrying of the lips from lip licking, as seen in children. Both of these conditions can beremedied by the use of lip balms, lip moisturizers, or lip sticks. Good occlusion is typicallyrequired to allow these conditions to resolve, achieved through the use of oily substances,such as petrolatum, waxes, and silicones. Some elderly individuals may appear to havechronic chelitis or chapped lips due to the continual presence of peeling skin over the lips.This may be due to dryness, but may also be due to insufficient exfoliation of the lipsurface or another condition known as actinic chelitis. Actinic chelitis presents as whitish lips with unrelenting skin scale. The word“actinic” means sun. The dry skin can be removed, but is quickly replaced by the liprenewal process that is unable to make quality smooth skin. Instead, the lip is replacedevery two weeks by skin made by cells containing sun damaged DNA. Actinic chelitis is aprecancerous condition that can possibly culminate in skin cancer after years of neglect.Actinic chelitis is cosmetically unattractive, since the lips lose their distinct outline and redcolor, and is best prevented through the use of sunscreen-containing lip balms andopaque lipsticks.Hygiene NeedsFrom the preceding discussion, it is apparent that the lips have some unique hygiene needs,because they are the gatekeeper of everything that is consumed orally. Typically, the lipsare washed with the face, but they are regularly cleansed with saliva. They are mostfrequently infected by direct contact with other infected individuals through kissing.Infection that enters the body through the mouth via hand/oral transmission is far morecommon than infection of the lips themselves.Skin Care NeedsThe best method for keeping the lips infection free is to maintain the vermillion intact, freeof fissures or openings. This requires the use of waxy, thick moisturizers designed to stayon the lips through saliva and food contact. The tiny yellow sebaceous glands that can beseen along the edge of the lips in elderly individuals do not function as abundantly withadvancing age. Dry lips are also more common in the elderly due to nasal obstructionpromoting mouth breathing and dentures that may not fit properly. Dry lips may also beseen at the other end of the spectrum in children who are endentulous or thumb suckers.Occlusive lip balms that prevent saliva from repeatedly wetting the skin surface are themost successful at alleviating the dry skin. Lip balms can be further adapted to provide both lip moisturization and sunprotection. A quality lip balm used on a daily basis with an SPF of at least 15 can prevent

Cutaneous Formulation Issues 13actinic chelitis, a medically and cosmetically significant condition. A sunscreen-containing lip balm is also the best way to prevent the recurrence of a herpes simplexfever blister, since the virus is photo-reactivated. Lastly, sunscreen-containing lip balmscan prevent skin cancer of the lip, a serious medical condition.HandsThe hands are one of the most expressive parts of the body, providing the structuresneeded to write, draw, paint, dance, and express affection. It is frequently said that muchcan be said about people from their handshake, which is an assessment of the skin, muscle,and bone that form the hand. The hand can express gender, occupation, and age. Femalehands are small while male hands are large and muscular. People who work with theirhands outdoors have a much different skin feel than persons who type on a computer formuch of the day. Children have soft, doughy, padded hands while the elderly have thin,sinewy, bony, arthritic hands. Hands are what make humans unique from every otherliving thing on the earth.Anatomy and PhysiologyThe hands are formed of many tiny muscles and bones that account for their agility. Theyare that part of the body that most frequently touches the outside world and can serve as avector, bringing infection to the vulnerable nose, eye, and mouth tissues. The hands alsosustain considerable chemical and physical trauma. They are washed more than any otherbody area, yet are completely devoid of oil glands on the palmar surface. While the stratum corneum of the palm is uniquely designed to withstand physicaltrauma, it is not designed to function optimally when wet. Water destroys the resistivephysical strength of the palmar skin, which is why hand blisters are more common whenthe hand is perspiring heavily. The palmar surface of the hand has numerous sweat glands,known as eccrine glands, which are largely under emotional control. Palm sweating mayoccur in warm weather, but may also occur under stressful conditions. The hand responds to trauma by forming thickened skin, known as a callus. Callusesare formed from retained layers of keratin that form a dead skin pad over the area subjectedto repeated physical trauma. For example, the palm of the hand will callus to protect thesmall bones in persons who use a hammer. The finger will callus in the location where apencil is held in both children and adults. While the body forms a callus to protectunderlying tender tissues, the callus can also cause dermatologic problems. Since a callusis made of retained keratin, it is dehydrated and inflexible and will fissure readily withtrauma. Once the keratin is fissured, it cannot be repaired, since the callus is nonliving.This leads to a discussion of the most common dermatologic disease considerationsinvolving the hand.Common Dermatologic Disease ConsiderationsDermatologic disease needs to be divided into those conditions that affect the dorsum orback of the hand and those that affect the palm of the hand. This is an important distinctionbecause the two skin surfaces are quite different. The dorsum of the hand is thinner skinthat becomes increasingly thinner with age. After the face, the back of the hand isgenerally the most photoaged skin location. The skin of the hand loses its dermal strengthearly leading to decreased skin elasticity, which can be simply measured by pinching theskin on the back of the hand and watching for the amount of time it takes for the skin to

14 Draelosrebound to its original conformation. This easy to perform test is an excellent measure ofthe hand skin age. Skin that takes a long time to return to normal configuration is morephotoaged than youthful skin that bounces back energetically. In addition to losingelasticity, photoaged skin also becomes irregularly pigmented leading to dark areas,known as lentigenes, and light areas, known as idiopathic guttate hypomelanosis. Thisirregular pigmentation is also accompanied by skin that is easily injured. Injury may beseen in the form of red bruises, affectionately named senile purpura, and tissue tears fromminimal trauma, which heal with unattractive white scars. The palm of the hand is affected uniquely by inflammatory conditions like eczemaand palmar psoriasis. Because the palm is the surface that the body uses to pick and touch,it more commonly is affected by chemical and physical trauma. This trauma may manifestas hand eczema, which is usually treated with high potency corticosteroids. In addition,highly occlusive and emollient hand creams are necessary to rehydrate damaged keratinand create an optimal environment for barrier repair. Hand creams are also important inthe treatment of psoriasis where too much poor quality skin is produced too quickly. Bothof these conditions require carefully selected cleansers and moisturizers, in addition toprescription therapy. Lastly, the palms can be affected by excessive sweating, a condition medicallyknown as hyperhidrosis. Palmar hyperhidrosis can be physically disabling to persons suchthat they cannot hold a pen to write or emotionally disabling such that they areuncomfortable shaking hands. As mentioned previously, the eccrine sweat glands on thepalms are under temperature and emotional control. Palmar hyperhidrosis is usually moreof an emotional condition, since the sweat released by the hands does little to cool thebody. The treatment of hyperhidrosis is addressed in Chapter 8.Hygiene NeedsThe hands receive more cleansing than any other part of the body. The basic ritual of“wash your hands before you eat” is an effective method of preventing diseasetransmission, but may take its toll on the physiologically sebum-lacking skin of the palms.Excessive hand washing can even be considered a medical disease, especially in personswith obsessive-compulsive disorder. There are a variety of methods of washing the hands.Basic hand washing is usually performed with a bar or liquid soap followed by waterrinsing. Regimented timed hand washing routines are used to thoroughly remove allbacteria from the hands prior to surgery. Lastly, a variety of hand cleansing antibacterialgels have been introduced, usually based on triclosan, that can be used without water toclean the hands. In general, it is felt that the physical rubbing of the hands to lather thecleanser followed by rubbing in a running stream of water to rinse away the cleanser isimportant. Both the physical rubbing of the hands and the chemical interaction of thecleanser and water are necessary for optimal hand hygiene.Skin Care NeedsThe skin care needs of the hands go beyond basic cleansing to moisturization, healing,photoprotection, and skin lightening. As mentioned previously, hand moisturization isvery important due to frequent cleansing. Hand moisturizers should be designed to occludethe skin reducing transepidermal water loss, rehydrate the skin through the use ofhumectants, alleviate itch and pain, and smooth the skin surface with emollients. Handmoisturizers with this type of construction can be used for simple dry skin, as well asproviding healing qualities for the dermatologic conditions previously discussed.

Cutaneous Formulation Issues 15 In addition to moisturization, the hands also need photoprotection both during sportsand while driving a car, since photoaging UVA radiation passes through the windshield ofa car. Sun protection is a unique challenge for the hands because they are frequentlyaggressively washed, removing the sunscreen. However, the need for sun protection isobvious when one considers the thin dyspigmented skin that characterizes mature hands.This means that the hands require aggressive anti-aging therapy, discussed in Chapter 11,and skin lightening, discussed in Chapters 13, 14.FeetThe hands and the feet have much in common. They both have a different type ofepithelium on the dorsal and plantar surface, they both have hair on the dorsal surface andnone on the plantar surface, and they both have few sebaceous glands and numerous sweatglands on the plantar surface. However, there are many differences between the hands andthe feet, the most important being that the feet constantly bear the weight of the body whilethe hands do not. The feet are used for locomotion, competitive athletics, and personalexpression in the form of dance. They are forced into shoes that can function both asprotection while walking and the source of bony deformity. One only need look at thebunions and overlapping toes of the woman who wore tall, spiked heel, pointed toe shoesduring her youth who cannot walk normally today due to misshapen feet that cannotproperly bear weight.Anatomy of PhysiologyThe feet form our most important point of contact between the body and the earth. Theygrow proportionately as we grow during adolescence, pregnancy, and old age to providethe body with stable balance. Unfortunately, their bones wear out with continued use andchronic inflammation to yield crippling arthritis. The sole of the foot is made of keratinremarkably resistant to trauma from torque and pressure, but this resiliency is decreasedwhen the keratin is wet. This most commonly occurs in individuals with sweaty feet. Theinteraction of sweat with the plantar keratin in the environment of the shoe createsunique hygiene challenges. The lack of oil glands on the sole of the foot also predisposesit to dry skin. This leads to our next topic of discussion, which is dermatologic disease ofthe feet.Common Dermatologic Disease ConsiderationsAs might be expected, the warm, moist, dark environment of the foot in the shoe is perfectfor infection of all types, especially between the toes. The foot is a common site forbacterial, fungal, and yeast infections. These organisms can live on the surface of the footor enter into the body through small wounds. Foot infection is a major medical issue indiabetics who have a reduced capacity to fight infection, poor blood circulation to the feet,and reduced sensation. In normal individuals, the most common infection of the feet isfungal, a condition known as tinea pedis. Tinea is the medical word for fungal infections ofall types with pedis referring to the feet. Tinea pedis most commonly occurs between thetoes, especially between the fourth and fifth toes, since these toes are usually closelyspaced. Mild infections of this type can occur in otherwise healthy athletic individuals;however, the incidence of fungal infection increases with advancing age due todeterioration of the body’s immune system. Most fungal infections of the toes or thesole of the foot can be easily treated with two weeks of a topical antifungal. However,fungal infections of the nail require oral medication, usually for three months.

16 Draelos The foot is also the site of frequent viral infections in the form of plantar warts. Thehighly infectious human papilloma virus causes warts. This virus only affects humans, thuswarts are passed by person-to-person contact through wounds in the foot. Common placesto contract warts include public pools, exercise facilities, dance studios, public showers,etc., basically any place where there is moisture and lots of bare feet. Other noninfectious growths that occur on the foot include calluses and corns.Calluses form over areas of the feet that are commonly traumatized, such as the side of thegreat toe, the side of the little toe, and the heel. Corns, on the other hand, occur over bonyprominences. Hard corns occur on the sole of the foot at the base of the toes while softcorns occur over bones between the toes. Both calluses and corns are deposits of excesskeratin designed to protect the foot from undue injury while walking. Unfortunately, thecalluses and corns themselves may produce pain while walking. Substances can be appliedto the growths to remove the keratin, but the callus or corn will return unless the exactcause for their formation has been determined. This can be ill-fitting shoes, arthriticchanges, or improper weight transfer over the foot while walking. The foot is also a common site for eczema or dry skin due to the complete lack of oilglands on the sole and the reduced number of oil glands on the top of the foot. The feetreceive the most cleanser and water contact of any part of the body while showering, thusexcessive removal of sebum on the feet is common. For all of the reasons put forth here,the feet have unique hygiene needs to balance the predilection for infection with thedryness of overcleansing.Hygiene NeedsThe feet need aggressive hygiene, not only to prevent infection, but also to control odor.Foot odor is primarily due to the mixture of sweat with bacteria in the closed environmentof the shoe. Bacteria digest the sweat to obtain nutrition and reproduce. Most individualshave several types of bacteria present in low numbers on the feet. The difference betweenindividuals with minimal foot odor and extreme foot malodor is the number and type ofbacteria present on the feet. Foot malodor is a much greater problem in persons withhyperhidrosis. Hyperhidrosis of the feet is identical in cause to hyperhidrosis of the palms,in that both are primarily under emotional control, although feet tend to sweat more forthermoregulatory purposes due to the presence of warm socks and shoes. Good cleansing of the feet is a prerequisite to skin health, but overly aggressivecleansing may set the stage for dry skin and foot eczema. Thus, foot cleansing must becarefully balanced with proper moisturization, our next topic of discussion.Skin Care NeedsOne way to minimize the dryness that may be associated with foot cleansing is through theuse of moisturizers. Moisturizers can be used to prevent foot dryness and soften callusesutilizing substances such as urea and lactic acid to open up water binding sites ondehydrated keratin. The physical act of rubbing a moisturizer on the feet can also helpdesquamate dead skin that may build up between the toes and on the arch of the foot,especially in elderly individuals. Foot moisturizers must be similar to hand moisturizers inthat both occlusive and humectant substances must be incorporated.Nails and CuticlesNo discussion of the hands and feet would be complete without consideration of the nailsand cuticles. Even though the nails are made of nonliving keratin, they are the source of

Cutaneous Formulation Issues 17considerable cosmetic attention. Manicures, pedicures, artificial nails, nail polishapplication, etc. are all popular activities. Certainly, the nails add glamour and enhancethe appearance of the hands and feet. In certain cultures, the fingernails are used todesignate class status. For example, Greek males allow their little fingernail to grow longerthan the rest to show that they work at a desk job rather than performing manual labor,since a long little fingernail cannot be maintained if people use their hands to make aliving. Similarly, women in United States use long nails for much the same purpose. Sincethe nails are made of nonliving tissue, their cosmetic needs are much different than any ofthe other body areas previously discussed.Anatomy and PhysiologyThe nail is a thin plate of nonliving keratin designed to protect the tip of the finger and toes.The nail is produced by a group of cells designated as the nail matrix that liesapproximately one-quarter inch below the visible nail. The nail matrix cells are formed atbirth and cannot regenerate following injury. For this reason, trauma to the nail matrix canresult in a permanently deformed nail that cannot repair and will not grow normally. Oneof the most important structures adjoining the nail from a dermatologic standpoint is thecuticle. The cuticle is a like a rubber gasket forming a watertight seal between thenonliving nail and the skin of the fingertip. Damage to the cuticle results in water,chemicals, or anything the hand touches reaching the nail matrix cells. It is for this reasonthat dermatologists recommend that the cuticle not be dislodged, pushed back, trimmed, ormanipulated in any way. Many of the abnormalities and diseases of the nail tissue can betraced back to a damaged cuticle.Common Dermatologic Disease ConsiderationsNail abnormalities and disease are extremely hard to treat because the visible nail cannotbe repaired; only the growth of new nail can be influenced. In most individuals, it takessix months to grow a new fingernail and one year to grow a new toenail. This means thatcreation of a new nail to replace a damaged nail is a long process requiring patience beforethe effects of successful treatment are visible. The common nail problem is loosening ofthe nail plate from the nail bed, a condition known as onycholysis. Onycholysis is usuallytraumatic in nature and is more common in individuals who wear artificial nails in the formof sculptures or tips. The bond between the artificial nail and the natural nail is strongerthan the bond between the natural nail and the underlying skin. This means that the naturalnail plate will rip from the skin causing pain and swelling of the finger. The natural nailnow appears white, because the nail is no longer attached to the pink flesh, and a space iscreated beneath the nail plate and the skin where infection can occur. Onycholysis is themost common condition predating a nail fungal infection. Fungal infections of the nail, medically known as tinea unguinum, are extremelycommon with advancing age. It is estimated that 80% of persons age 80 or older willdevelop a nail fungal infection. The infection becomes more common with advancing ageas the immune system’s ability to protect against a fungal invader is diminished. The samefungus that causes infection of the feet also causes nail fungus, as mentioned previouslyduring our discussion of foot diseases. Nail fungal infections of the hands and feet are verydifficult to treat since medication cannot be administered to the nonliving nail. The site ofthe nail fungal infection is not actually the nail itself, but the living tissues beneath the nail.This makes topical treatment minimally effective because any topically appliedmedication must penetrate the hard nail plate to reach the infected tissues below. Forthis reason, fungal nail infections are traditionally treated orally with medications that

18 Draelosmust be taken for three months. The oral medication allows an antifungal to beincorporated into the newly grown nail, forming a barrier for the advancing fungalinfection. The old infected nail is then cut away to physically remove the infected nailplate, and eventually the treated nail, resistant to fungal invasion, is formed. However, thenail containing the oral antifungal medication is removed with further nail growth andreinfection commonly occurs. Nail fungus is actually transmitted through fungal spores which are extremelyresistant to destruction. Traditional disinfectants used to clean manicure and pedicureinstruments are ineffective against the spores, thus fungal disease can be transmittedthrough nail salons. Nail fungus is also not susceptible to triclosan or other antibacterialagents traditionally used in soaps and cleansers. Thus, the best protection against a nailfungus infection is an intact nail and surrounding cuticle. Another common nail problem is peeling and cracking of the nail plate. While theseare largely cosmetic concerns, they can result in pain and leave the nail weakened toinfection. Nail peeling and cracking are more common with advancing age. This may be dueto decreased blood flow to the cells of the nail matrix from arthritis or blood vessel disease ordue to declining nutritional intake. The body certainly recognizes that the nails are notessential to maintain life, thus under times of stress or illness nail growth is not optimal.However, there are conditions where nutrients may not be absorbed from the intestinal tractthat becomes more common with advancing age. One of these nutrients is biotin. Biotin isnecessary for hard nails and may not be properly absorbed. For this reason, one of the maintreatments for peeling, cracking nails is an oral biotin supplement. Nail dehydration maycontribute as well, but this topic is addressed under skin and nail care needs. There are a variety of inherited or acquired nail deformities for which notreatment exists. For this reason, many dermatologists run the other way when a patientpresents with nail problems. Probably the common somewhat treatable nail deformity ispsoriasis. As we discussed previously, psoriasis is the production of too much poorquality skin too quickly. Psoriasis of the nail is similar in that the nail that is producedis also poor quality such that little chunks of the nail plate fall out leaving tiny holes orpits. Thus, the hallmark of nail psoriasis is pitted nails. The nails improve slowly as thebody psoriasis improves, but methods of camouflaging the problem with nail polish orartificial nails are a more rapid solution. Most dermatologic nail conditions are besttreated in the short term with cosmetic techniques, which are beyond the scope ofthis text.Hygiene NeedsAs mentioned previously, the most important way to keep the nail plate healthy is to leavethe cuticle undisturbed. For some, this answer is almost too simple. The nail is designed totake care of itself, and any manipulation interferes with the perfect design. Typically, handhygiene and nail hygiene are taken care of simultaneously with good hand washing. The most common infection that affects the nail is known as a paronychia. Aparonychia is actually an infection of the skin surrounding the nail to include the cuticle.Here the cuticle is disrupted and water enters the tissue around the nail. This forms a warm,dark, moist space perfect for the growth of yeast organisms. The yeast breakdown the skinand make an environment appropriate for bacterial infection, which occurs secondarily.The bacteria then multiply and produce pain and pus. Use of antibacterial cleanserscontaining triclosan are very helpful in preventing a paronychial infection along with goodmoisturization of the tissues around the nail to prevent cracking. Oral antibiotics areusually required to treat nail and cuticle infections of this type.

Cutaneous Formulation Issues 19Skin and Nail Care NeedsMoisturizing the nail and the cuticle are important to prevent disease. Usually thesestructures are moisturized at the same time the hands are moisturized, but there are somekey differences to consider. The outer stratum corneum layer of the skin of the hands isreplaced every two weeks, but the nails are nonliving, thus, any dehydration damageinflicted is permanent. Remoisturizing the nails can be minimally enhanced with urea andlactic acid, which increase the water binding sites on the nail keratin, but their effect istemporary until the next hand washing. Also, too much urea and lactic acid can over softenthe nail plate, making it more susceptible to fracture. Water is the main plasticizer of thenail plate and it should not be removed with aggressive cleansing.ScalpThe scalp/hair interface is very similar to the nail/cuticle interface in many respects.Here the nonliving hair abuts the living scalp, just like the nonliving nail abuts the livingcuticle. The skin needs of the scalp are complex due to the presence of abundant sweat,sebum, and nerves all complicated by the presence of numerous hair follicles. It is beyondthe scope of this text to deal with the many issues surrounding hair growth and cleansing,thus this section will focus strictly on the skin forming the scalp.Anatomy and PhysiologyIt is important to recognize that healthy hair begins with a healthy scalp. The hair growsactually below the skin of the scalp with follicles protected in the subcutaneous fatcovering the skull. The scalp has an abundant blood supply to provide the necessarynutrients for hair growth and an extensive nerve network. This is why injuries to the scalpbleed profusely and are quite painful. In addition to blood vessels and nerves, thescalp also has numerous eccrine sweat glands and sebaceous glands. These secretionsprovide nutrients for bacteria and fungus that can infect the skin of the scalp. The hair alsoincreases the chances for infection by providing abundant surface area for organisms togrow. Lastly, sweat can function as an irritant, accounting for the frequent itchingassociated with areas of sweat collection, such as the nape of the neck. The presence of theneural network around the hairs also provides more opportunities for sensation of itch tobe induced.Common Dermatologic Disease ConsiderationsThe scalp is the site of many dermatologic diseases, the most common of which isdandruff. Dandruff lies on a spectrum between occasional mild flaking of the scalp tothick oozing plaques devoid of hair, known as seborrheic dermatitis. Both of theconditions are caused by the same fungal organism named Malassezia globosa. Thisfungal organism is present in the air and lands on the scalp rich in sebum. It consumesthe sebum and leaves behind free fatty acids that are extremely irritating to the scalpskin. These free fatty acids induce itching, inflammation, and increase the scalp skinturnover resulting in flaking. If the immune system is intact, the body will not allow theMalassezia to proliferate and the skin remains healthy. If the immune system is notintact, such as with advancing age, the presence of illness, or human immunodeficiencyvirus (HIV) infection, the Malassezia organisms will multiply and their sheer numberwill induce an infection. A mild infection may be perceived as dandruff, but a moresevere infection is termed seborrheic dermatitis. The key to preventing a Malassezia

20 Draelosscalp infection is the use of topical antifungals in the form of shampoos containing zincpyrithione or selenium sulfide or ketoconazole. Active infection can be treated withprescription oral and/or topical antifungals. It should be mentioned that other fungal organisms, besides Malassezia, couldalso infect the scalp. These include the same fungal organisms that cause athlete’s foot(tinea pedis) and nail fungal infections (tinea unguinum). Fungal infections of the scalp,medically known as tinea capitas, are commonly termed ringworm. A worm is notinvolved, but the areas of hair loss are round, hence the early misnomer that a roundworm was causing the problem. The organisms that cause scalp fungal infections canbe transmitted person to person on combs or through direct contact. For this reason,tinea capitas is mainly seen in children. It is a highly contagious infection requiring theuse of oral prescription antifungal medication for eradication. Bacteria can also affect the scalp creating an infection known as folliculitis. In thiscondition, the bacteria enter the scalp at the site where the hair exits the scalp, known asthe follicular ostia. This is the weakest point of the scalp to infection, since the hair slightlytents the scalp, allowing this skin to sit above the rest of the scalp. When the scalp isscratched, the skin around the hair is preferentially injured and bacteria from beneath thefingernail placed in the scalp skin causes infection. As might be expected, folliculitis is acommon complication of an itchy scalp. Folliculitis is usually treated with shampooing forgood scalp hygiene, treatment of the scalp itch with topical corticosteroids, and oralantibiotics for the scalp bacterial infection. Shampoos and scalp products that prevent itchare important for maintenance therapy, since an itchy scalp is usually the initiating factorfor scalp folliculitis. Lastly, no discussion of scalp skin could be complete without the mentionof psoriasis. As in all other body areas, psoriasis of the scalp is due to the production oftoo much poor quality skin too quickly. It presents with severe thick silvery plaquesof scalp scale that may interfere with hair growth. It is best treated medically; however,shampoos and scalp solutions containing keratolytics, such as salicylic acid, or anti-inflammatories, such as tar derivatives, are helpful. Antidandruff preparations, asdiscussed previously, may be helpful since the presence of Malassezia my initiate a flareof scalp psoriasis.Hygiene NeedsThe hygiene of the scalp must be maintained while beautifying the hair, which can be acosmetic challenge. Cleanliness of the scalp is very important to prevent fungal andbacterial infection that can induce subclinical and clinical disease, without overdrying thenonliving hair. It is interesting to note that shaving the hair, which provides a ready surfacefor infection, can cure many scalp diseases. Certainly, this is not an alternative that wouldbe considered by many!Skin Care NeedsThe skin care needs of the scalp are to remove excess skin scale, loosen shedding hair, andmaintain the biofilm of sweat, sebum, and organisms in balance. Many might suggest thatthe scalp should be moisturized to smooth down the skin scale and allow barrier repair tooccur. While this is generally the case in other body areas, this logic does not pertain to thescalp. Skin scale provides a home for the fungal and bacterial organisms and allows sweatand sebum to accumulate on the scalp. Removal of the skin scale is key to scalpskin health.

Cutaneous Formulation Issues 21NeckThe neck is an interesting area of highly mobile skin that provides a transition between thethin skin of the neck and the thicker skin of the upper chest and back. It contains fullymature hairs in the male and thin vellus hairs in the female. It is an important area from acosmetic standpoint since it is an area affected by shaving in the male, fragranceapplication in the female, and photodamage in both sexes.Anatomy and PhysiologyThe neck skin covers important underlying structures, such as the blood and nerve supplyto the head. The neck also contains the cervical spine and numerous muscles allowing thehead to move side to side. It is for this reason that the neck is a difficult area cosmetically.It does not heal well from cosmetic surgical or traumatic injuries due to this continuousmovement. It is also is subject to photodamage, since many forget to wear protectiveclothing or apply sunscreen to the neck. Most hats do not provide adequate neckprotection, thus the neck skin tends to show age more quickly than other body areas.Common Dermatologic Disease ConsiderationsThe photodamage condition that most commonly affects the neck is known aspoikiloderma. Poikiloderma describes the thinned skin present from lost dermal collagen.It resembles chicken skin because the lower dermal oil glands become more visible as littletiny yellow dots. The thinned skin also allows better visualization of the underlying smallvessel network creating the “red neck” terminology, used to describe those who work outof doors, such as cowboys. Lastly, poikiloderma describes the irregular pigmentation thatresults from prolonged photodamage characterized by both lighter and darker areas inalmost a lace-like pattern. It is interesting to note that the neck skin beneath the chin is sunprotected. For this reason, neck photodamage is almost in the shape of a butterfly beingmore pronounced on the sides of the neck. The degree of photodamage present on the skinof an individual can be easily determined by comparing the sun protected skin beneath thechin with the appearance of the sun damaged skin on the sides of the neck. The neck is also the site where women apply fragrance. For this reason, the neck is acommon site of fragrance allergy. This allergy can manifest as allergic contact dermatitis,which presents as red skin with little tiny bumps, known as papules, and blisters, known asvesicles. Patch testing fragrances is usually performed to determine the exact cause aftertreatment with topical corticosteroids. Fragrances can also cause irritant contactdermatitis, which presents as simply red, itchy skin, due to the drying volatile vehiclein the perfume.Hygiene NeedsThe hygiene needs of the neck are similar to the rest of the body. The neck does not containmany oil glands and thus cleansing should be thorough, but not over drying. Probably themost unique hygiene need for the neck area is in males who shave the hair in this location.The neck is a transition area for hair growth between the beard of the face and the bodyhair of the chest. For this reason, the hair exits the skin in many different directions, whichpredisposes to inflammation of the hair follicular ostia, more commonly known as razorburn. Severe razor burn accompanied by ingrown hairs in African-American males isknown as pseudofolliculitis barbae. In this condition, the curved hair shafts re-enter theskin causing inflammation and infection. It is a difficult condition to treat. Growing a beard

22 Draelosand not shaving obtain the best results, since the long hairs cannot ingrow. The second bestoption to shave frequently and keep the hairs so short that they cannot ingrow.Skin Care NeedsThe major skin care needs of the neck are good moisturization accompanied by sunprotection. The neck receives almost as much sun as the face and is a common site forprecancerous and cancerous growths.BodyThe body encompasses all the rest of the skin not previously discussed, except for the skinfold areas. Most notable body areas for discussion are the back, chest, arms, and legs. Theskin on the body does not heal as well as the face and neck. The further the skin is awayfrom the face, the poorer the surgical result. This is due to the thicker skin in theselocations accompanied by the distance away from the heart and a poorer blood supply.Anatomy and PhysiologyThe thickest skin of the body is present on the upper back due to the need to sustain pullingand twisting movements from arm motion. This thick skin does not heal well and is acommon site of unsightly scars. The poorest healing parts of the body are the upper chest,upper arms, and upper back where hypertrophic scars (thickened scars) and keloids (scarsthat extend beyond the boundary of the injury) may form with increased frequency. Oilglands are also reduced in these areas making careful cleanser selection and the use ofmoisturizers important. One of the itchiest spots on the entire body is at the base of theshoulder blade on the back. It is not quite clear why is this the case; however, this spot isextraordinarily difficult to reach and is a common place where people routinely rub againsta doorframe! The arms and legs form another anatomic area. Both sites possess skin that isdesigned for movement accompanied by hair growth. The oil glands are more numeroushere than on the back and chest, but these are frequent sites of skin dryness in the elderly.Common Dermatologic Disease ConsiderationsMost dermatologic diseases affect the body, thus a complete discussion of this topic isbeyond the scope of this text. For those who wish additional information, a recommendedreading list is presented at the end of the chapter. However, it is worthwhile mentioningthat the most common skin disease of the body seen by the dermatologist is dry skin,known as eczema. Why is this the case? The reason can be simply stated as overbathing.Many people feel a need to bathe daily and some twice daily. Bathing the body has becomea ritual. Some bathe to relax prior to retiring for the night while others bathe to wake up.Athletically inclined individuals bathe after each exercise session. The elderly, who areotherwise inactive, may bathe frequently as they find the warm water soothing for achymuscles and joints. This excessive amount of cleanser and water contact eventuallyremoves not only the sebum, but also the intercellular lipids, causing dry skin. The skincracks, exposing tender dermal nerve endings, and itching ensues followed by scratching.This further damages the skin barrier and more itching and more scratching occur. Finally,the skin barrier is in complete disarray and the dermatologic disease of eczema is present.This sequence of events is known as the itch-scratch cycle. Successfully controlling the

Cutaneous Formulation Issues 23eczema depends on stopping the itching, repairing the barrier, and restoring the skinto health.Hygiene NeedsThis means body hygiene is a careful balance between removing enough bacteria toprevent disease and body odor while leaving the skin barrier undamaged. This is indeedquite a challenge. It would be nice to somehow develop a cleanser that could distinguishbetween sebum and intercellular lipids, removing the former while leaving the lateruntouched. This should be the goal of all therapeutic body cleansers.Skin Care NeedsThe desire to bathe frequently has created moisturization as the major skin need of thebody. Body moisturizers should create an optimal environment for healing and quell itch,leaving the skin smooth and soft. The moisturizer must function in hairy body areas andleave behind a breathable film that does not prevent sweat from evaporating from the bodysurface. The construction of moisturizers for this purpose is discussed in Chapter 6.UnderarmsThe underarms have been removed from the general body discussion as they represent aunique body area medically known as an intertrigenous site. Intertrigenous sites are bodyareas where two skin surfaces meet. They include the armpit, beneath the female breasts,and between the upper inner thighs. In persons who are obese, other intertrigenous sitesmay be present beneath the chin, beneath the abdomen, behind the knees, etc.Intertrigenous sites are characterized by moisture retention, skin movement, and warmth.This environment, as mentioned previously, is perfect for the growth of fungus, yeast, andbacteria, thus the intertrigenous sites are frequent sites of dermatologic disease.Anatomy and PhysiologyThe armpit is a particularly interesting intertrigenous site because it combines theaforementioned factors with hair and abundant sweat glands. The armpit contains twotypes of sweat glands, eccrine and apocrine. Up to this point, the discussion regardingsweat glands has referred to eccrine sweat glands that produce a clear odorless sweatdesigned to cool the body and prevent overheating. Apocrine sweat glands do notparticipate in thermoregulation, but rather produce a yellowish scented sweat. Apocrineglands are well developed in skunks and deer, but not so well developed in humans. It isthe scented apocrine sweat that interacts with special perfumes to produce a unique smell.It is theorized that babies who cannot see recognize their mother from the unique scent ofher apocrine sweat. Indeed, there are abundant apocrine sweat glands around the areola ofthe breast. Other locations of apocrine sweat glands include the groin, buttocks, and scalp.Apocrine sweat provides a perfect growth media for odor producing bacteria. Furthergrowth of these bacteria, in combination with fungus and yeast, can result in infectionsseen in the armpit, our next topic of discussion.Common Dermatologic Disease ConsiderationsInfection is clearly the most common dermatologic condition seen in the armpits. Infectionmay be due to fungus, yeast, or bacteria. The most common condition seen in the armpit isknown as intertrigo. This is the growth of yeast and possibly fungus in the warm moist

24 Draelosenvironment of the armpit that has had the skin barrier damaged by overhydration witheccrine sweat. Intertrigo presents as red, inflamed skin that may itch or burn. It is typicallytreated with a combination of topical antiyeast/antifungals and topical corticosteroidcreams. Elimination of the sweat can prevent recurrence through the use of antiperspirants,discussed in Chapter 8. Bacterial infections of the armpit are usually due to staph or strep organisms.These are the most common pathogens found in the environment and on the body.The apocrine sweat in the armpit provides an excellent bacterial growth media. If thebacterial infection involves the skin of the armpit, it is known as impetigo. Ifthe bacterial infection involves the skin around the exit of the hair from the skin, it isknown as folliculitis. Open wounds that may be scabbed or oozing pus characterize bothconditions. They are treated with oral and/or topical antibiotics. Again, elimination of thesweat is key to prevention.Hygiene NeedsIt comes as no surprise that the key hygiene need in the armpit is the elimination of eccrineand apocrine sweat. Sweating is normal part of human physiology, but excessive sweatingmay occur in the armpits, just like on the hands and feet, and is characterized ashyperhidrosis. Controlling the sweat prevents body odor, skin barrier damage, infection,and emotionally disturbing wetness. This is the realm of antiperspirants, but oralmedications and chemodenervation through botulinum toxin A are also used. These topicsare more fully explored in Chapter 8.Skin Care NeedsThe skin care needs of the armpit are mainly irritation reduction from the aluminum saltsused in antiperspirants and hair removal. Unfortunately, most topical antiperspirantscause irritation in the sensitive skin of the armpit. This can result in irritant contactdermatitis, especially if the skin barrier has already been damaged from overhydration.Thus, the best way to maintain the health of the armpit is to use an effective, nonirritatingantiperspirant. The armpit skin barrier may be further irritated from hair removal techniques,especially in the female. The armpit is a challenging area to shave with a razor due to itsconcave nature. Using a well-designed razor and shaving cream to both soften and reducefriction are key in the armpit. Depilatories are typically too irritating for armpit hairremoval. However, hair removal is an important method to control armpit odor, since thehair provides a large surface area for bacterial growth. Removal of the hair limits theamount of bacteria that can be present in the armpit.Female GenitaliaOur last body areas to discuss are the female and male genitalia. These areas have beenseparated for individual discussion because they represent unique skin interfaces withimportant hygiene and skin care needs.Anatomy and PhysiologyThe female genitalia forms several skin interfaces. The hair bearing skin of the mons pubisjoins the nonhair bearing skin of the labia and the mucosal surface of the labia abuts theurethra and vagina. A further skin interface is created where the keratinized skin of the

Cutaneous Formulation Issues 25inner thigh joins the transitional skin of the anus. Each of these sites form a location whereskin disease can occur. The female genitalia is one of the intertrigenous zones previously discussed and assuch is a warm, moist, dark place prone to infection from fungus, yeast, bacteria, andviruses. It is easily irritated and fragile with worsening fragility arising from the mucosalthinning that occurs with menopause.Common Dermatologic Disease ConsiderationsThe most common dermatologic conditions involving the genitalia would then beinfection and irritation. Infection is frequent, since the mucosa presents little barrier toinfection. Common infections of the genitalia include herpes simplex, genital warts, yeast(usually Candida albicans), and fungus. Fungal infections of the groin, medically knownas tinea cruris, occur from the same organism that causes fungal foot and toenailinfections. Irritation in the groin usually arises from tight fitting clothing that does not controlmoisture. Just like other skin areas, overhydrated skin is easily damaged. Since this is anarea of abundant apocrine and eccrine sweat glands accompanied by the wetness ofvaginal secretions and urine, hygiene assumes great importance.Hygiene NeedsHygiene of the female genitalia is an important, but overlooked, area. Most cleansers thatare designed for keratinized body skin do not function well as cleansers for the mucousmembranes of the female genitalia. They damage the mucosa causing itching, stinging,and pain. Yet, there is a need for cleansing to prevent infection and control odor.Skin Care NeedsThus, the basic skin care need of the female genitalia is the management of wetnesswithout the removal of the natural vaginal lubricants necessary to keep the tissues soft andsupple. This is quite a challenge, which has not yet been met. It is desirable to absorb andremove the sweat, but the mucous secretions must remain in place to lubricate the tissuesas they glide across one another with walking and movement.Male GenitaliaThe male genitalia also form an interface between various skin types with and withouthair. The lack of a large mucosal surface makes infection less of a problem, but thepresence of hair is a complicating factor.Anatomy and PhysiologyThe male genitalia is characterized by the thin skin of the scrotum interfacing with thekeratinized skin of the penis abuting the transitional mucosal skin of the head of the penis.In uncircumcised males, the head of the penis and the part of the penis beneath the foreskinis true mucosa. This true mucosa is a common site of infection, but is not found in thecircumcised male.

26 DraelosCommon Dermatologic Disease ConsiderationsThe most common dermatologic disease seen in the male is known as “jock itch.” Itrepresents a fungal infection, medically known as tinea cruris, again due to the sameorganisms that cause ringworm and toenail infections. The fungus can be passed betweenpartners with direct contact, which is usually how females acquire the infection. Yeastinfections of the penis can also occur, but this is less common in the circumcised male.Other infections, such as venereal disease may occur, but this is beyond the scope ofthis discussion.Hygiene NeedsThe hygiene needs of the male genitalia mainly focus around moisture and body odorcontrol. Both are related because moisture is necessary for the growth of bacteria thatcause body odor, thus eliminating wetness solves both problems. No personalantiperspirants exist for the area and moisture-absorbing powders usually become sticky,creating another problem.Skin Care NeedsThe need for skin lubrication does not exist for the male like it does for the female. All ofthe body surfaces that move with locomotion are keratinized and do notrequire lubrication.SummaryThis section has presented an overview of cutaneous formulation issues that must beconsidered when developing successful products for a given body area. Each major bodyarea has been discussed in terms of anatomy and physiology of the anatomic site, commondermatologic disease considerations, hygiene needs, and skin care needs. Yet, there ismuch more that could be written for the person who wishes further study. This list containsmajor dermatology textbooks that should consulted for additional information.SUGGESTED READINGS1. Bolognia JL, Jorizzo JL, Rapini RP: Dermatology, Mosby, London.2. Schachner LA, Hansen RC: Pediatric Dermatology, Mosby, London.3. Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, Firzpatrick TB: Dermatology in General Medicine, McGraw-Hill, New York.

3Formulation for Special PopulationsZoe Diana DraelosDepartment of Dermatology, Wake Forest University School of Medicine,Winston-Salem, and Dermatology Consulting Services, High Point,North Carolina, U.S.A.Not all skin is the same. This is one of the key challenges in the treatment of dermatologicdisease and successful global cosmetic formulation. The same skin disease can look verydifferent in Caucasian versus African American skin. The pigmentation problems commonin Asian skin are not seen in northern Europeans. The effects of aging are much different inmen versus women. Adolescents are more likely to develop acne in response to productuse than mature individuals. Persons with easy flushing experience stinging and burning inresponse to product application more frequently. Thus, issues of ethnicity, skin color, age,gender, and skin sensitivity must be considered when formulating skin care products for aglobal market. This chapter discusses these important formulation issues.GENDERGender difference issues are some of the most basic when considering cosmeticformulation. Male skin is visually much different than female skin and has a uniqueresponse to aging and adverse product reactions. When discussing female versus maleskin, we shall be talking about fully mature individuals. The unique skin care needs ofchildren will be discussed later. Probably the most important difference between male and female skin is the skinthickness. Male skin is thicker than female skin, in part due to the presence of terminal hairfollicles over much of the body. This difference is most pronounced on the face wherewomen have only vellus hairs while men have fully developed terminal hairs taking upspace within the skin. The presence of male facial hair is partially responsible for the morefavorable appearance of mature men over mature women. As UV radiation activatescollagenase to destroy dermal collagen, the male beard allows the skin to resist wrinkling,which is not the case in females. Thus, photoaged males do not exhibit the pronouncedredundant facial skin seen in photoaged females. The thicker male skin is also better atdiffusing UV radiation, especially in the UVA range, which penetrates more deeplycausing greater damage in female skin. The media that tends to prefer images of youngerwomen and older men further magnifies the gender differences in photoaging. 27

28 Draelos Differences in skin thickness also impact the frequency of adverse product reactionssuffered by the two sexes. Women experience adverse reactions more commonly thanmen. The thinner skin may allow irritants and allergens to penetrate deeper in female skin,but the increased incidence may also be due to greater product usage. Women overall usemore skin care products and cosmetics than men. This increased usage magnifies thechances of contacting an irritant or an allergen. Women are also more likely to undergoprocedures that destroy the skin barrier, such as facial peels, microdermabrasion, spatreatments, etc. Furthermore, women are more likely to engage in anti-aging topicalproducts that can create barrier damage, such as topical tretinoin, glycolic acid, lactic acid,etc. This damage to the stratum corneum further increases the chance for magnification ofa mild adverse reaction into a more major problem. This artificially created increase inadverse reactions experienced by women has been termed “polypharmacy” by some whowish to impart the concept of overusage of prescription and over-the-counter products byyouth-seeking women. Others use the term “iatrogenic sensitive skin” to emphasize theskin sensitivity created by exaggerated product use. Perhaps one of the most important differences between male and female skin is therelative balance between male testosterone and female estrogen and progesterone. Maleand female skin is quite similar up until puberty, at which time sexual differences becomemore pronounced. Both testosterone and estrogen cause the production of facial and bodysebum. This onset of oil production sets the stage for acne whereby the (Propionibacteriumacnes) bacteria now has a food supply to encourage abundant growth. More sebumproduction is triggered by testosterone accounting for the generally greater severity ofacne in males over females. However, females with higher than normal testosteroneproduction, due to hormonal abnormalities, such as polycystic ovary disease, mayexperience acne equally severe to any male. The onset of hormones also triggers anincrease in apocrine sweat, the scented type of sweat that is produced by specialized sweatglands on the eyelids, breasts, scalp, buttocks, and in the armpits. Both sebum and apocrinesweat create different skin cleansing needs and alter the skin biofilm in ways that candramatically affect cosmetics and skin care products. The formulator must consider thesubstances on top of the skin.AGE ISSUESIn addition to gender issues, age issues are also important to the formulator. Newbornchildren produce little sebum and eccrine sweat. Sebum production typically does notbegin until the hormonal changes of puberty occur, as discussed previously; thus, mostchildren have dry skin. This creates a challenge, since children frequently get their skindirty, which necessitates washing. The child may not produce enough sebum to combat theeffect of cleansing that may remove the intercellular lipids resulting in barrier damage.This creates the need for thorough mild cleansers and moisturizers for children. Carefulformulation is essential, since the skin of children is also thin and their well-functioningimmune system is likely to respond aggressively to irritants and allergens. It is for thisreason that children are considered to have sensitive skin. Puberty brings full functioning of the sebaceous, apocrine, and eccrine glands. Thismay be advantageous to dry skinned children who will no longer suffer from eczema.Many times allergies also become attenuated at this age. But, of course, oil, and sweatremoval become more of a problem as acne and body odor emerge. The next complexionchange generally occurs around age 40 as sebum production begins to decline. There isgreat variability in the age at which sebum production changes. In women, dramatically

Formulation for Special Populations 29decreased sebum production occurs at menopause, which usually begins by age 50 and iscompleted by age 60. Usually about age 60 there is a transition in both men and women to geriatric skin.While this is not a proper medical term, there are unique skin needs of the elderly. Theseinclude skin fragility that results in easy skin tears and bruising due to loss of dermalcollagen, which confers the skin’s strength. Even the rubbing of thick viscous skin creamscan cause bruising in elderly skin, medically known as senile purpura. Elderly skin is alsounique in that it appears chronically dry, even though noninvasive skin measurements,such as transepidermal water loss, are normal. This may be due to the decreased ability ofdead skin scale to slough in a timely manner. The buildup of corneocytes appears like dryskin even though the viable epidermis is well moisturized. This means that moisturizersdesigned for geriatric skin should encourage desquamation and provide superioremolliency to smooth the dry-appearing corneocytes. The last area to discuss in elderly skin is itching. Geriatric skin is uniquely itchy, eventhough there is little visible evidence of barrier disruption. Itching is typically due to barrierdisruption, medically termed dermatitis, and lack of protection of underlying dermal nerveendings. In the elderly, severe itching may be reported even though no dermatitis is present.This is a diagnostic enigma for the dermatologist. Skin itching appears to become worse inthe postmenopausal female; thus, estrogen may play a role. However, the exact cause of theitching is not always apparent. It may be due to depression, poor dermal support of the nerveendings, abnormal intercellular lipids, etc. Thus, itch reduction is a skin care need in theelderly, not frequently seen in younger populations.SKIN COLORWe shall now turn our discussion to skin color. Skin color produces as many variations inskin care needs as age. All colors of skin possess melanin, but the differences arise fromhow the melanin is packaged within the skin. This difference in melanin packaging givesrise to light and dark skin and also to the skin sunburn characteristics. These topics arecovered in more detail in the sunscreen chapter; however, here we shall address the uniquedifferences between skin color and skin care product response. Very light skin that doesnot tan well typically does not respond to injury with pigmentation problems. There maybe some transient hypopigmentation, or reduced skin color, especially with skin drynesswhere the skin does not tan well, a condition medically known as pityriasis alba.Hypopigmentation may also be seen following a traumatic skin injury, especially if themelanocytes have been damaged. However, a burn injury usually results in increasedpigmentation, medically known as post-inflammatory hyperpigmentation. This is incontrast to persons with darker skin, to include Asian, Mediterranean, African American,and Hispanic persons, who experience frequent post-inflammatory hyperpigmentation,which is a larger cosmetic concern than wrinkling in these ethnic groups. Postinflammatory hyperpigmentation is darkening of the skin in response to injury.The injury can be from acne, sunburn, skin disease, irritant contact dermatitis, allgericcontact dermatitis, or a traumatic scratch. Since melanocytes are felt to be an importantpart of the immune system, it is postulated that this hyperpigmentation is an immuneresponse to skin injury, but the exact reason for this reaction is largely unknown. Thus,products designed for skin of color must be carefully formulated to minimize any skinirritation, since postinflammatory hyperpigmentation is the inevitable result. It may takesix months to one year to return the skin to normal color after the injury, which accountsfor the tremendous skin lightening product focus in cultures with darker complected

30 Draelosindividuals. In order to return the skin to proper color, the extra melanin produced must bephagocytized or consumed by white blood cells and then removed from the skin. Moresuperficial pigmentation can be readily removed while some deeper dermal pigmentationmay be permanent. Skin color also confers photoprotection. Darker skin can sunburn and tan just likefair skin, but deepening of the skin color is generally considered undesirable. This is notthe case in fair complected individuals who try to achieve a tan by natural sun exposure,the use of artificial UVA radiation in a tanning booth, or dyeing of the skin with self-tanning products containing dihydroxyacetone. Melanin is basically an unstable radicalthat can absorb an electron from highly energetic unstable oxygen species, preventing theactivation of collagenase and the resulting dermal damage. This is why darker complectedpersons typically do not demonstrate photoaging to the same degree as their lighter age-matched counterparts. In addition to the different skin color responses to injury and photoaging, anotherimportant reaction pattern, known as follicular predilection, is unique to skin of color.Follicular predilection refers to the presence of disease around the follicle and at theopening of the hair onto the skin surface, known as the follicular ostia. For example,eczema due to dry skin usually occurs evenly over the skin surface in fair complectedindividuals, but in African American persons, the eczema occurs around the follicularostia giving the skin a unique goose bump type of appearance. Whether this reactionpattern is due to the increased melanin or the kinky hair is unknown, but this type ofeczema is considerably more difficult to treat. Mild skin irritation or full blown irritantcontact dermatitis may also be present with this follicular pattern. Thus, problemsassociated with skin care products or cosmetics may appear differently in skin of color,sometimes confusing the proper diagnosis.HAIR SHAFT ARCHITECTURENo discussion of skin is complete without considering the contribution of the hair to thephysiology of the skin. Different hair architecture accompanies different skin colors; thus,the hair and the skin are inter-related special considerations. Caucasian persons with veryfair skin typically have straight to slightly curly hair while African American persons withdark skin typically have kinky hair; however, many variations exist. Follicular skinproblems are usually minimal in Caucasian, Asian, Hispanic, and Mediterraneanindividuals where the oval to elliptical hair cross-section yields body hair that is straightto curly. Unique follicular problems exist in African American persons where the flattenedelliptical hair cross-section yields tightly kinked hair. This tight kink predisposes the hairto ingrowing, especially on the face, in the armpits and groin, and on the legs. Shaving ofthe hair in any of these areas cuts the hair at an angle and the tight kink of the hair shaftallows the short hair to re-enter the skin after exiting the follicular ostia due to the sharptip. The ingrown hair then burrows beneath the skin surface causing inflammation, whichcan result in the formation of a pustule, the appearance of post-inflammatoryhyperpigmentation, and/or a scar. When these findings arise in connection with ingrownfacial hairs, it is known as pseudofolliculitis barbae. This means that African American persons can develop skin disease based on themanner in which they groom their body hair. This problem with ingrown hairs explainswhy many African American women do not shave their armpits, groin, and legs. It alsoexplains why many African American men wear a short beard. The only way to avoid theingrown hair is to keep the hair so short that it cannot ingrow, which may mean twice daily

Formulation for Special Populations 31shaving for some, or to allow the hair to grow so long that it cannot ingrow, which is muchsimpler. Depilatories, waxing, and laser hair removal techniques are generally not anoption in African American individuals, since these methods do not work well on thedeeply pigmented kinky hair shafts.SENSITIVE SKINProbably the biggest formulation challenge for the cosmetic chemist and the biggesttreatment challenge for the dermatologist is sensitive skin. Sensitive skin can present withvisible outward changes, easily recognized by the dermatologist, or invisible signs withmarked symptoms presenting a treatment challenge. Visible sensitive skin is the easiest condition to diagnose, since the outwardmanifestations of erythema, desquamation, lichenification, and inflammation identify thepresence of a severe barrier defect. Any patient with a barrier defect will possess the signs andsymptoms of sensitive skin until complete healing occurs. The three most common causes ofbarrier defect induced facial sensitive skin are eczema, atopic dermatitis, and rosacea. Thesethree diseases nicely illustrate the three components of sensitive skin, which include barrierdisruption, immune hyper-reactivity, and heightened neurosensory response.EczemaEczema is characterized by barrier disruption, which is the most common cause ofsensitive skin. The barrier can be disrupted chemically through the use of cleansers andcosmetics that remove intercellular lipids or physically through the use of abrasivesubstances that induce stratum corneum exfoliation. In some cases, the barrier may bedefective due to insufficient sebum production, inadequate intercellular lipids, abnormalkeratinocyte organization, etc. The end result is the induction of the inflammatory cascadeaccompanied by erythema, desquamation, itching, stinging, burning, and possibly pain.The immediate goal of treatment is to stop the inflammation through the use of topical,oral, or injectable corticosteroids, depending on the severity of the eczema and the percentof body surface area involved, and proper skin care products and cosmetics.Atopic DermatitisSensitive skin due to eczema is predicated only on physical barrier disruption, while thesensitive skin associated with atopic dermatitis is predicated both on a barrier defect andan immune hyper-reactivity, as manifested by the association of asthma and hay fever.Patients with atopic dermatitis not only have sensitive skin on the exterior of the body, butalso sensitive mucosa lining the eyes, nose, and lungs. Thus, the treatment of sensitive skinin the atopic population involves topical and systemic considerations. There is also aprominent link between the worsening of hay fever and the onset of skin symptoms,requiring broader treatment considerations. All of the treatments previously described for eczema also apply to atopicdermatitis, but additional therapy is required to minimize the immune hyper-reactivity.While this may take the form of oral or injectable corticosteroids, antihistamines(hydroxyzine, cetirizine hydrochloride, diphenhydramine, fexofenadine hydrochloride,etc.) are typically added to decrease cutaneous and ocular itching. Antihistamines alsoimprove the symptoms of hay fever and may prevent a flare up should the patient beexposed to pollens or other inhaled allergens. The avoidance of sensitive skin in the atopicpatient is largely predicated on avoidance of inciting substances. This means creating an

32 Draelosallergy-free environment by removing old carpet, nonwashable drapes, items likely tocollect dust, feather pillows and bedding, stuffed animal toys, heavy pollinating trees andplants, pets, etc. The prevention of the release of histamine is the key to controlling thesensitive skin of atopic dermatitis.RosaceaRosacea is an example of the third component of sensitive skin, which is heightenedneurosensory response. This means that patients with rosacea experience stinging andburning to minor irritants more frequently than the general population. For example, Idemonstrated that 62.5% of randomly selected rosacea patients demonstrated a positivelactic acid sting test for sensitive skin (1). Furthermore, rapid prolonged facial flushing isone of the main diagnostic criteria for rosacea. Whether this sensitive skin is due to nervealterations from chronic photodamage, vasomotor instability, altered systemic effects toingested histamine, or central facial lymphedema is unclear. The treatments for rosacea-induced sensitive skin are much different than those foreczema or atopic dermatitis. Anti-inflammatories in the form of oral and topical antibioticsform the therapeutic armamentarium. Antibiotics of the tetracycline family are mostcommonly used orally, while azelaic acid, metronidazole, sulfur, and sodiumsulfacetamide are the most popular topical agents. However, the effect of the anti-inflammatory antibiotic can be enhanced through the use of complementary skin careproducts that enhance barrier function. Eczema, atopic dermatitis, and rosacea are in some ways the easiest forms ofsensitive skin to treat. The skin disease is easily seen and treatment success can bemonitored visibly. If the skin looks more normal, generally the symptoms of itching,stinging, burning, and pain will also be improved. Unfortunately, there are some patientswho present with sensitive skin and no clinical findings. These patients typically presentwith a bag full of skin care products they claim cannot be used because they cause facialacne, rashes, and/or discomfort. This situation presents a challenge for the physician, sinceit is unclear how to proceed. Several treatment ideas are worth considering. The patient may have subclinicalbarrier disruption. For this reason, treatment with an appropriate strength topicalcorticosteroid for two weeks may be advisable. If symptoms improve, then the answer isclear. The patient may have subclinical eczematous disease. If the symptoms do notimprove, it is then worthwhile to examine the next most common cause of invisiblesensitive skin, which is contact dermatitis. This is accomplished by considering the ideaspresented in Table 1 (2). Sometimes a more regimented approach to contact dermatitis isrequired, as represented by the basic product selection ideas presented in Table 2. Sensitive skin products are increasing in the marketplace, since many individualsconsider themselves to possess sensitive skin while others feel that products labeled forsensitive skin are less likely to cause problems in all populations. Exactly what is unique tosensitive skin products is unclear. In many ways, it is simply a marketing statement;however, some manufacturers will elect to test their formulations on persons with eczema,atopic dermatitis, and rosacea as part of a sensitive skin panel to substantiate the claim.CONTACT DERMATITIS ISSUESOur prior discussion of sensitive skin focused on those special skin conditions, namelyeczema, atopic dermatitis, and rosacea, which form the basis for a sensitive skin panel.However, we must also consider issues of contact dermatitis. Traditionally, issues of

Formulation for Special Populations 33Table 1 Considerations for the Minimization of Contact Dermatitis from Skin Care Productsand Cosmetics1. Eliminate common allergens and irritants, or reduce their concentration2. Select products from a reputable manufacturer that uses high-quality pure ingredients free of contaminants3. Products should be well-preserved to prevent the formation of auto-oxidation byproducts4. Paraben preservatives have proven to be the least problematic5. Avoid solvents, volatile vehicles, vasodilatory substances, and sensory stimulators in all products6. Minimize the use of surfactants and select minimally irritating emulsifier systemsirritant contact dermatitis are implied under the claim umbrella of sensitive skin, butallergic contact dermatitis issues are sometimes separately claimed. Allergic contactdermatitis issues may fall under the claim of hypoallergenic. Exactly what hypoallergenicmeans is unclear. In the strictest sense, the word hypoallergenic is used to indicate reducedallergy. Many products that are labeled hypoallergenic are also labeled as appropriate forsensitive skin, but the claims are somewhat different. All sensitive skin products should behypoallergenic, but all hypoallergenic products are not necessarily appropriate forsensitive skin. In my mind, hypoallergenic simply means that common allergens havebeen removed from the formulation, but irritants may still be present. Formulating products with reduced allergy is sometimes difficult. It is obvious thatpoison ivy, a common allergen, should never be included as an ingredient, but otherguidelines are sometimes difficult to develop. It is probably for this reason thathypoallergenic has never been defined by any regulatory body. Hypoallergenic productsare probably best formulated by using the fewest, purest ingredients possible and stayingaway from unusual botanical extracts. A poor approach would be to put anti-inflammatorysubstances, such as bisabolol or allantoin, in the formulation to minimize any allergicreaction. A quick review of the contact dermatitis literature shows that the most commonlycited cases of skin care product induced problems arise when contaminated raw materialsare used, such as nickel-contaminated eye shadow pigments or oxidized vitamin E, orwhen product preservatives break down. The best guarantee of formulating ahypoallergenic product is to use time-tested ingredients in a stable formulation.Table 2 Cosmetic Selection Criteria in Sensitive Skin Patients1. Powder cosmetics should be selected2. Cosmetics should be water removable3. Old cosmetics should be discarded4. Eyeliner and mascara should be black5. Pencil formulations should be used for eyeliner and eyebrow cosmetics6. Eye shadows should be earth-toned (tan, beige, light pink, cream)7. Avoid chemical sunscreens in cosmetic formulations8. Select cosmetic formulations with as few ingredients as possible9. Avoid nail polishes10. Select cream/powder facial foundations or, if liquid, silicone-based formulations

34 DraelosACNE ISSUESThe last two claims for special populations are non-comedogenic and non-acnegenic.These claims are aimed at individuals who develop acne in response to the facial use ofskin care products and cosmetics. Non-comedogenic refers to the testing of products todetermine that they do not produce blackheads, known as open comedones, or whiteheads,known as closed comedones, after wearing. Comedogenicity was a much greater problemwhen petrolatum was contaminated with tar, a known comedogen. Presently,comedogenicity is not a great problem, except in the ethnic hair care market wherecomedogenic vegetable oils, such as olive oil, are used in pomades to moisturize the hair. Testing must be done to substantiate the non-comedogenic claim. In the past,comedogenicity was assessed in the rabbit ear assay by applying the final formulationinside a rabbit ear and then visually assessing the presence or absence of comedones. Thistest was not felt to have much human validity and animal testing has fallen out of favor;thus, the rabbit ear assay has given way to testing on human volunteers. Typically, the finalformulation for testing is applied to the upper back in persons capable of formingcomedones on the upper back daily for 14 days. A positive control, in the form of tar, isapplied, and a negative control, in the form of pure petroleum jelly, is also used. Thecomedones are extracted from the upper back with cyanoacrylate glue placed on amicroscope slide. Any increase in comedone formation following the 14-day exposure tothe final cosmetic formulation is considered comedogenic. The non-acnegenic claim is much different. It implies that the finished product doesnot produce true acne, which is identified as red bumps, known as papules, or pus bumps,known as pustules. It takes much longer for acne to develop from product use, typicallyabout four weeks. There is no standard test done for acnegenicity, except for use testing.Volunteers use the product as intended for one month and are examined for the presence ofpapules and pustules. Yet, there are a number of individuals who will develop tinyperifollicular papules and pustules within 48 hours of wearing a skin care product orcosmetic. Is this acne? The answer is no. True acne cannot develop in 48 hours. In myopinion, this is perifollicular irritant contact dermatitis. It looks much like acne, but thepresence of lesions at the follicular ostia and the rapid onset lead to the diagnosis ofperifollicular contact dermatitis. This problem is best avoided by minimizing the presenceof irritants in the formulation as previously discussed.SUMMARYFormulating for special populations is indeed a challenge. There are unique dermatologicreaction patterns that must be considered. Failure to consider these reaction patterns couldresult in a product that is not globally acceptable. The globalization of the cosmeticsindustry means that skin care and cosmetic products must be suitable for both sexes, allages, all skin types, all ethnic groups, all skin colors, etc. Understanding the unique needsof all world populations is vital to success.REFERENCES1. Draelos ZD. Noxious sensory perceptions in patients with mild to moderate rosacea treated with azelaic acid 15% gel. Cutis 2004; 74:257.2. Draelos ZD. Sensitive skin: perceptions, evaluation, and treatment. Contact Dermat 1997; 8:67.

PART II: FORMULATION DEVELOPMENT AND APPLICATION4Personal Cleansing Products:Properties and UseKeith ErtelP&G Beauty, Sharon Woods Technical Center, Cincinnati, Ohio, U.S.A.INTRODUCTION “Let it be observed, that slovenliness is no part of religion, that neither this, nor any text of Scripture condemns neatness of apparel. Certainly this is a duty not a sin. Cleanliness, indeed, is next to Godliness.” —John Wesley (1703-1791), Sermon XCII “Cleanliness becomes more important when Godliness is unlikely.” —P. J. O’Rourke In today’s marketplace personal cleansing products are found on the shelves of massretailers and behind cosmetic counters at prestige stores, where they are offered as part of atotal skin care and beauty package. Nearly every shopping mall has a purveyor of specialtycleansing products and a simple search on the Internet reveals a number of suppliers whosedistinctive personal cleansers are purported to remedy the deficiencies of the productsmade by large-scale manufacturers. New cleanser forms offer increased convenience andconsumers can choose from myriad product scents, colors, and functional ingredientsintended to help them achieve relaxation and escape from the cares of everyday life, and toimprove their skin’s health and appearance (1–4). Yet despite their increased variety andcomplexity, present day cleansers have the same basic function as their counterparts oftimes past: to cleanse the skin.SKIN CLEANSINGSoil RemovalThe skin is covered with a hydrolipid film that, depending on the area of the body,comprises secretions from sebaceous glands and from apocrine and eccrine sweat glands.Decomposition products from cornification (cellular debris and stratum corneum lipids)and corneocytes in the process of being shed are also present. This film provides a degreeof waterproofing to the skin’s surface, traps water to help maintain skin pliability, andprovides a natural defense against pathogenic organisms. But this film also attracts 35

36 Erteland holds dirt and pollutants from the environment. The skin’s surface is also home to avariety of microorganisms. In most cases these organisms, the so-called resident flora,cause no harm and provide an additional defense against overgrowth by potentialpathogens. But these organisms can act on components of the surface film and createundesirable by-products, such as those resulting from the metabolism of compounds foundin apocrine sweat that create body odor. Thus, while the surface hydrolipid film is animportant skin integument, periodic cleansing to remove dirt, debris, and odor is essentialto maintaining skin health and in many cultures, social acceptance. Additionally, periodiccleansing is necessary to remove soil (including bacteria) from the skin surface that isacquired by incidental contact or by intentional application, e.g., medications or makeupand other cosmetic products. Water alone is capable of removing much of the soil from the skin’s surface (5).However, water has a limited ability to dissolve and remove oils; as the old adage goes,“oil and water don’t mix.” The surfactants that make up the bulk of most personalcleansing products aid this process. A surfactant, or surface active agent, is a material thatlowers the interfacial tension of the medium it is dissolved in, and the interfacial tensionwith other phases. Said more simply, a surfactant increases the affinity of dissimilar phasesfor each other. This ability is based on surfactants’ unique structure, which combines bothhydrophilic and hydrophobic moieties at opposite ends of the surfactant molecule. In adilute aqueous solution, surfactant molecules will arrange themselves such that thehydrophilic portion of the molecule is oriented toward the bulk solution while thehydrophobic portion orients itself in the opposite direction. For water in contact with skinthe presence of surfactant molecules at the interface lowers the interfacial tension and aidswetting, which improves water’s ability to spread over the skin’s surface. This, along withthe mechanical action of applying the cleanser, helps to remove soil. As the concentrationof surfactant in solution increases a point is reached at which the surfactant moleculesbegin self-association into micellar structures. This point is known as the critical micelleconcentration (CMC). Surfactants in aqueous micelles have their hydrophilic end orientedtoward the bulk (water) phase and their hydrophobic end oriented toward the interior of themicelle. The hydrophobic interior provides a good environment for dissolving lipids, andmicellar solubilization is an important mechanism by which surfactants remove oily soilsfrom the skin’s surface and help keep the soils suspended until they are rinsed away. Otherfactors may aid this process. For example, the skin’s surface possesses a net negativecharge at physiological pH and repulsive forces between the skin and anionic surfactantsor their associated micelles help keep suspended soils from redepositing, making thesesurfactants particularly good cleansers.Tests of Cleansing EfficiencyA personal cleanser’s ability to clean the skin is dependent on a number of factorsincluding its (surfactant) composition, its in-use concentration, the application time andmethod, the soil load, and the surface characteristics of the particular skin being cleaned.The past several decades saw a change in how personal cleansers are viewed, thefocus shifting from their role as skin cleansing aids to their role as agents with a potential todamage skin (6). Thus, while numerous publications describing methods to assessand compare personal cleansers’ skin compatibility appeared in this time frame, in-usecleansing performance was largely ignored. However, this question deserves considerationgiven the greatly expanded range of personal cleansing products now available, both interms of forms and ingredients.

Personal Cleansing Products 37 Weber described a method to assess cleansing that employed a device designed towash forearm skin in a controlled manner (7). A colored model soil was applied to forearmskin of normal subjects and three subject groups with psoriasis, atopic dermatitis, or non-lesional skin disease. Four cleansing bars ranging from full soap to synthetic detergent(syndet) were tested on each subject group. The amount of color on skin was measuredphotometrically before and after cleansing. Weber found differences in cleansing, not onlybetween the cleaner types but also between subject populations. Skin cleansing was in allcases best with the syndet bar, poorest with the soap. The measured cleansing responsewas greatest in psoriatics, which could reflect soil removal by detergency and themechanical removal of stained psoriatic plaques by the washing process. Cleansing waspoorest in atopics, which the author attributed to higher skin dryness (roughness) andgreater adherence of the model soil. Schrader and Rohr also used a device to assess personal cleansers’ skin cleansingability under controlled conditions (8). Their device was designed for use on the forearm,with a dual-chamber arrangement for simultaneous testing of two products. Agitators withfelt inserts rested on the forearm surface at a controlled pressure and moved in a back-and-forth motion to effect washing. A mixture comprising oleaginous materials (includinglanolin, petrolatum, and mineral oil) and lipid- and water-soluble dyes was used as a modelsoil. The published study compared soap-based and syndet-based liquid cleansers at 2%and 8% concentrations. Water and a 2% solution of sodium lauryl sulfate (SLS) were usedas controls. The color (L*-value) on skin before and after “washing” was measured with achromameter. This work showed greater cleansing efficiency for the soap-based cleanser. These authors conducted a separate experiment to assess the skin roughening effectof the test cleansers. Subjects used the test solutions for forearm washing over a two-weekperiod. Skin roughness was assessed using silicon replicas taken at baseline and study endand analyzed by laser profilometry. The 2% solution of the soap-based cleanser producedgreater roughening than did the 2% solution of the syndet-based cleanser. Changing theconcentration of soap-based cleanser from 2% to 8% did not increase skin roughness.However, skin roughening for the syndet-based cleanser showed a concentration effect andat the higher concentration skin roughening was comparable to that produced by the soap-based cleanser. This illustrates the concentration-dependence of cleanser effects on skinand, since an 8% concentration is representative of cleansers’ concentration on the skinduring actual use (9), the importance of understanding test conditions when judging how acleanser will affect skin. This is particularly important when attempting to predictcleansers’ in-use skin effects. Wolf and Friedman used a modification of Schrader’s method to assess the skincleansing effect of soaps (10). An oleaginous mixture (petrolatum, lanolin, mineral oil)was again used as a model soil but in this case it was applied to the dorsum of the hand. Thesoiled hand was immersed for five minutes in a beaker filled with a stirred, 1% solution ofthe test cleanser maintained at 378C. Sebumeterw readings made before and 30 minutesafter immersion were used to determine the amount of soil removed. The authors reportthat this method is a convenient and economical alternative to the method of Schraderthat can reliably and reproducibly measure and discriminate the skin cleansing abilityof different products. A study comparing a syndet to a mild cleanser containing “25%hydrating soothing cream” showed that the latter product removed less of the model soilfrom the skin, i.e., it was a poorer cleanser. The authors conclude that for a product tofunction as an effective cleanser it must also dry the skin to a certain degree. Imokawa used a model soil consisting of a mixture of triolein, cholesterol, squalene,palmitic acid, and Sudan Black dye (11). This mixture was applied to six glass slides,which were placed into a beaker containing 408C surfactant solution and stirred at

38 Ertel1300 rpm for 10 or 30 minutes. Cleansing efficiency was judged by spectrophoto-metrically or gravimetrically measuring the amount of soil removed from the slides. Lockhart and Lazer presented work that examined the impact of various physicalconditions on cleansing (12). Charcoal applied to the dorsum of the hand served as a modelsoil. Four “wash” conditions were examined: simple soaking and placing the hand in awhirlpool, a simulated shower, or in an ultrasonic bath. Water temperature was maintainedbetween 328C and 388C in all cases. Cleansing efficacy was judged by measuring color atthe charcoal-stained area with a chromameter before and after washing. The resultsshowed that the conditions ranked, in order of increasing cleansing effectiveness, soaking! whirlpool ! shower ! ultrasonic bath. While this study did not involve a cleansingagent or oleaginous soil, it demonstrates the potential for physical conditions andmechanical action to influence removal of a simple soil from the skin’s surface. Personalcleansers are used under a range of conditions and with a variety of implements, and thesefactors will affect overall cleansing efficacy. The above methods all used a device in an attempt to reduce variability associatedwith the washing process. Other authors describe cleansing efficacy methods that moreclosely approximate in-use conditions. Sauermann et al. used mineral oil containing 0.1%anthracene as a model soil (13). The material was applied to the lower inner forearm, andthe site was washed in a regular manner for 30 seconds with warm (328C) water and thengently blotted dry. Cleansing efficacy was calculated based on fluorescence measured atthe site before and after washing. These authors reported greater cleansing efficacy forsoap bars than for syndet bars. Puvvada et al. describe a method using makeup materials (e.g., lipstick or mascara)as model soils (14). Washing involved rubbing a (wetted) bar on the skin for one minute,rinsing with 358C water for 30 seconds, and then patting dry. Cleansing efficacy wasestimated from the difference in chromameter measurements taken before and afterwashing. While this method employs model soils that represent everyday cleansing needs,the wash conditions are exaggerated beyond expected use. Mills et al. also described amethod using makeup (opaque camouflage cream) as a model soil (15). The makeup wasapplied to nine test sites on the ventral forearms, and then a technician washed each site ina controlled manner with a pad lathered with one of the test cleansers. The sites wererinsed to remove all traces of lather then rank-ordered based on the level of cleansing. Ofthe cleanser types tested, a bar soap product was ranked among those with the poorestcleansing efficacy, followed by a liquid soap marketed for sensitive skin. Cleansingproducts based on sugar surfactants (polyhydroxy fatty acid amides) were ranked ashaving the best cleansing efficacy. These products were also found to have the best skincompatibility in a chamber scarification test (16). We also assess cleansing efficacy using a makeup removal model. Subjects arescreened on the basis of skin tone (chromameter L*-value); only subjects with sufficientlylight skin are enrolled to assure good contrast with the model soil. A dark, oil-basedmakeup is applied to application areas marked on the volar forearms, and 30 minutes laterthe color at each site is measured again. Then a bar or liquid cleanser lather is generated,and a technician washes a randomly assigned site with lathered fingers for 10 seconds; thesite is rinsed for 10 seconds with warm water and gently patted dry. A water-only wash iscommonly included as a control. Thirty minutes after rinsing the color at the site ismeasured again. The color difference (DE) is calculated from the pre- and post-washL*a*b* values as an indicator of cleansing efficacy. This method is useful for assessing therelative cleansing efficacy of a variety of personal cleanser types. For example, themakeup removal method was used to compare cleansing efficacy of traditional soap bars

Personal Cleansing Products 39Color Difference, ∆E Makeup Removal Study Mean +− SEM Cleansing Bars Better Cleansing12 10 8 6 4 2 0 Water Syndet Bar Soap Bar #1 Soap Bar #2Figure 1 Results from a makeup removal study comparing two soap bars and a syndet bar. Thesoap bars cleaned significantly better than the syndet bar (P!0.05), and all of the cleansing productsremoved significantly more of the model soil than water.and a syndet bar. The cleansing efficacy for the soap bars was significantly better than thatfor the syndet bar under this method (Fig. 1). Liquid personal cleanser forms are becoming increasingly popular, and some ofthese cleansers incorporate benefit agents such as petrolatum that deposit on skin duringuse. This product performance model seems inconsistent with a cleanser’s purpose, i.e.,how can products that are designed to deposit material onto the skin function effectively ascleansers? One strategy involves employing technology that takes advantage of varyingconditions that exist at different stages of the wash process. The benefit agent remainssuspended in the lather during cleansing but upon rinsing this lather becomes dilute andthe emulsion suspending the benefit agent “breaks,” depositing the benefit agent onto theskin. To demonstrate that this type of cleanser can effectively remove soil, we used themakeup removal test to assess the cleansing efficacy of two marketed liquid hand cleansersand three prototype liquid hand cleansers containing different levels of petrolatum (Fig. 2).The petrolatum-depositing products showed significantly better cleansing efficacy than themarketed cleansers under this model, and the results suggest that cleansing efficacyimproved with increasing petrolatum level. Since the model soil is an oil-based makeupproduct this could reflect a “like dissolves like” phenomenon, which should translate togood removal of lipophilic soils from the skin in actual use. There are other examples ofusing lipophilic materials to aid soil removal. In ancient times the Romans applied oil totheir skin during the cleansing process (17), and lipid-based washing products are againbeing promoted for use by patients with sensitive skin and atopic dermatitis (18,19). Cleansing efficacy is important but for a product like a hand wash, which is usedmultiple times each day for washing, good skin compatibility is also necessary. Weconducted a controlled application pilot study simulating in-use exposure to assess thisparameter for the petrolatum-depositing hand wash (25% petrolatum). Healthy adultfemales were enrolled in a hand washing study comprising a seven-day pre-treatmentperiod and a five-day treatment period. Subjects were provided with a regular liquid handcleanser for hand washing and a syndet-based bar to use for showering. They wereinstructed not to apply cleansing products to the dorsal part of their hands and to avoid anyactivity that required hand immersion in a surfactant solution, e.g., washing dishes.Moisturizer use was prohibited. Ten subjects who exhibited a sufficient level of handdryness entered the treatment phase. Treatment was conducted as a paired comparison.

40 Ertel Makeup Removal Study Liquid Hand Wash Products765Color Difference, ∆E4 Mean +− SEM3 Better Cleansing210 Water Marketed Marketed Prototype Prototype Prototype Control Cleanser 1 Cleanser 2 Cleanser 1 Cleanser 2 Cleanser 3 (12% pet) (20% pet) (25% pet)Figure 2 Results from a makeup removal study comparing three prototype petrolatum-depositinghand wash formulas to two marketed hand wash products. The percentages of petrolatum are shownin parentheses. The prototype formulas cleaned significantly better than the marketed hand washesand water (P!0.05).A technician washed one randomly assigned hand with the petrolatum-depositing handwash product for 10 seconds following a prescribed procedure; the other hand was wet,rinsed, and patted dry. There were five wash visits each day, spaced by 30 minutes, with thewashing procedure conducted four times in succession at each visit. Thus, subjects’ handswere washed a total of 20 times each day. Hand condition was evaluated visually (20) andinstrumentally (CM-825) at baseline, before washing, and two hours after the final washeach day. Subjects acclimatized for 30 minutes in a controlled environment room beforeeach evaluation. Expert visual evaluation showed little difference in erythema production betweenthe hand wash and control (Fig. 3). In fact, the hand wash generally produced somewhatless erythema than the control. In addition, the hand wash produced marked drynessimprovement compared to control at the post-wash evaluations, and there was progressiveimprovement in dryness observed at the pre-wash evaluations over the course of treatment(Fig. 3). Trends in the skin capacitance measurements, which provide an indirectassessment of stratum corneum hydration, paralleled the expert dryness scores. Theseresults demonstrate that this petrolatum-depositing hand wash shows good skincompatibility and can actually improve dry skin condition, even under exaggeratedexposure conditions.PERSONAL CLEANSER EFFECTS ON SKINSurfactant Types Commonly Used in Personal CleansersWhile some new cleanser technologies can combine effective cleansing with the potentialto improve skin condition, the focus for the majority of personal cleansing productsremains on minimizing the potential for skin damage. Surfactants make up the bulk ofmost personal cleansing products and are primarily responsible for a product’s in-use

Personal Cleansing Products 41 Expert Visual Assessment - 20 Daily Washes Petrolatum-Depositing Hand Wash Relative to Water Control2.5 Expert Dryness Scoring ***2.0 Expert Erythema Scoring * *p < 0.05 compared to control **1.5 *1.0Relative Clinical Score Mean ∆ +− SEM0.5 Greater Improvement0.0−0.5 Day 1 Day 2 Day 2 Day 3 Day 3 Day 4 Day 4 Day 5 Day 5 Post-Wash Pre-Wash Post-Wash Pre-Wash Post-Wash Pre-Wash Post-Wash Pre-Wash Post-WashFigure 3 Expert visual dryness and erythema results from a hand washing pilot study comparing apetrolatum-depositing hand wash product to a water control. The hand wash product improved dryskin condition, even when used for washing hands 20 times daily.properties, e.g., lather, and for its effects on skin. While all surfactant molecules areamphiphilic, there are distinct surfactant types. A surfactant’s dissociation behavior inwater provides a convenient basis for classification.Anionic SurfactantsThese surfactants dissociate in water to yield a surfactant with a negatively chargedhydrophilic group and a cation that is usually an alkali metal (sodium or potassium) or aquaternary ammonium species. Anionic surfactants are used in a wide variety of bar andliquid personal cleansing products and account for about 50% of worldwide surfactantproduction (21,22). Soap, which is chemically the alkali salt of a fatty acid, is the best-known anionic surfactant, but a variety of synthetic (i.e., non-soap) anionic surfactants arecommonly used in personal cleansing products, including the acyl isethionates, alkylsulfates, and alkyl ether sulfates (AES). The acyl isethionates have good skincompatibility and are good detergents and lime soap dispersants, viz they inhibit theformation of hard water scum. Sodium cocoyl isethionate is an example; this surfactant is acommon primary surfactant in “mild” cleansing bars. The alkyl sulfates are widely used incosmetic products ranging from skin cleansers to toothpastes. They have good foam-forming properties and produce creamy lather but do not perform well in hard water. Alkylsulfates have a marked potential to irritate skin. Sodium lauryl sulfate (SLS), an alkylsulfate found in many personal care products, is often used as a model irritant. The AESare similar to the alkyl sulfates but their hydrophobic portion comprises ethylene oxideunits rather than a straight-chain hydrocarbon. This gives AES a number of advantagesover alkyl sulfates, including better lather formation in hard water and better lime soapdispersion. AES are also less irritating than alkyl sulfates, and their skin compatibility isimproved by increasing the degree of ethoxylation (23,24). Sodium laureth sulfate is anexample of an AES that is commonly found in personal cleansing products.Cationic SurfactantsThese surfactants dissociate in water to yield a surfactant with a positively chargedhydrophilic group and an anion. Fatty amine or ammonium salts and quaternaryammonium salts are examples. Cationic surfactants are generally not good detergents or

42 Ertelfoaming agents, and they are usually incompatible with anionic surfactants. However,being positively charged they adsorb to biological (and other) surfaces, which tend to havea net negative charge at a neutral pH. This property makes cationic surfactants useful asantistatic agents in hair conditioning products. The quaternary ammonium compoundshave marked antibacterial activity and are often found in toiletries such as deodorantsand mouthwashes.NonionicThese surfactants do not dissociate in water. Instead, their hydrophilic group is commonlyan alcohol, phenol, ether, ester, or an amide. Alcohol ethoxylates and alkylphenylethoxylates are two common examples of this type of surfactant. A “new” class ofnonionic surfactants employs various sugars as hydrophilic groups. The uncharged natureof nonionic surfactants makes them compatible with other surfactant types, and they alsoshow reduced sensitivity to conditions such as water hardness or salinity and toformulation pH. Common examples are the sorbitan esters (marketed as SPAN) and theirethoxylated counterparts (marketed as TWEEN). As a class, nonionic surfactants tend toexhibit good skin compatibility (15,25), but they still have a potential to interact with andnegatively impact the stratum corneum (26).Amphoteric SurfactantsThese surfactants have two functional groups, one anionic and one cationic. Theircharacter is determined by the pH of their environment; amphoteric surfactants are anionicunder alkaline conditions and cationic near or below their isoelectric point, i.e., the point atwhich the surfactant molecule carries no net charge. Betaines, which actually carry apositive charge in both acidic and alkaline media (27), are among the most widely usedamphoteric surfactants and are found in both bar and liquid cleanser formulations. Betainesare used to improve lather quality or to increase the viscosity of liquid formulations. Theygenerally show good skin compatibility and can decrease the skin irritation potentialof harsher anionic surfactants when used in combination with them (24,28). But betainesare not without issues. There are a number of reported cases of contact allergy tococamidopropyl betaine (29–32), one of the most commonly used surfactants in this group,and this surfactant was named the contact allergen of the year in 2004 (30). However, theeffective incidence of issues is low given the widespread use of this surfactant in personalcare products. Still, manufacturers may be able to reduce the risk of contact allergy byusing a higher grade of betaine material as data suggest the allergic response is caused byimpurities rather than by the surfactant itself (32–34).Surfactant Interactions with the SkinPersonal cleansing products are complex systems that often contain several surfactants.Even a seemingly simple cleanser such as a soap bar comprises a mixture of soap species.Several of the mechanisms believed to drive surfactant interactions with the skin arediscussed below. These are presented separately for convenience but the mechanisms areundoubtedly interdependent to some degree.Surfactant Structural ConsiderationsThe surfactant composition of a personal cleanser in large part determines the product’spotential to impact skin, and there are numerous published studies that compare and

Personal Cleansing Products 43contrast the skin effects of individual surfactants and full formula cleansers. But skincompatibility can vary even within a given surfactant type. Soap provides a good example.As defined previously, soap is the alkali salt of a fatty acid. The regulatory definition ofsoap is quite narrow and only a few true soaps remain on the market in the United States(35–37), but products based on soap-syndet mixtures (so-called combo bars) persist in theU.S. market, and soap remains a popular cleansing form in many other countries. The rawmaterial used in soap manufacture is often a mixture derived from tallow, vegetable oils,and their processed derivatives (38,39). Being derived from natural sources, these rawmaterials comprise a mixture of fatty acid species. The fatty acid compositions oftriglycerides from several different sources that are used in soap manufacture are shown inFigure 4 (21). The varying composition of the raw materials used in soap manufacture means thatsaponfication, i.e., reacting triglyceride with alkali to form soap and glycerin, yields amixture of soap species. The chemical composition of the finished soap productdetermines its skin compatibility. For example, Dahlgren et al. used soap bars preparedwith different relative amounts of tallowate and cocoate soaps to demonstrate that the levelof dryness and erythema following controlled washing is dependent on the ratio of thesesoap species (40). In this work a bar based entirely on coconut-derived soap was harshestto skin, while a bar based entirely on tallow-derived soap was mildest. The mildness ofbars based on intermediate combinations of cocoate and tallowate soap fell between theseextremes. These results, and the differences in the fatty acid compositions of the rawmaterials (Fig. 4), indicate that the distribution of soap species in a personal cleansingproduct is an important determinant of its skin compatibility. Studies conducted with pure fatty acids demonstrate this effect at a morefundamental level. Blank conducted patch tests using coconut oil and pure fatty acidscommonly found in soap (41). Patches were applied for 24 hours to intact skin on theupper arms of normal (healthy) subjects, subjects who previously exhibited a reaction tosoap (pruritus or vessiculation), and subjects with evidence of contact or atopic dermatitis.Reactions were read one hour after patch removal. The results are summarized in Fig. 5.The percentage of positive reactions in each test group shows clear fatty acid chain lengthdependence, with the incidence decreasing as the chain length increases. KellumPercentage Fatty Acid Compostion of Triglycerides from Various Sources 100 Coconut Oil Olive Oil 80 Palm Oil Pork Fat Beef Fat (tallow) 60 40 20 0 C10:0 C12:0 C14:0 C16:0 C18:0 C18:1 C18:2 C18:3 C8:0 (Lauric) (Myristic) (Palmific) (Stearic) (Oleic) (Linoleic) (Linolenic) (Caprilic) (Capric) Fatty Acid Species (carbons:double bonds)Figure 4 Typical fatty acid composition of some triglycerides commonly used to manufacturesoap. Source: From Ref. 21.

44 ErtelPercentage of Positive Reactions Patch Test Reactions to Fatty Acids 100 Normals Soap Reactive 80 Contact or Atopic Dermatitis 60 40 20 0 Caprylic Capric Lauric Myristic Palmitic Stearic Oleic Coconut Oil Caproic C8:0 C10:0 C12:0 C14:0 C16:0 C18:0 C18:1 mixed C6:0 Fatty Acid Species (carbons:double bonds)Figure 5 Results from a patch test study conducted among normals, soap reactive individuals, andindividuals with contact or atopic dermatitis. There is a decreased irritation potential with increasingfatty acid chain length. Source: From Ref. 41.conducted a similar study, patching saturated fatty acids with even-numbered chainlengths from C2-C16 on the backs of healthy volunteers for up to 15 days (42). Responsewas greatest to the C8-C12 acids, with the C12 homologue producing the most severereactions. The author hypothesized that the C12 chain length might be optimum forincorporation into or passage through biological membranes. Stillman et al. conductedpatch testing with even- and odd-numbered saturated fatty acids ranging from C3-C18;several unsaturated C18 species were also tested (43). The results again showed thegreatest reaction to the C8-C12 acids. Of the unsaturated species tested, only linoleic acid(C18:2) produced irritation. Garc´ıa-Dom´ınguez and coworkers proposed a five-step model to account for theincreased irritancy of C12 ionic surfactants (44). The model involves both ionic andhydrophobic interaction between the surfactant molecule and proteins at the skin surface,ultimately leading to migration of the charged and hydrophobic portions of the surfactantmolecule into the protein. Irritation results from localized environmental changes withinthe protein structure induced by the presence of surfactant. Thus, the higher irritancy ofC12 surfactants is again attributed to structural characteristics that favor their interactionwith the skin. These studies show that soap composition, in particular the chain length distributionof fatty acids in the soap, is an important determinant of soaps’ skin compatibility. Usingtailored mixtures of fatty acid starting material, in which the longer chain length speciespredominate, is one approach that is used to effectively improve the skin compatibility ofsoap bars (45,46). The skin compatibility of many synthetic detergents exhibits a structuraldependence similar to that of soap. Kligman and Wooding used patch testing to estimatethe ID50, the concentration needed to produce a discernible irritant reaction in 50% ofthe study population in 24 hours, and the IT50, the number of days of continuous exposureto produce a threshold reaction in 50% of the study population, for a series of sodiumalkyl sulfates (47). They observed minimum values for both parameters, i.e., greatestirritancy, for the C12 chain length (SLS). Dugard and Scheuplein measured the effect ofC8-C16 homologues of the sodium salts of primary aliphatic acids (soap), sodium n-alkylsulphates, and n-alkylamine hydrochlorides on the permeability of human epidermal

Personal Cleansing Products 45membranes (48). They observed the greatest permeability increase with the C12 and C14members in each series. Robbins and Fernee reported a maximum in the swellingbehavior of epidermal membrane, a parameter reported to parallel anionic surfactants’ability to elicit erythema in vivo, for the C12 homologue in a series of alkyl sulfates (49).They note that surfactant binding to keratin is also optimal at this chain length. Rheinet al. used a similar experimental procedure and reported maximal swelling for the C12or C14 homologues of alpha olefin sulfonates, paraffin sulfonates, linear alkylbenzenesulfonates, and alkyl sulfates (23). Increases in swelling response with time suggestedsurfactant effects on keratin secondary and tertiary structure. Imokawa and co-workersconducted experiments using a surfactant solution circulation apparatus to assess the skinroughening potential of C8-C14 soaps and of homologous series of various syntheticsurfactants (50,51). The C12 soap and synthetic surfactants produced the greatest skinroughening effect within each homologous series. These examples illustrate a common surfactant feature that reduces skincompatibility, namely, a chain length of about C12. Thus, one way to improve skincompatibility of syndet-based cleansers is to minimize their content of short-chainedsurfactants, especially C12 species, analogous to the soap bar example given earlier. Usinga modified surfactant can also improve skin compatibility. For example, Rhein et al.reported a reduction in stratum corneum swelling produced by C12-C14 alkyl ethoxysulfates as the degree of ethoxylation increases (23). Finally, personal cleansers’ skincompatibility is often improved by using mixtures of different synthetic surfactants(23,24,28,52).Removal of Skin Lipids (Delipidization)As noted earlier, the hydrolipid film on the surface of the skin is important for maintainingskin health. Epidermal lipids, which serve as the “mortar” between the corneocyte“bricks” in the stratum corneum, are also important to maintaining skin health and stratumcorneum barrier function (53–55). Patient populations that exhibit heightened sensitivityto personal cleansing products, such as individuals with atopic dermatitis, often exhibitaberrant epidermal lipid composition or structure (56,57), and di Nardo et al. found aninverse relationship between susceptibility to irritation from SLS and levels of certainstratum corneum ceramides in normals (58). Visscher et al. reported an increase intransepidermal water loss rate, consistent with stratum corneum barrier compromise,following acetone/ether extraction of lipid from the skin surface and upper stratumcorneum (59). Findings such as these, coupled with surfactants’ natural ability to emulsifyoils and lipids, suggest that surfactants’ negative impact on skin could result fromdelipidization or selective removal of lipid components from the stratum corneum. Kirk examined the amount of casual lipid, i.e., lipid on the skin surface, removed byone minute of controlled hand washing (60). Results from washing with water and withseveral bar cleansers are summarized in Figure 6. As expected, water is relativelyinefficient at removing skin surface lipid. The surfactant bars are more efficient but stilldo not completely strip the skin surface of lipid. However, even partial removal of thehydrolipid film may effect changes in skin condition. Morganti reported that washing theskin with water decreases surface lipids by about 24%, while washing with soap reducessurface lipids by about 36% (61). Surprisingly, using a syndet bar to wash the skinreduced surface lipids by about 50%. Removal of skin surface lipids was hypothesized todecrease the skin’s ability to retain natural moisturizing factors (NMF), ultimatelyleading to dry skin. Sauermann et al. also reported removal of NMF by exposure to waterand to soap or syndet solutions, but these authors did not measure lipid removal (13).

46 Ertel Casual Lipid Removed by Hand Washing Bar of Fatty Alcohol Sulfates Soap Bar with 5% Mineral Oil (80% tallow, 20% coconut) Soap Bar with 5% Lanolin (80% tallow, 20% coconut)Soap Bar with 5% Cottonseed Oil (80% tallow, 20% coconut) Soap Bar (80% tallow, 20% coconut) Water 0 20 40 60 80 100 % of Casual Lipid RemovedFigure 6 Percentage of casual lipid removed by 1 minute of hand washing. Washing with wateralone removes about 25% of casual lipid; the amount of casual lipid removed increases to 50%–60%when a cleanser is used. Source: From Ref. 60.Bechor et al. reported O70% relative change in casual sebum levels after washing thecheek for 30 seconds with water or various personal cleansing products (62). Sebumremoval was not linked with clinical symptoms in this study, and sebum levels returned tobaseline values in about one to two hours. Gfatter et al. examined the effect of washing onskin surface lipid content in a group of infants aged two weeks to 16 months (mean age3.2 months) (63). Treatment consisted of a one-minute wash performed on each child’schest and buttock with tap water (control), a synthetic detergent liquid, a syntheticdetergent bar, or a soap bar. Skin surface lipid content and several other parameters weremeasured 10 minutes after washing. All of the washes removed a significant amount ofskin surface lipid. Not unexpectedly the least removal was observed for the control group(K0.93 mg/cm2), the greatest removal for the soap bar group (K4.81 mg/cm2). Theauthors conclude that removal of surface lipid might reduce stratum corneum hydrationand lead to dryness and scaling. Personal cleansers can also induce changes in epidermal lipids, which areresponsible for maintaining the skin’s barrier function. Imokawa et al. reported that thestratum corneum lipid lamellar structure of forearm skin was disrupted following a30-minute exposure to 5% aqueous sodium dodecyl sulfate (64). Post-exposure analysisshowed a selective loss of various lipid components including cholesterol, cholesterolester, free fatty acids, and sphingolipid. The authors noted that surfactant exposureproduced an enduring chapped, scaly appearance and reduced hydration. Recovery studiesconducted by applying isolated lipid fractions to surfactant-treated skin suggested a role forsphingolipids in helping to restore the skin’s ability to retain water. Rawlings et al.examined lipid structure and composition in the normal skin of adult females and in xeroticskin induced by soap washing (65). Xerotic skin samples were obtained by tape strippingthe backs of subjects’ hands following one week of three-times-daily washing with soap;normal skin samples were obtained from a control group of subjects. The authors noted anapparent perturbation of desmosomal degradation, with intact desmosomes persisting tohigher levels in the stratum corneum in soap-treated skin. The lipid bilayer structure in theouter stratum corneum was degraded in both skin types, but the normal and soap-treatedstructures had a different appearance. The authors found a decreased stratum corneum

Personal Cleansing Products 47ceramide content in soap-treated skin, with a progressive, deeper loss accompanying moresevere dry skin grades. However, the relative levels of the various ceramide species werenot different in the two skin types. The authors concluded that alterations in stratumcorneum lipid composition and organization, along with reduced desmosomal degradation,are responsible for the scaling that accompanies soap washing. Fulmer and Kramer compared lipid content in normal and surfactant-induced dryskin in a paired, dry leg study (66). Subjects washed one randomly assigned leg three timesdaily with 4% sodium dodecyl sulfate solution for a period of two weeks; the other legremained untreated as a control. At the end of treatment shave biopsies were taken for lipidanalysis. In contrast to the results reported by some other groups, no alteration in the totalamount of lipid per gram of stratum corneum protein resulted from the surfactant washing.In particular, the total ceramide level was not changed. However, ceramide, cholesterol,and free fatty acid profiles were altered in the surfactant-treated skin compared to control.The authors concluded that surfactant washing affects the quality, but not the quantity, ofstratum corneum lipids, suggesting that surfactants’ role in the dry skin process is related toperturbation of the stratum corneum formation process, not lipid extraction. Other studies also call the hypothesized relationship between lipid extraction andsurfactant-induced skin damage into question. Scheuplein and Ross examined the effect ofthree classes of compounds on human epidermal membrane permeability to tritiatedwater: lipid solvents (e.g., chloroform:methanol), hydrogen-bonded solvents (e.g., water,DMSO), and surfactants (sodium laurate, SLS) (67). Lipid extraction decreased the dryweight of the stratum corneum by up to 20% even though its gross appearance remainedunchanged. Solvent extraction of epidermal lipids resulted in a large increase in membranepermeability; this effect was irreversible. Hydrogen-bonded solvents also increasedpermeability, which was attributed to resolvation and membrane expansion. Unlikesolvent extraction, the increase in permeability from hydrogen-bonded solvents waslargely reversible. Exposure to surfactant caused visible expansion in the plane of thetissue, suggesting that the anionic surfactants initiate uncoiling of alpha-keratin moleculesto form beta-keratin. The effect was reversible for mild surfactant exposures butirreversible for more severe exposures. Follow-up work by Dugard and Scheuplein againshowed reversible changes in human epidermal membrane permeability followingexposure to surfactants belonging to three n-alkyl homologous series (48). They concludedthat extraction of lipids or other epidermal components was not the primary mechanismresponsible for the increased membrane permeability, and instead suggested thatsurfactants act on membrane proteins. Rhein et al. reported that the swelling responseof stratum corneum exposed to surfactant solutions was reversible, again suggesting alimited role for lipid extraction in surfactant interactions with skin (23). Froebe et al.examined in vitro stratum corneum lipid removal by SLS and linear alkyl benzenesulfonate (68). Both materials removed detectable levels of lipid only above their CMC,demonstrating that lipid removal is a micellar phenomenon. The primary lipid speciesinvolved were cholesterol and free fatty acids; little or no ceramide was extracted. Even atthe highest surfactant concentration used (2%), the amount of lipid material removedfrom the skin represented less than 7% of the total stratum corneum lipid, indicating thatdelipidization, or at least the removal of sizable amounts of stratum corneum lipid, is not aprimary mechanism for surfactant-induced irritation.Surfactant Binding to Stratum Corneum Proteins and Surfactant PenetrationOther studies also support a role for surfactant-protein interaction in the develop-ment of skin irritation. Imokawa et al. measured the specific rotation of bovine serum

48 Ertelalbumin (BSA) in the presence of surfactant to assess surfactant-protein interaction (69).Changes in the specific rotation were the result of conformational changes in BSA due tointeractions with surfactant. Studies conducted with a range of surfactants suggested thatboth ionic and hydrophobic interactions between the surfactant molecule and BSAdetermine the extent of denaturation. For example, the authors proposed a stepwiseinteraction between ionic surfactants and BSA that would ultimately lead to completedenaturation of the protein molecule. They reported an excellent correlation betweensurfactant-protein interaction, as determined by the BSA specific rotation method, andskin roughness measurements made with a circulation apparatus (69). Imokawa also used a technique based on indigo carmine dye displacement toexamine binding of surfactant to stratum corneum and reported that the skin rougheningeffects of surfactants are related to their ability to adsorb onto skin (11,51,70). Keratindenaturation was believed to follow surfactant adsorption, as in the BSA model, ultimatelyleading to skin roughness. Kawai and Imokawa later extended this model to explain thesensation of tightness (71). Their work showed that lipid removal from skin was related totightness induction; however, delipidization of the skin with ether did not result in markedtightness, and surfactants’ ability to remove lipids did not always parallel their potential toinduce tightness. There was, however, a strong correlation between surfactant adsorptionand tightness, and removal of skin surface lipids enhanced tightness upon subsequentsurfactant exposure. The authors proposed a model in which stratum corneum lipidextraction by surfactant is a necessary step to induce skin tightness, but is itself notsufficient to cause tightness. Prottey et al. analyzed tape strip or cup scrub samples collected from the backsof hands following immersion in surfactant solutions or water for acid phosphataseactivity (72). They found a decrease in enzyme activity following surfactant exposure,which was attributed to acid phosphatase denaturation and subsequent enzymaticinactivation resulting from surfactant interaction with the protein. The authors reported aninverse relationship between remaining acid phosphatase activity and hand dryness, andproposed this enzyme as a marker for monitoring interactions between surfactants andstratum corneum proteins. Ananthapadmanabhan et al. examined the binding behavior ofseveral surfactants to isolated guinea pig or human stratum corneum and reported that theextent of surfactant binding to stratum corneum correlated well with the irritationpotential predicted by in vitro and in vivo methods (73). Rhein et al. noted a time-dependent effect on stratum corneum swelling for SLS, which was attributed to theinteraction of surfactant with keratin and disruption of the keratin’s secondary and tertiarystructure (23). As noted earlier, swelling induced by this and other surfactants studiedexhibited a maximum for C12-C14 chain lengths. The swelling response was for themost part reversible except following exposure to soap concentrations O1% or prolonged(O24 hours) soap exposure. In a later review Rhein proposed a model by whichsurfactants interact with stratum corneum proteins that explains the observed swellingbehavior (74). This model incorporates ionic and hydrophobic binding interactions andaccounts for the effect of pH on both stratum corneum proteins and on anionic andcationic surfactants. Mukherjee et al. examined the interaction of pure anionic surfactants and cleansingbars based on anionic surfactants with isolated stratum corneum in vitro by measuringdisplacement of 1-anilinonaphthalene-8-sulfonic acid (ANS), a fluorescent probe knownto bind to stratum corneum proteins (75). Their results showed agreement betweensurfactants’ ability to displace ANS from stratum corneum samples and their potential toirritate skin as predicted by in vitro and in vivo methods, suggesting that surfactants’potential for binding to stratum corneum proteins determines their in-use skin

Personal Cleansing Products 49compatibility. Lo´pez et al. exposed porcine stratum corneum to solvent (chloroform-methanol) and nonionic surfactant (octyl glucoside) solutions (26). Solvent exposureremoved stratum corneum lipids but did not affect stratum corneum adhesion. In contrast,surfactant exposure preserved epidermal lipids; however, the lipid domain structure wasdisrupted. The surfactant also damaged corneocyte envelopes and caused corneocytedishesion, suggesting that surfactant-protein interaction plays a role in irritationdevelopment. Shukuwa et al. studied the impact of pure surfactants and 1% solutionsprepared from full formula bars on corneocyte disaggregation and swelling, and onmorphologic deterioration using stratum corneum disks isolated from forearm suctionblisters (76). The test materials’ tendency to induce corneocyte disaggregation did notcorrespond well with induced swelling behavior, e.g., SLS caused significant corneocytedisaggregation but only slightly greater swelling than water. The ranking of the test soapsbased on corneocyte swelling was consistent with irritation potential predicted by the soapchamber test (77), and the authors propose corneocyte swelling as an in vitro model forpredicting cleansers’ skin effects. One caution with the extrapolations made in several ofthese studies, however, is that the results generated under controlled exposure protocolsthat are used to “validate” the in vitro test data are themselves not always predictive ofconsumer experience with personal care products (9,78,79). Factors related to the personal cleanser use environment will also influencesurfactant-skin interactions. For example, Berardesca et al. examined irritation resultingfrom 5% SLS applied to the forearm at temperatures of 48C, 208C, and 408C (80).Measurements made after four days of once-daily treatment showed that barriercompromise and erythema production increased with temperature. Desquamation andreflectance (L*-value) also exhibited temperature-dependent behavior. Clarys et al.demonstrated a temperature-dependent increase in the irritant response to two dishwashing liquids over a much narrower temperature range: 378C and 408C (81). In both ofthese studies the increase in irritation with temperature was attributed to greater fluidity ofthe epidermal lipids and enhanced irritant penetration. Water hardness is another variable that varies in different use situations. Weshowed that water hardness impacts the absolute and relative skin compatibility ofcommercial personal cleansing products; soap-containing bars being more affected thansyndet-based cleansers (82). Fujiwara and coworkers conducted arm immersionexperiments using solutions of sodium laurate to examine the relationship betweenwater hardness (calcium ion) and calcium soap-deposition onto skin (83). They found thathardness in water increased soap deposition, driven especially by the presence of calciumin the rinse water. We extended this work using marketed cleansing bars tested under aconsumer-relevant arm wash protocol (84,85). A syndet bar, a triethanolamine (TEA)soap bar, and a sodium soap bar were tested. Washing was divided into two phases: awash phase and a rinse phase conducted with various combinations of deionized waterand hardened water (11 grains/gallon calcium). The syndet and TEA soap bars producedsignificantly less dryness and erythema than the sodium soap bar in the presence ofcalcium, but the difference between the products was negligible in deionized water(PR0.48 for inter-product comparisons). Greater deposition of calcium soap onto skinoccurred under the hard water conditions. As reported by Fujiwara, the rinse step wasparticularly important in determining the compatibility of these cleansing bars withthe skin. Although the specific interaction between the calcium soap and skin wasnot examined in either of the above studies, both provide an example of the rolesurfactant-skin interaction (i.e., calcium soap deposition) plays in determiningpersonal cleansers’ skin compatibility.

50 ErtelEffect of Personal Cleanser pHThe pH is thermodynamically defined as the negative logarithm of the hydrogen ionactivity in aqueous solution. The pH is often defined in more practical terms as thenegative logarithm of hydrogen ion concentration. Strictly speaking the hydrogen ionactivity and concentration are not identical but in dilute solution this is a reasonableassumption. Many publications refer to the pH of the skin, but since the skin is not anaqueous solution it clearly does not have a pH. When a wet pH electrode is placed onto theskin, water-soluble materials on the skin surface dissolve; the pH of this solution is what isactually measured. Also, personal cleansing products, and even the preparations madefrom them, are usually not dilute solutions. In what follows, “pH” is used to remainconsistent with the original references, even though in many instances what is measured ismore correctly called an apparent pH. Soap dissolves in water to form free fatty acid and strong base, e.g., sodium soapwill react with water to produce small quantities of free fatty acid and sodium hydroxide.As a result soap-based cleansing bars usually produce lather with a higher pH than doproducts based on synthetic detergents. The inherent tendency for soap-based cleansers toproduce lather/solutions with pH values in the range of about 9–10, coupled with theirgenerally poor skin compatibility, frequently forms the basis for a hypothesized cause-and-effect relationship between a cleanser’s pH and its potential to irritate the skin. At a fundamental level, Ananthapadmanabhan et al. reported a pH dependence forsodium lauroyl isethionate adsorption to skin, showing a minimum from pH 7 to pH 9,suggesting that pH might play a role in determining surfactant-skin interactions (73).However, van Scott and Lyon examined the potential for tap water with its pH adjustedfrom 4.5-10.5 or 1% solutions of various soap and detergent products to denature keratin(86). Water had no effect on the denaturation of defatted keratin or keratin plus 1% sebumover the pH range studied. Similarly, there was no significant relationship betweenproduct pH values, which ranged from pH 6.7 to pH 10.1, and denaturation of any of thekeratins studied. Robbins and Fernee reported no significant in vitro swelling changewhen stratum corneum was exposed to water with pH values adjusted to between 3 and 9(49). They also examined the effect of pH on stratum corneum swelling response to threedifferent surfactants: SLS, linear alkylbenzene sulfonate (LAS), or dodecyl trimethylammonium bromide (DTAB). SLS and LAS are anionic; DTAB is cationic. Decreasingthe pH value from 9 to 3 reduced the swelling responses for SLS and LAS. However, theswelling response was unchanged or increased when the pH was lowered from pH 9 to 6,a range that is relevant to many personal cleansers. The swelling response for DTABincreased when the pH was lowered from pH 9 to pH 3. Dugard and Schuepleinobserved that buffer in the pH range 3.0–9.5 produced no increase in stratum corneumpermeability in the absence of surfactant (48). These authors found no change in therate of permeability increase as a function of pH for the three surfactants studied: sodiumdodecanoate (pH range 7.5-9.5), sodium dodecyl sulphate (pH range 5.0–9.0), andsodium dodecylamine hydrochloride (pH range 3.0–7.5). Bettley and Donoghue alsoperformed water permeability experiments using isolated human stratum corneum (87).Their work showed that water, pH 10 buffer, and “Teepol” (28 alkyl sulphate detergent) atits natural pH or buffered to pH 10 had a minimal effect on membrane permeability.However, membrane permeability was markedly increased by exposure to 1% or 5%solutions of sodium palmitate. Membrane permeability gradually recovered uponremoval of the soap, which as mentioned earlier argues against epidermal lipid extractionas a mechanism of irritation. The authors instead suggested that irritancy is related to asurfactant’s ability to penetrate the stratum corneum.

Personal Cleansing Products 51 In vivo studies show a similar trend. Bettley and Donoghue also conducted patchtesting with toilet soap and TEA soap (88). The TEA soap was less irritating than the toiletsoap even though the solutions prepared from each product had a comparable pH value.This may reflect a counterion effect; Rhein et al. also reported reduction in swellingresponse, i.e., a reduced potential for skin irritation, from TEA salts of surfactants (23).Frosch reported the relative skin irritation potential of 23 cleansing bars marketed in theUnited States and Germany determined using a soap chamber test (9). These productsrepresented a range of surfactant compositions and covered a pH range from 5.4 to 10.7.The published results do not support a cause-and-effect relationship between a cleanser’spotential to irritate skin and its pH value. Van der Valk et al. conducted a similarexperiment and assessed the skin compatibility of 13 marketed personal cleansers (89).Irritation from 2% aqueous solutions of the products applied to subjects’ volar forearms onstratum corneum barrier function was assessed by evaporimetry. All of the cleanserssignificantly increased transepidermal water loss (TEWL) compared to control, but theresults showed no relationship between cleanser pH and irritation TEWL. In a similarstudy, van der Valk conducted patch testing with pure surfactant solutions on unaffectedforearm skin of healthy subjects and subjects with irritant contact dermatitis or atopicdermatitis (90). The results again did not support a relationship between surfactant pH andirritation. Van Ketel et al. examined the irritation potential of several liquid hand cleansersspanning a pH range from 3.5 to 10.0 by applying 8% aqueous solutions of each productunder patch (91). These authors concluded that the pH value of a cleanser is not a usefulparameter for predicting its irritancy. Murahata et al. used a modified soap chamber test tostudy the skin irritation from a series of buffer solutions covering a pH range from 4.0 to10.5, 8% (w/w) detergent solutions prepared from marketed syndet and soap bars, and 8%solutions prepared from altered soap base in which low molecular weight free fatty acidswere added to the bars during processing (92). The buffers altered the skin surface pH butdid not produce irritation. Likewise, the cleanser preparations changed the skin surfacepH, but there was no correlation between pH and irritancy. One seeming exception is apatch test study by Baranda et al. conducted with 27 cleansing bars (tested as 8%emulsions), two undiluted liquid cleansers, and water (93). These authors reported asignificant correlation between irritation and cleanser pH. However, the coefficient ofdetermination calculated from the reported results is r2Z0.244. Thus, only about 25% ofthe variability in irritation that was observed in the study is explained by differences incleanser pH. Taken together, these in vitro and in vivo results suggest that the skin irritationpotential of a personal cleansing product is primarily driven by differences in the chemicaland physical properties of its component surfactants rather than by the pH value. However,personal cleansing products could affect skin condition in other ways. For example,Ananthapadmanabhan et al. conducted experiments to study the effect of pH on thephysical properties of the stratum corneum (94). A series of in vitro experiments wasconducted using Yucatan piglet skin as a model substrate. Sections of isolated stratumcorneum were placed into the wells of microtiter plates and buffer or buffered surfactantsolutions were added. Samples intended for swelling analysis (optical coherencetomography) were soaked for five or 21 hours at 378C. Samples intended for lipid fluidityanalysis were soaked for about 16 hours at room temperature. These experiments showedan increase in stratum corneum swelling at pH 10 compared to the other pH values; thiseffect was increased by the addition of surfactant. Lipid fluidity decreased at pH 10relative to the other pH values; surfactant again increased this effect. The authors concludethat there is a direct effect of pH on stratum corneum protein swelling and lipid rigidity;both are greater at pH 10 than at pH 6.5 or pH 4.

52 Ertel Sznitowska et al. studied the effect of pH on the lipoidal route of stratum corneumpenetration (95). Suspensions of two model compounds, hydrocortisone and testosterone,were prepared at pH values ranging from 2.0 to 10.0 (hydrocortisone) and from 1.0 to 12.0(testosterone). Penetration was studied using full thickness cadaver skin mounted in flow-through diffusion cells. The studies were conducted with untreated skin and with skinpretreated with methanol-chloroform (11) or Azone, a material that alters stratum corneumlipid organization. The results from the experiments conducted with intact skin showed nosignificant effect of pH on the penetration of the model compounds in the range from1.0 to 11.0. Removal of skin lipids with methanol-chloroform increased penetration, as didpretreatment with Azone. However, no significant pH effect on penetration was found foreither pre-treatment method. A follow-up study was conducted to examine the effect of pHon lipid and free fatty acid extraction, lipid packing, and keratin conformation (96).Human stratum corneum samples were shaken for 24 hours with buffers ranging from pH1 to 12. Buffer pH had no large impact on the amount of sterols or ceramides extracted, butfree fatty acid extraction was pH-dependent, being maximal at pH 11 and 12. Differentialscanning calorimetry showed some disordering of lipid packing in alkaline-treatedsamples. The changes were not instantaneous and required O1 hour exposure, becomingmaximal after about eight hours. Fourier transform infrared spectroscopic analysis showedthat the stratum corneum was largely unaffected by exposure to the buffer solutions, withno major changes to lipid packing motifs. Keratin conformation also appeared to belargely unaffected by buffer exposure, though there was some evidence that intracellularkeratin took on a more ordered conformation at alkaline pH values. These authorsconcluded that the stratum corneum is remarkably resilient to extended exposure to bothhighly acidic and highly alkaline environments. In adults the skin surface is normally slightly acidic, giving rise to the concept ofthe so-called “acid mantle.” Healthy adult skin exhibits a very good ability to recoverfrom pH changes even when challenged with alkaline solutions having a pH valuearound 13 (97). Literature indicates that personal cleansing products can transiently affectthe skin surface pH in both adults and infants. As was mentioned previously, Gfatter et al.examined the effect of washing infants’ skin with synthetic detergent and soap-basedcleansing products (63). Washes were conducted with water (pH 7.9–8.2), a syntheticdetergent bar (pH 5.5), a liquid synthetic detergent cleanser (pH 5.5), or a soap bar(pH 9.5). Skin surface pH measurements were made 10 minutes after washing. All washesincreased the skin surface pH, with the water control producing the smallest increase(C0.20 units). Both synthetic detergent cleansers increased the skin surface pH byC0.29 units, significantly greater than the control. The soap produced the greatest skinsurface pH increase, C0.45 units. This increase was significantly greater than thatproduced by the control or the synthetic detergent cleansers. Changes in the skin surface pH resulting from washing with personal cleansingproducts can persist for longer periods. Bechor et al. examined the time course of changesin skin surface pH following controlled washing (62). Adult volunteers washed their facesfor 30 seconds with one of 41 cleansing products covering the surfactant compositionrange from soap to synthetic. The skin surface pH was measured at defined times for up to200 minutes after washing. The results from this study show that cleanser-inducedelevation of skin surface pH persisted for as long as 94 minutes after washing. Korting et al. conducted eight-week crossover studies to demonstrate the potentialfor personal cleansers to alter skin surface pH. Liquid syndet cleansing preparationsadjusted to pH 5.5 or 8.5 were used as test products. Subjects washed sites on theirforehead and the ventral forearm twice daily for one minute. One cleanser was used for thefirst four weeks, the other for the remaining four weeks. Skin parameters were assessed at

Personal Cleansing Products 53various times during each period, at least six hours after the previous wash. Both studiesshowed that washing with the pH 8.5 product resulted in a higher skin surface pH thanwashing with the pH 5.5 product. The cleansers produced no consistent difference inTEWL or skin surface roughness (98) but did influence the skin’s microflora (99). Nocleanser effect was observed on coagulase-negative Staphylococci populations, butPropionibacteria counts were increased when the cleanser at pH 8.5 was used. A similareffect on bacterial populations was demonstrated in a crossover study in which subjectsused a full syndet bar or a soap bar for cleansing (100). The authors report that overall theskin surface pH was higher by 0.3 units and that Propionibacteria counts were elevatedduring the period of soap washing. These products were later compared in a three-monthuse study conducted among adolescents and young adults with acne (101). Fewerinflammatory lesions were observed in the group using the full syndet bar product. Theauthors extrapolate results from the earlier study conducted with liquid cleansers to ruleout an effect due to differences in cleanser composition. Alteration of skin surface pH might also effect more fundamental changes in thestratum corneum. For example, Fluhr et al. examined the impact of pH on stratumcorneum acidification and integrity in a murine model (102). The backs and flanks ofhairless mice were treated twice daily for three days with secretory phospholipaseinhibitor (bromphenacylbromide or 1-hexadecyl-3-trifluoroethylglycero-sn-2-phospho-methanol) or vehicle control. Free fatty acid (palmitic, stearic, or linoleic acid) was co-applied to some animals. The effect of pH was examined by immersing flanks ofanesthetized mice in bffer solution (pH 5.5 or pH 7.4) for three hours. The authorsfound that treatment with secretory phospholipase inhibitor increased skin surface pHand decreased barrier function (TEWL) and integrity (tape stripping), demonstrating arole for phospholipid metabolism in both these processes. Co-application of free fattyacid or exposure to pH 5.5 buffer normalized these effects. However, exposure to pH7.4 buffer alone produced barrier alterations similar to the inhibitors, and exacerbatedbarrier effects in inhibitor-treated mice. Barel et al. compared the skin effects resulting from use of a syndet bar (pH of 2%solutionZ6.9) or a soap bar (pH of 2% solutionZ9.6) in a blinded home-use test (103).Subjects washed their entire body with the assigned product at least once daily for a periodof 10 weeks. Skin surface pH, TEWL, redness (chromameter a*-value) and stratumcorneum hydration were measured at baseline and endpoint on the hand, forearm, upperarm, neck, and leg. The skin surface pH after using with soap was significantly higher thanafter using the syndet bar on the upper arm, neck, and leg. The difference between the meanpH values measured at study end was %0.4 unit, and the mean skin surface pH was in allcases %6.0. None of the other instrumental measurements showed a difference between thetwo treatment groups, and expert evaluation of dryness and erythema showed that daily useof the products did not induce visible skin changes. Subjective ratings of overall irritation/mildness showed a trend favoring the syndet bar at the end of the 10-week use period, but itseems likely based on the earlier discussion (e.g., the work of Imokawa) that this was due toa factor other than the product pH. The results of this study again highlight the difficulty ofpredicting in-use experience with controlled exposure models.Other Ingredient ConsiderationsSurfactants determine many of the actions personal cleansing products have onthe skin, but other ingredients can also have an effect. For example, certain polymersare used in personal cleansing products as formulation aids, to alter skin feel, or aresubstantive on skin, providing skin-protective properties (104–106). Glycerin is a

54 Ertelhumectant ingredient used in many leave-on moisturizers that can also facilitatedesmosome degradation (107). But being water soluble, it is difficult to deposit aneffective level of glycerin on the skin in the rinse-off context that applies to mostpersonal cleansers. However, glycerin can have other effects when used in personalcleansers. For example, Dahlgren et al. showed that incorporating glycerin into a soapbar improved the product’s perceived moisturization benefit even though clinicalendpoints are unchanged (40). As was mentioned earlier, some personal cleansers cannow deposit effective levels of petrolatum onto the skin during use. These newpetrolatum-depositing cleansers can produce marked improvement in dry skincondition; the prototype hand wash products described earlier are an example. Beyondthis, there is evidence that topically applied petrolatum permeates the stratum corneumand improves barrier function (108), and that petrolatum deposited from a body washcan improve lipid bilayer structure in the outer stratum corneum (109) and improvestratum corneum barrier function (110). Ancillary ingredients can also negatively impact skin condition. Fragrances arewidely used in personal cleansing products. These materials often serve a functional role,covering the base odor of other formula components, and enhance product aesthetics andthe cleansing experience. However, fragrances are frequently implicated as a cause ofcontact dermatitis and as a potential triggering factor in disease conditions such as atopicdermatitis. Since manufacturers rarely identify specific fragrances or fragrancecomponents, identifying an offending agent is difficult. Using a cleanser that is labeledas “unscented” or “fragrance-free” does not guarantee that fragrance will not be an issue.Fragrance-free, for example, implies that a product has no perceptible odor, but theseproducts can contain a low level of fragrance, smaller than the amount needed to imparta noticeable scent, to mask the odor from raw materials (111). A complicating factor isthat some fragrance-free products contain ingredients such as preservatives or natural oilsthat provide scent as a secondary function, but that can also be a covert source ofdermatitis (112,113).SOME PRACTICAL CONSIDERATIONS WHEN CHOOSINGA PERSONAL CLEANSERDermatologists and consumers are faced with a variety of choices when recommending orselecting a personal cleansing product. The previous sections of this chapter reviewedsome of the available literature that examines factors governing the interaction betweensurfactants and the skin from a theoretical standpoint. While many of the studies presentedwere not conducted under in-use conditions, and some of the conclusions differ, theydemonstrate that personal cleansers can impact skin in a number of ways and produce arange of skin effects. What does this mean from a practical standpoint?Facial CleansingFacial cleansing is a primary need for most individuals. Apart from being a key interfacefor social interaction (“put your best face forward”), the face is a prime location for theaccumulation of endogenous and exogenous soils. Sebaceous gland size and density aregreatest on the face, upper back, and chest. The secretions from these glands, inconjunction with applied cosmetic products, help create a hydrolipid film on the skinsurface that can effectively trap environmental pollutants (e.g., dust, and cigarette smoke).But while the accumulation of soil necessitates effective facial cleansing there are also

Personal Cleansing Products 55considerations that argue against excessive cleansing. For example, the facial stratumcorneum has fewer cell layers than other parts of the body, except for the genitalia (114).A thinner stratum corneum barrier could increase susceptibility to irritation. The face is asite commonly associated with “sensitive skin,” which by definition is based on subjectiveirritation and excludes individuals with pre-existing skin disease (115). This condition,which is estimated to affect about 50% of females, is reportedly associated with a defectivestratum corneum barrier and to improve with a controlled skin care regimen (116). Facialskin is also moveable and rich in sensory nerves, so sensations such as tightness or tautnessare more easily noticed. A retrospective study conducted by de Groot showed that the facefar exceeded other body sites as an area for adverse effects from cosmetics among bothfemales and males surveyed (117). Both sexes identified cleansers (soaps) as the agentsmost often responsible for these effects. Bars are a convenient and popular facial cleansing option. These cleansers areavailable in a wide range of compositions. Traditional soaps provide effective cleansingand results presented previously indicate that with normal washing even soap bars do notcompletely strip the hydrolipid layer from the skin surface. However, soap may still induceor predispose the skin to sensations of tightness. Cleansing in adolescents or acne-pronepopulations requires special consideration. Acne is not caused by dirt on the skin surface,but regular cleansing is important. While soap is an effective cleanser, some evidencesuggests that soap washing may predispose the skin to acne (101). More importantly, soapcan irritate already inflamed acne lesions. Washing with a mild cleanser and warm water isrecommended (118). Exfoliating agents help to physically remove dirt and cellular debris from thesurface of the skin, provide a rejuvenated look, stimulate the skin through a massageeffect, and smooth the skin surface (119). The latter can increase the cleansing efficacy ofpersonal cleansers. Exfoliating agents take several forms. There are exfoliatingimplements; those intended for use on the face are often made of a non-woven polyestermaterial and are used to apply a cleansing product to the skin; some incorporate a cleanserthat is activated by wetting. Proper use is important to avoid damaging the stratumcorneum barrier, which will increase the likelihood of cleanser irritation, andmanufacturers’ directions for use should be followed. Some bar and liquid cleansersincorporate particles intended to act as exfoliating agents. Materials such as polyethylene,silica, various ground seeds (e.g., apricot, almond, or walnut seed), jojoba esters, loofapowder, cross-linked polymethacrylate, or calcium carbonate are used for these beads.The effectiveness of these exfoliating products and their potential to impact the skin isdependent on the concentration of the exfoliating agent and the properties of the particularagent used (119–121). As with exfoliating implements, manufacturers’ directions for useshould be followed to avoid damaging the skin when using these products. Cleansing cloths are a relatively new introduction into the personal cleansingmarket. These cloths are available in dry and wet forms. The former, like the cleansingsponges mentioned above, incorporate cleansers that are activated when the cloth is wet.The textured surface of these cloths provides exfoliation and, in conjunction with theintegrated surfactants, effective cleansing (122). These cloths can incorporate additionalagents, such as petrolatum, that are transferred to the skin during use to provide skinbenefits such as improved hydration. A four-week study conducted among a subjectpopulation with stage 1 or stage 2 rosacea showed good in-use tolerance for a dry latheringfacial cleansing cloth with petrolatum (123). Thus, these facial cleansing cloths mayprovide a good cleansing option for individuals with sensitive skin. Astringents and toners are sometimes used after cleansing to remove soap residue orremaining oil. These products may contain water, alcohol, propylene glycol, witch hazel,

56 Ertelor salicylic acid (124). Astringents and toners can dry the skin and leave it with a tightfeeling, a cleansing endpoint that is considered desirable by some consumers. However,Wortzman reported that using a toner after cleansing increases irritation (125), either by adirect effect for toners with high alcohol content, or paradoxically for toners with moderateto low alcohol content. Propylene glycol that is found in some products is a mild irritantthat may cause stinging in some individuals, and is also a potential contact allergen.Body CleansingThe number of cleansing forms available for use on the body is more limited than for theface, but the range of surfactants used in these products is no less varied. Soap is a cleanserused since antiquity, and it remains a popular cleanser despite much negative press and theintroduction of syndets. In fact, soap is an effective, economical, and acceptable cleansingalternative for many people. The large number of soap-based products sold by large-scaleand specialty manufacturers attests to this, and results from studies like the one conducedby Barel et al. suggest its effects on healthy skin may be limited in normal use (103). Butnumerous controlled application studies demonstrate the potential for soap to negativelyimpact skin and for this reason prudence dictates choosing an alternative cleanser incertain situations. For example, while some studies suggest that soap is well-tolerated inand may actually benefit conditions such as atopic dermatitis (126,127), there are betteroptions for cleansing diseased skin. For patients who prefer a bar form, syndet cleansingbars provide good cleansing and are usually well-tolerated. Those who prefer a liquidcleanser form can benefit from using one of the newer body wash technologies, such asa product that will deposit petrolatum on the skin during use (128). An added benefitto using a body wash product is that they are applied with a polyethylene mesh“cleansing puff.” This type of implement provides a mild exfoliation benefit (129) that canhelp remove the dry skin that accompanies many dermatoses. There are situations were personal cleanser choice can be important, even forindividuals with healthy skin. As mentioned above, the stratum corneum is thinnest onthe genitalia (114), and the presence of a thin barrier in this intertriginous area seemsa formula for personal cleanser issues. Cleanser irritation of the external genitalia is agreater issue for females than for males (130), and cleansing residue may also be asource of discomfort in females (131). In both sexes, cleansing with water only isadvised, or if a cleanser must be used, a syndet-based product followed by thoroughrinsing (130). Aged skin also presents a cleansing challenge. The skin undergoes many changeswith age, some of which can impact the response to personal cleansing products: themicrovasculature that supplies the epidermis degrades and circulation decreases(132,133), the stratum corneum lipid content decreases (134), the stratum corneumturnover rate decreases (135), and the skin becomes drier and rougher (136). RestingTEWL values are lower in aged skin than in young skin, (134,137) which is usuallyassociated with better barrier function. Aged skin does show a decreased response toirritants (133,137), but it also shows altered permeability to a variety of topically appliedmaterials, suggesting that the decreased irritation reflects an attenuated inflammatoryresponse rather than an improved barrier. Once perturbed, barrier recovery occurs moreslowly in old than in young skin (134). Cleanser choice can impact the elderly in a number of ways. The natural decrease instratum corneum lipids and increased dryness can predispose aged skin to the dryingeffects of cleansers. Apart from its affect on skin appearance, increased dryness can worsenpruritus that commonly accompanies aging, which can lead to scratching, excoriation, and

Personal Cleansing Products 57infection (138). The loss of hydration and elasticity also makes the stratum corneum moresusceptible to mechanical damage; a study conducted among residents of a long-term carefacility showed an increased incidence of skin tears during periods when a non-emollientsoap was used, compared to periods of emollient soap use (139). Regular skin cleansingremains important, but decreasing bathing or showering frequency and using a non-soapcleanser is recommended (140,141). Emollient cleansers can help, but their benefit must bebalanced with the potential for slipping in the tub or shower (140). Since water temperatureimpacts skin-cleanser interactions (80,81), bathing in warm rather than hot water can helpreduce drying and irritation. If a cleanser is used, thorough rinsing is important to assurethat the cleanser residue is removed from the furrowed skin surface (142). Race can also be a consideration when recommending or choosing a personalcleansing product. There are numerous published works describing physiologicaldifferences between different racial groups and controlled exposure studies that examinedifferences in irritant susceptibility (143–149), but the practical implications of thereported results in terms of susceptibility to in-use irritation remain unclear. Regardless ofwhether there are differences in the magnitude of the physiological response to personalcleansing products, the potential to induce some level of dryness or irritation undoubtedlyexists for all skin types and this could have different implications for different groups. For Forearm Skin Dryness and Ashiness Parameters Scored on A 0-3 Scale 0.0 Syndet Bar −0.5 Body WashMean Change +− SEM−1.0 Improvement −1.5 P<0.01 P<0.01 0.0 Dryness Ashiness Leg Skin Dryness and Ashiness Parameters Scored on A 0-3 Scale Syndet Bar Body WashMean Change +− SEM −0.5 −1.0 Improvement P<0.01 P<0.01 −1.5 Dryness AshinessFigure 7 Change in dryness and ashiness on African American subjects’ arms (top) and legs(bottom) assessed by the dermatologist investigator during a four-week home use study.

58 Ertelexample, dry skin flakes are more visible when viewed against a dark background and lightscattered by dry skin gives dark skin a dull, gray, “ashy” appearance, a condition that isconsidered undesirable or even disturbing to individuals with skin of color. Moisturizersare often used to mitigate skin dryness and the ashy appearance, but proper cleanserselection is also important to help minimize dry skin production. To demonstrate the potential impact of personal cleanser choice on dryness andashiness, we conducted a blinded, parallel group study among African American womenwith self-perceived dry/ashy skin, especially on their legs (150). Approximately half of the83 women enrolled were randomly assigned to use a petrolatum-depositing body wash fordaily showering for four weeks, and the remainder of the subjects were assigned to use asyndet bar. Moisturizer use was prohibited to eliminate this variable as a potentialconfounding effect and tub bathing was restricted. The dermatologist investigator scoreddryness and ashiness on the lateral surface of subjects’ arms and legs at baseline and study Based on the appearance of my Agree I am satisfied with the Agree leg skin, I feel good about myself appearance of my leg skin 3 3 Syndet Bar Syndet Bar Body Wash 2 Body Wash 2Mean Rating–+SEM 11 Mean Rating–+SEM 00 –1 –1 Disagree Disagree–2 –2 p = 0.48 p < 0.01 p < 0.01 Week 4 p = 0.55 Week 4–3 Baseline –3 Baseline I am confident of letting Agree others see my legs 3 Syndet Bar Body Wash 2 Mean Rating–+SEM 1 0 –1 Disagree –2 p < 0.01 p = 0.59 Week 4 –3 BaselineFigure 8 African American subjects’ responses to a psychosocial questionnaire administered atbaseline and after four weeks of using a petrolatum-depositing body wash or a syndet bar. Theresponses from subjects who used the body wash showed a marked improvement over the course ofthe study.

Personal Cleansing Products 59end. Subjects also completed a brief psychosocial questionnaire at these times to assess theimpact of their dry/ashy leg skin on self-image. The dermatologist’s evaluations showedthat both personal cleansing products reduced dryness and ashiness over the course oftreatment; a significantly greater reduction was observed for those subjects using thepetrolatum-depositing body wash (Fig. 7). Weather conditions were reasonably consistentduring the study, but a baseline habits and practices questionnaire showed that a highpercentage of the enrolled subjects used a soap or combo bar (soapCsyndet) as their usualcleanser. Since the study did not include a pretreatment period, some improvement indryness and ashiness was expected as a result of switching to a less drying (i.e., non-soap)cleanser. While the test cleansers had a positive impact on these clinical parameters, aneven more striking effect was shown on subjects’ self-image (Fig. 8). Mean responses tothese questions were relatively poor at baseline. Responses for subjects using the syndetbar exhibited a shift toward neutrality over the course of the study. However, responses forsubjects who used the petrolatum-depositing body wash exhibited a strong positive shift,demonstrating that modern personal cleansing products can have a much broader impactthan simply providing a means to remove soil from the skin.REFERENCES 1. Fellingham C. Soaps that fight skin problems. Glamour 1997; September:135. 2. Dyett L. The super cleansers. Glamour 1998; August:192–197. 3. Kintish L. Soap: it’s not just for cleansing anymore. Soap/Cosmet/Chem Spec 1998; October:50–54. 4. Bronner A. The energizing shower. An alternative to the morning cup of coffee. Self 1998; August:145–146. 5. Kuehl BL, Fyfe KS, Shear NH. Cutaneous cleansers. Skin Ther Lett 2003; 8:1–4. 6. Wolf R. Has mildness replaced cleanliness next to godliness? Dermatology 1994; 189:217–221. 7. Weber G. A new method for measuring the skin cleansing effect of soaps and detergents. Acta Derm Venereol (Stockh) 1987; 134:33–34. 8. Schrader K, Rohr M. Methods for measuring the skin-cleansing effect of surfactants in comparison with skin roughness and compatibility. Clin Dermatol 1996; 14:57–65. 9. Frosch PJ. Irritancy of soaps and detergent bars. In: Frost P, Horwitz S, eds. Principles of Cosmetics for the Dermatologist. St. Louis: CV Mosby, 1982:1–12. 10. Wolf R, Friedman M. Measurement of the skin-cleaning effects of soaps. Int J Dermatol 1996; 35:598–600. 11. Imokawa G. Comparative study on the mechanism of irritation by sulfate and phosphate type of anionic surfactants. J Soc Cosmet Chem 1980; 31:45–66. 12. Lockhart L, Lazer W. A novel technique for assessing cleansing efficacy, 53rd Annual Meeting of the American Academy of Dermatololgy, New Orleans, LA, 1995, Schaumburg, IL: American Academy of Dermatology. 13. Sauermann G, Doerschner A, Hoppe U, et al. Comparative study of skin care efficacy and in- use properties of soap and surfactant bars. J Soc Cosmet Chem 1986; 37:309–327. 14. Puvvada S, Post AJ, Subramanyan KK, et al. (inventors), Unilever Home & Personal Care U.S.A. (assignee), Exfoliating and moisturizing toilet bar, U.S. Patent 6,764,991, July 20, 2004. 15. Mills OH, Rizer RL, DeRosa A. Using sugar surfactants for cleansing and soothing sensitive skin. 63rd Annual Meeting of the American Academy of Dermatology, New Orleans, LA, Feb 18–22, 2005, Schaumburg, IL: American Academy of Dermatology. 16. Frosch PJ, Kligman AM. The chamber-scarification test for irritancy. Contact Dermatitis 1976; 2:314–324.

60 Ertel 17. Routh HB, Bhowmik KR, Parish LC, et al. Soaps: from the Phoenicians to the 20th century— a historical review. Clin Dermatol 1996; 14:3–6. 18. Subramanyan K, Johnson AW, Leyden J. Skin care regimen with emollients benefits patients with sensitive facial skin. J Am Acad Dermatol 2005; 52:P72. 19. Msika P, Piccardi N, Choulot JC, et al. Washing oil: a new concept for the management of atopic dermatitis., 63rd Annual Meeting of the American Academy of Dermatology, New Orleans, LA, February 18–22, 2005, Schaumburg, IL: American Academy of Dermatology. 20. Lukacovic MF, Dunlap FE, Michaels SE, et al. Forearm wash test to evaluate the clinical mildness of cleansing products. J Soc Cosmet Chem 1988; 39:355–366. 21. Accessed June, 2005 at http://www.firp.ula.ve/cuadernos/E300A.pdf. 22. Accessed July, 2005 at http://www.kcpc.usyd.edu.au/discovery/9.5.5-short/9.5.5_anionic.html. 23. Rhein LD, Robbins CR, Fernee K, et al. Surfactant structure effects on swelling of isolated human stratum corneum. J Soc Cosmet Chem 1986; 37:125–139. 24. Speiss E. Raw materials. In: Williams DF, Schmitt WH, eds. Chemistry and Technology of the Cosmetics and Toiletries Industry. London: Blackie Academic & Professional, 1996:1–35. 25. Simon P, Veyrat S, Piquemal P, et al. Surfactants and the skin. The revival of sugar esters. Cosmet Toilet 1998; 113:69–72. 26. Lo´pez O, Walther P, Co´cera M, et al. Structural modifications in the stratum corneum by effect of different solubilizing agents: a study based on high-resolution low-temperature scanning electron microscopy. Skin Pharmacol Appl Skin Physiol 2000; 13:265–272. 27. Thau P. Surfactants for skin cleansers. In: Rieger MM, ed. Surfactants in Cosmetics, Vol. 16. New York: Marcel Dekker, Inc., 1985:349–376. 28. Dom´ınguez JG, Balaguer F, Parra JL, et al. The inhibitory effect of some amphoteric surfactants on the irritation potential of alkylsulphates. Int J Cosmet Sci 1981; 3:57–68. 29. de Groot AC, van der Walle HB, Weyland JW. Contact allergy to cocamidylpropyl betaine. Contact Dermatitis 1995; 33:419–422. 30. Fowler JF, Jr. Cocamidopropyl betaine. Dermatitis 2004; 15:3–4. 31. Fowler JF, Jr., Zug KM, Taylor JS, et al. Allergy to cocamidopropyl betaine and amidoamine in North America. Dermatitis 2004; 15:5–6. 32. Moreau L, Sasseville D. Allergic contact dermatitis from cocamidopropyl betaine, cocamidoamine, 3-(dimethylamino)propylamine, and oleamidopropyl dimethylamine: co-reactions or cross-reactions? Dermatitis 2004; 15:146–149. 33. Fowler JF, Fowler LM, Junter JE. Allergy to cocamidopropyl betaine may be due to amidoamine: a patch test and product use study. Contact Dermatitis 1997; 37:276–281. 34. Vilaplana J, Mascaro JM, Trullas C, et al. Human irritant response to different qualities and concentrations of cocoamidopropylbetaines: a possible model of paradoxical irritant response. Contact Dermatitis 1992; 26:289–294. 35. Wood TE. Regulatory considerations for soap products in the U.S.A. Cosmet Toiletries 1989; 104:75–79. 36. Hopkins H. All that lathers is not soap. FDA Consum 1979; 13:12–13. 37. Bachrach EE. Federal regulation of soap products. Soap Cosmet Chem Spec 1981; 57:35–38. See also page 64. 38. Kuntom A, Kifli H. Properties of soaps derived from distilled palm stearin and palm kernel fatty acids. J Surfact Detergent 1998; 1:329–334. 39. Friedman M, Wolf R. Chemistry of soaps and detergents: various types of commercial products and their ingredients. Clin Dermatol 1996; 14:7–13. 40. Dahlgren RM, Lukacovic MF, Michaels SE, et al. Effects of bar soap constituents on product mildness. Proceedings of the Second World Conference on Detergents, Montreux, Switzerland, October 1986, Champaign, IL. Am Oil Chem Soc 1987:127–134. 41. Blank IH. Action of soap on skin. Arch Derm Syph 1939; 39:811–824. 42. Kellum RE. Acne vulgaris. Studies in pathogenesis: relative irritancy of free fatty acids from C12 to C16. Arch Derm 1968; 97:722–726.

Personal Cleansing Products 6143. Stillman MA, Maibach HI, Shalita AR. Relative irritancy of free fatty acids of different chain length. Contact Dermatitis 1975; 1:65–69.44. Garc´ıa-Dom´ınguez J, Parra JL, Infante MR, et al. A new approach to the theory of adsorption and permeability of surfactants on keratinic proteins: the specific behaviour of certain hydrophobic chains. J Soc Cosmet Chem 1977; 28:165–182.45. Kefauver PJ, Tollens FR, Syfert SW. (inventors), The Procter & Gamble Company (assignee), Personal cleansing bar with tailored fatty acid soap, U.S. Patent 5,540,852, July 30, 1996.46. Tollens FR, Kefauver PJ, Syfert SW. (inventors), The Procter & Gamble Company (assignee), Personal cleansing bar with tailored base soaps and mixed with counterions for improved mildness and processability without lather negatives, U.S. Patent 5,387,362, Feb 7, 1995.47. Kligman AM, Wooding WM. A method for the measurement and evaluation of irritants on human skin. J Invest Dermatol 1967; 49:78–94.48. Dugard PH, Scheuplein RJ. Effects of ionic surfactants on the permeability of human epidermis: an electrometric study. J Invest Dermatol 1973; 60:263–269.49. Robbins CR, Fernee KM. Some observations on the swelling of human epidermal membrane. J Soc Cosmet Chem 1983; 34:21–34.50. Imokawa G, Sumura K, Katsumi M. Study on skin roughness caused by surfactants: I. A new method in vivo for evaluation of skin roughness. J Am Oil Chem Soc 1975; 52:479–483.51. Imokawa G, Takeuchi T. Surfactants and skin-roughness. Cosmet Toilet 1976; 91:32–46.52. White IR. Skin tolerance to cleansing agents. Wien Med Wochenschr Suppl 1990; 108:13–16.53. Brod J. Characterization and physiological role of epidermal lipids. Int J Dermatol 1991; 30:84–90.54. Grubauer G, Feingold KR, Harris RM, et al. Lipid content and lipid type as determinants of the epidermal permeability barrier. J Lipid Res 1989; 30:89–96.55. Wertz PW. Lipids and barrier function of the skin. Acta Derm Venereol Suppl (Stockh) 2000; 208:7–11.56. Pilgram GS, Vissers DC, van der Meulen H, et al. Aberrant lipid organization in stratum corneum of patients with atopic dermatitis and lamellar ichthyosis. J Invest Dermatol 2001; 117:710–717.57. Melnik B, Hollmann J, Hofmann U, et al. Lipid composition of outer stratum corneum and nails in atopic and control subjects. Arch Dermatol Res 1990; 282:549–551.58. di Nardo A, Sugino K, Wertz P, et al. Sodium lauryl sulfate (SLS) induced irritant contact dermatitis: a correlation study between ceramides and in vivo parameters of irritation. Contact Dermatitis 1996; 35:86–91.59. Visscher MO, Tolia GT, Wickett RR, et al. Effect of soaking and natural moisturizing factor on stratum corneum water-handling properties. J Cosmet Sci 2003; 54:289–300.60. Kirk JF. Effect of hand washing on skin lipid removal. Acta Derm Venereol (Stockh) 1966; 46:24–68.61. Morganti P. Natural soap and syndet bars. Cosmet Toilet 1995; 110:89–97.62. Bechor R, Zlotogorski A, Dikstein S. Effect of soaps and detergents on the pH and casual lipid levels of the skin surface. J Appl Cosmetol 1988; 6:123–128.63. Gfatter R, Hackl P, Braun F. Effects of soap and detergents on skin surface pH, stratum corneum hydration and fat content in infants. Dermatology 1997; 195:258–262.64. Imokawa G, Akasaki S, Minematsu Y, et al. Importance of intercellular lipids in water- retention properties of the stratum corneum: induction and recovery study of surfactant dry skin. Arch Derm Res 1989; 281:45–51.65. Rawlings AV, Watkinson A, Rogers J, et al. Abnormalities in stratum corneum structure, lipid composition, and desmosome degradation in soap-induced winter xerosis. J Soc Cosmet Chem 1994; 45:203–220.66. Fulmer AW, Kramer GJ. Stratum corneum lipid abnormalities in surfactant-induced dry scaly skin. J Invest Dermatol 1986; 86:598–602.67. Scheuplein R, Ross L. Effects of surfactants and solvents on the permeability of epidermis. J Soc Cosmet Chem 1970; 21:853–873.

62 Ertel 68. Froebe CL, Simion FA, Rhein LD, et al. Stratum corneum lipid removal by surfactants: relation to in vivo irritation. Dermatologica 1990; 181:277–283. 69. Imokawa G, Sumura K, Katsumi M. Study on skin roughness caused by surfactants: II. Correlation between protein denaturation and skin roughness. J Am Oil Chem Soc 1975; 52:484–489. 70. Imokawa G, Mishima Y. Cumulative effect of surfactants on cutaneous horny layers: adsorption onto human keratin layers in vivo. Contact Dermatitis 1979; 5:357–366. 71. Kawai M, Imokawa G. The induction of skin tightness by surfactants. J Soc Cosmet Chem 1984; 35:147–156. 72. Prottey C, Oliver D, Coxon AC. Prediction and measurement of surfactant irritation upon human skin under realistic conditions. Int J Cosmet Sci 1984; 6:263–273. 73. Ananthapadmanabhan KP, Yu KK, Meyers CL, et al. Binding of surfactants to stratum corneum. J Soc Cosmet Chem 1996; 47:185–200. 74. Rhein LD. Review of properties of surfactants that determine their interactions with stratum corneum. J Soc Cosmet Chem 1997; 48:253–274. 75. Mukherjee S, Margosiak M, Ananthapadmanabhan K, et al. Interactions of cleansing bars with stratum corneum proteins: an in vitro fluorescence spectroscopic study. J Soc Cosmet Chem 1995; 46:301–320. 76. Shukuwa T, Kligman A, Stoudemayer T. A new model for assessing the damaging effects of soaps and surfactants on human stratum corneum. Acta Derm Venereol (Stockh) 1997; 77:29–34. 77. Frosch PJ, Kligman AM. The soap chamber test. A new method for assessing the irritancy of soaps. J Am Acad Dermatol 1979; 1:35–41. 78. Ertel KD, Neumann PB, Keswick BH, et al. A comparison of two antecubital fossa tests with personal care products. J Toxicol Cut Ocular Toxicol 1997; 16:19–30. 79. Mills OH Jr., Swinyer LJ, Kligman AM. Assessment of irritancy of cleansers, 43rd Annual Meeting of the American Academy of Dermatololgy, Washington, DC, Dec 1–6, 1984, Schaumburg, IL: American Academy of Dermatololgy. 80. Berardesca E, Vignoli GP, Disante F, et al. Effects of water temperature on surfactant-induced skin irritation. Contact Dermatitis 1995; 32:83–87. 81. Clarys P, Manou I, Barel AO. Influence of temperature on irritation in the hand/forearm immersion test. Contact Dermatitis 1997; 36:240–243. 82. Ertel KD, Knight EA, Rains GY et al. A body wash personal cleansing option to provide mild cleansing under a wide range of water hardness conditions, Academy ’97 Meeting, New York, NY, Jul 30–Aug 3, 1997, Schaumburg, IL: American Academy of Dermatology. 83. Fujiwara N, Toyooka I, Ohnishi K, et al. Absorbed residue of fatty acid soap on human skin. Analysis of human skin surface in situ using infrared spectroscopy. J Soc Cosmet Chem Jpn 1992; 26:107–112. 84. Warren R, Ertel KD, Bartolo RG, et al. The influence of hard water (calcium) and surfactants on irritant contact dermatitis. Contact Dermatitis 1996; 35:337–343. 85. Ertel KD, Keswick BH, Bryant PB. A forearm controlled application technique for estimating the relative mildness of personal cleansing products. J Soc Cosmet Chem 1995; 46:67–76. 86. van Scott EJ, Lyon JB. A chemical measure of the effect of soaps and detergents on the skin. J Invest Dermatol 1953; 21:199–203. 87. Bettley FR, Donoghue E. Effect of soap on the diffusion of water through isolated human epidermis. Nature 1960; 185:17–20. 88. Bettley FR, Donoghue E. The irritant effect of soap upon the normal skin. Br J Dermatol 1960; 72:67–76. 89. van der Valk PGM, Crijns MC, Nater JP, et al. Skin irritancy of commercially available soap and detergent bars as measured by water vapour loss. Dermatosen 1984; 32:87–90. 90. van der Valk PGM, Nater JP, Bleumink E. Vulnerability of the skin to surfactants in different groups of eczema patients and controls as measured by water vapour loss. Clin Exp Dermatol 1985; 10:98–103.

Personal Cleansing Products 63 91. van Ketel WG, Bruynzeel DP, Bezemer PD, et al. Toxicity of handcleaners. Dermatologica 1984; 168:94–99. 92. Murahata RI, Toton-Quinn R, Finkey MB. Effect of pH on the production of irritation in a chamber irritation test. J Am Acad Dermatol 1988; 18:62–66. 93. Baranda L, Gonza´lez-Amaro R, Torres-Alvarez B, et al. Correlation between pH and irritant effect of cleansers marketed for dry skin. Int J Dermatol 2002; 41:494–499. 94. Ananthapadmanabhan KP, Lips A, Vincent C, et al. pH-induced alterations in stratum corneum properties. Int J Cosmet Sci 2003; 25:103–112. 95. Sznitowska M, Janicki S, Baczek A. Studies on the effect of pH on the lipoidal route of penetration across stratum corneum. J Control Release 2001; 76:327–335. 96. Sznitowska M, Janicki S, Williams A, et al. pH-induced modifications to stratum corneum lipids investigated using thermal, spectroscopic, and chromatographic techniques. J Pharm Sci 2003; 92:173–179. 97. Hostynek JJ, Wilhelm KP, Cua AB, et al. Irritation factors of sodium hypochlorite solutions in human skin. Contact Dermatitis 1990; 23:316–324. 98. Korting HC, Megele M, Mehringer L, et al. Influence of skin cleansing preparation acidity on skin surface properties. Int J Cosmet Sci 1991; 13:91–102. 99. Korting HC, Greiner K, Hu¨bner K, et al. Changes in skin pH and resident flora by washing with synthetic detergent preparations at pH 5.5 and 8.5. J Soc Cosmet Chem 1991; 42:147–158.100. Korting HC, Kober M, Mueller M, et al. Influence of repeated washings with soap and synthetic detergents on pH and resident flora of the skin of forehead and forearm. Acta Derm Venereol (Stockh) 1987; 67:41–47.101. Korting HC, Ponce-Po¨schl E, Klo¨vekorn W, et al. The influence of the regular use of a soap or an acidic syndet bar on pre-acne. Infection 1995; 23:89–93.102. Fluhr JW, Kao J, Jain M, et al. Generation of free fatty acids from phospholipids regulates stratum corneum acidification and integrity. J Invest Dermatol 2001; 117:44–51.103. Barel AO, Lambrecht R, Clarys P, et al. A comparative study of the effects on the skin of a classical bar soap and a syndet cleansing bar in normal use conditions and in the soap chamber test. Skin Res Technol 2001; 7:98–104.104. Faucher JA, Goddard ED. Sorption of a cationic polymer by stratum corneum. J Soc Cosmet Chem 1976; 27:543–553.105. Faucher JA, Goddard ED, Hannan RB. Protection of the skin by a cationic cellulose polymer. Cosmet Toilet 1977; 92:39–44.106. Pugliese P, Hines G, Wielinga W. Skin protective properties of a cationic guar derivative. Cosmet Toilet 1990; 105:105–111.107. Rawlings A, Harding C, Watkinson A, et al. The effect of glycerol and humidity on desmosome degradation in stratum corneum. Arch Dermatol Res 1995; 287:457–464.108. Ghadially R, Halkier-Sorensen L, Elias PM. Effects of petrolatum on stratum corneum structure and function. J Am Acad Dermatol 1992; 26:387–396.109. Warner RR, Boissy YL. Effect of moisturizing products on the structure of lipids in the outer stratum corneum of humans. In: Lode´n M, Maibach HE, eds. Dry Skin and Moisturizers. In: Chemistry and Function. Boca Raton: CRC Press, 2000:349–369.110. Ertel KD, Focht HL, Plante JE, et al. Challenging the personal cleanser paradigm: a body wash that provides skin improvement benefits, 63rd Annual Meeting of the American Academy of Dermatology, New Orleans, LA, Feb 18–22, 2005, Schaumburg, IL: American Academy of Dermatololgy.111. Lewis C. Clearing up cosmetic confusion. FDA Consum 1998; 32:6–11.112. Scheinman PL. Is it really fragrance-free? Am J Contact Dermat 1997; 8:239–242.113. Scheinman PL. The foul side of fragrance-free products: what every clinician should know about managing patients with fragrance allergy. J Am Acad Dermatol 1999; 41:1020–1024.114. Ya-Xian Z, Suetake T, Tagami H. Number of cell layers of the stratum corneum in normal skin—relationship to the anatomical location on the body, age, sex, and physical parameters. Arch Derm Res 1999; 291:555–559.

64 Ertel115. Christensen M, Kligman AM. An improved procedure for conducting lactic acid stinging tests on facial skin. J Soc Cosmet Chem 1996; 47:1–11.116. Muizzuddin N, Marenus KD, Maes DH. Factors defining sensitive skin and its treatment. Am J Contact Dermat 1998; 9:170–175.117. De Groot AC. Adverse effects of cosmetics and toiletries: a retrospective study in the general population. Int J Cosmet Sci 1988; 9:255–259.118. Accessed August, 2005 at http://www.aad.org/public/Publications/pamphlets/Acne.htm.119. Morea-Swift G. Looking Good. New skin cleansing particles improve personal care formulations. Soap Cosmet 2003; 79:17–18. See also pp. 20,24.120. Wigger-Alberti W, Fischer T, Greif C, et al. Effects of various grit-containing cleanser on skin barrier function. Contact Dermatitis 1999; 41:136–140.121. Mills OH, Jr., Kligman AM. Evaluation of abrasives in acne therapy. Cutis 1979; 23:704–705.122. Doughty DG, Blatz BA, Ertel KD, et al. Clinical and technical characterization of a breakthrough option for daily facial cleansing, 58th Annual Meeting of the American Academy of Dermatology, San Francisco, CA, Mar 10–15, 2000, Schaumburg, IL: American Academy of Dermatololgy.123. Plante JE, Ertel KD, Amburgey MS, et al. Novel facial cleansing cloth provides a new daily cleansing option for sensitive skin, Academy 2000 Meeting, Nashville, TN, Aug 2–6, 2000, Schaumburg IL: American Academy of Dermatology.124. Accessed August, 2005 at http://www.aad.org/NR/exeres/7430E3C2-E0E9-4C3D-A8A3- 4E25CB1E48AB.htm? NRMODEZPublished.125. Wortzman MS. Evaluation of mild skin cleansers. Dermatol Clin 1991; 9:35–44.126. Breneman DL, Hanifin JM, Berge CA, et al. The effect of antibacterial soap with 1.5% triclocarban on Staphylococcus aureus in patients with atopic dermatitis. Cutis 2000; 66:296–300.127. Uehara M, Takada K. Use of soap in the management of atopic dermatitis. Clin Exp Dermatol 1985; 10:419–425.128. Draelos ZD, Ertel K, Hartwig P, et al. The effect of two skin cleansing systems on moderate xerotic eczema. J Am Acad Dermatol 2004; 50:883–888.129. Ertel KD, Werchowski KM, Rains GY, et al. Potential for enhanced clinical mildness from a body wash plus cleansing puff system, Academy ’98 Meeting, Chicago, IL, Jul 31–Aug 4, (1998), Schaumburg, IL: American Academy of Dermatology.130. Nu¨rnberger F. Skin cleansing of the mucous membrane and skin borders. Wien Med Wochenschr Suppl 1990; 108:27–28.131. Lindell ME, Olsson HM. Personal hygiene in external genitalia of healthy and hospitalized elderly women. Health Care Women Int 1990; 11:151–158.132. Montagna W, Carlisle K. Structural changes in aging human skin. J Invest Dermatol 1979; 73:47–53.133. Kligman AM. Perspectives and problems in cutaneous gerontology. J Invest Dermatol 1979; 73:39–46.134. Ghadially R, Brown BE, Sequeira-Martin SM, et al. The aged epidermal permeability barrier. Structural, functional, and lipid biochemical abnormalities in humans and a senescent murine model. J Clin Invest 1995; 95:2281–2290.135. Roberts D, Marks R. The determination of regional and age variations in the rate of desquamation: a comparison of four techniques. J Invest Dermatol 1980; 74:13–16.136. Manuskiatti W, Schwindt DA, Maibach HI. Influence of age, anatomic site and race on skin roughness and scaliness. Dermatology 1998; 196:401–407.137. Cua AB, Wilhelm KP, Maibach HI. Cutaneous sodium lauryl sulphate irritation potential: age and regional variability. Br J Dermatol 1990; 123:607–613.138. Kligman AM. Perspectives in cutaneous geriatrics: skin care for the old-old. J Geriatr Derm 1993; 1:A18–A20.139. Mason SR. Type of soap and the incidence of skin tears among residents of a long-term care facility. Ostomy Wound Manage 1997; 43:26–30.140. Graham-Brown R. Soaps and detergents in the elderly. Clin Dermatol 1996; 14:85–87.

Personal Cleansing Products 65141. Accessed August, 2005 at http://www.aad.org/NR/exeres/5C8EABAB-1380-4BDF-9DF1- 378951AC3B09.htm?NRMODEZPublished.142. Swanbeck G. Cleansing problems in senile skin. Wien Med Wochenschr Suppl 1990; 108:23.143. Berardesca E. Racial differences in skin function. Acta Derm Venereol (Stockh) 1994; 185:44–46.144. Berardesca E, Maibach HI. Racial differences in skin pathophysiology. J Am Acad Dermatol 1996; 34:667–672.145. Corcuff P, Lotte C, Rougier A, et al. Racial differences in corneocytes. A comparison between black, white, and Oriental skin. Acta Derm Venereol (Stockh) 1991; 71:146–148.146. Ertel KD, Werchowski KM, Rains GY. Irritation potential of personal cleansers: response of different skin types to a range of cleanser compositions, 60th Annual Meeting of the American Academy of Dermatololgy, New Orleans, LA, February 22–27, 2002, Schaumburg, IL: American Academy of Dermatology.147. Montagna W, Carlisle K. The architecture of black and white facial skin. J Am Acad Dermatol 1991; 24:929–937.148. Robinson MK. Population differences in skin structure and physiology and the susceptibility to irritant and allergic contact dermatitis: implications for skin safety and risk assessment. Contact Dermatitis 1999; 41:65–79.149. Warrier AG, Kligman AM, Harper RA, et al. A comparison of black and white skin using noninvasive methods. J Soc Cosmet Chem 1996; 47:229–240.150. Grimes PE. Double-blind study of a body wash containing petrolatum for relief of ashy, dry skin in African American women. Cosmet Dermatol 2001; 14:25–27.

5Toners and AstringentsMelanie SmithMary Kay Inc., Dallas, Texas, U.S.A.INTRODUCTIONSkin care sales continue to grow globally, driven by innovative new product forms,multifunctional products, consumer interest in reducing the signs of aging, a rise indisposable income, and the availability of foreign product lines in formerly less-developedcountries. Most of the increase in sales is generated by anti-aging/nourishing products.Dermatologists’ skin care lines with scientific-sounding names and minimalist packagingare increasingly popular with the consumer who feels these lines may provide efficacy atan affordable price without a prescription. Euromonitor (1) reported toner sales worldwidein 2004 at $4.7 billion, growing at a lower rate than other skin care categories. Growth intoner sales in 2004 came from Asia-Pacific, Western Europe, Eastern Europe, and LatinAmerica where multistep regimens are well received. In the U.S., where convenienceis a key factor in product usage, sales peaked at $384.7 million in 1999 and then begana gradual decline which is forecasted to continue. The perception among some consumersthat toners are unnecessary or harmful because they “strip” the skin, the lack of innovationin the product form, and inconvenience are among the reasons toner sales have declined.Toners are often perceived as harmful because consumers tend to associate them withdrying of the skin and high alcohol levels. At one time toners were touted as pH balancersand necessary to remove the highly alkaline, drying, irritating residue of cleansers andsoaps of the past. Most cleansers marketed today are mild and well formulated so as not todisrupt the skin’s pH level, thus minimizing the perceived need for toners. In addition,toners have not advanced from the traditional solution form. Consumers prefer theconvenience of facial cleansing wipes and multifunctional products, such as two-in-onecleanser/toner and three-in-one cleanser/toner/mask products, rather than the additionalstep of a toner. Despite this, there are opportunities for the dermatologist, aesthetician, andconsumer to use a toner that is cosmetically acceptable, provides a sensorial experience,is suitable as a delivery vehicle, and is formulated appropriately for skin type.PRODUCT NOMENCLATUREToners, astringents, skin fresheners, skin lotions, softeners, tonics, balancers, cleansingwaters and other terms are used for products in this category. The choice of nomenclature 67

68 Smithcan vary by manufacturer and even within product lines. Also, the product name does notnecessarily indicate strength or inclusion of a particular ingredient. For this chapter theterm toners will be used to cover all these nomenclatures unless specified. Toners may becategorized as cosmetics or over-the-counter (OTC) drug products, depending upon theclaims and ingredients. There is an astringent category under the Food and DrugAdministration’s (FDA’s) Skin Protectant Drug Products for Over-the-Counter HumanUse (2) defining astringents as “. (products) applied to the skin or mucous membranes fora local and limited protein coagulant effect.” This definition covers the use of aluminumacetate, aluminum sulfate, and witch hazel. Active ingredients and labeling claims inastringent drug products are dictated by the FDA OTC Monograph (2). Except for witchhazel (hamamelis water) USP, these actives are reserved for OTC uses and are nottypically used in cosmetic toners and, therefore, will not be considered for purposes of thischapter. To add to this confusion, there are products branded as toners and astringentscontaining cosmetic ingredients as well as toners and astringents containing salicylic acidthat are sold in accordance with the FDA’s OTC Acne Drug Monograph (3).FUNCTION AND ORDER OF APPLICATION WITHINA SKIN CARE REGIMENToners are leave-on products. They are the second cleansing step within a skin careregimen designed to freshen and tone, and they also prepare the skin for the application ofmoisturizer. After cleansing, toners are typically applied by saturating a cotton ball or padand wiping this across the face. Men may use them as a splash-on after shaving. Tonersremove any makeup residue, and oily skin patients find them beneficial to remove excesssebaceous secretions. Toners can provide a mild exfoliating action and a stimulatingor cooling sensation. Toners may also serve as a delivery vehicle for active orcosmeticeutically important ingredients such as anti-acne, anti-aging, and whitening/lightening. Although toners are typically designed for facial use, they may also be used forthe upper chest and back in acne treatment.FORMULATION CONSIDERATIONSProduct Forms and IngredientsToners are typically clear to translucent aqueous or hydroalcoholic solutions. The choiceof ingredients, function of these ingredients, and claims determine the product’sappearance and type of solution. A generic base formulation is shown in Table 1.Water is typically the major component and main vehicle or delivery system for active orother cosmetically important ingredients. Ethanol may be added as part of the vehicle asdesired for skin type and/or ingredient solubility. Ethanol is generally not used in tonersformulated for dry or sensitive skin or in the Asia-Pacific market, but it is found at varyinglevels in normal, combination, oily, and acne-prone skin types. Ethanol also serves asa preservative when used at levels of 20% or higher. Various types of denatured ethanolare used in toners, depending on country regulations on the denaturant. Isopropanol wasused years ago, but it is now out of favor because of its strong odor. Humectants are added to attract moisture to the skin, mitigate the drying effects ofalcohol, lower the freeze point to ensure stability in cold temperatures, solubilize other

Toners and Astringents 69Table 1 Skin Toner—Base Formula with Typical Concentration Ranges %Ingredients Qs to 100.00% 0.00–65.00Water 1.00–5.00Ethanol 0.10–10.00Humectants 0.10–3.00Key ingredients 0.10–0.50Emollients 0.05–0.20Cosolubilizers As neededThickeners/film formers QsPreservativesColor, fragranceingredients, and adjust the aesthetics. Glycerin and sorbitol are the most cost effectivehumectants, but they can lend a tacky afterfeel. Sodium polycarboxylic acid (PCA) is lesstacky, but more importantly, it is similar to the PCA which is found in the skin’s ownnatural moisturizing factor (NMF). When additional solubility and an elegant, smooth,non-tacky feel is desirable, propylene glycol, butylene glycol, polyethylene glycols, andthe ethoxylated glycerins, such as methyl gluceth-10 or methyl gluceth-20, are used.Sodium hyaluronate and other water-soluble moisturizing agents may be added. Emollients, such as dimethicone copolyols and small amounts of natural oils, arebeneficial for skin lubricity and soothing. They require the use of cosolubilizers to assureingredient solubility to maintain product clarity and stability. Cosolubilizers includeethoxylates and propoxylates, such as PEG-40 hydrogenated castor oil, PPG-5-ceteth-20,or polysorbate 20. They are added at concentrations of 0.10–0.50%, depending on theoil-soluble ingredient and level used. The ethoxylated and proproxylated humectants arealso useful but less efficient cosolubilizers. Botanical extracts are added for a variety of reasons (4–6). The concentration isdependent on many factors, including the type of extraction and the percent solids of theextract. For example, aloe extract and witch hazel distillate are often used as vehicles.Frequently, several botanicals will be incorporated into a toner. Some extracts aremore suitable for specific skin types; some offer multiple benefits. They are frequentlytouted as the key ingredient that offers benefits such as astringency, anti-inflammation,antioxidant, exfoliating, soothing, and cooling. It is the extracts’ polyphenolic content thatoffers one or more of these benefits. Especially popular and beneficial are the polyphenolicbioflavinoids found in green tea, rosemary, blueberry, raspberry, strawberry, red wine,grapeseed, and pine bark extracts. They provide antioxidant and anti-inflammatorybenefits. The anti-inflammatory benefits equate to soothing the skin by reducingskin stinging, itching, and redness. Extracts of honey, mallow, soy, aloe, lavender, greentea, algae, licorice, and chamomile may be added for their soothing and conditioningeffects on the skin. The high tannin levels in botanical extracts such as witch hazel,sage, horsechestnut, and quercus lusitanica oak provide astringency. In addition to itsastringency, the distillate of witch hazel, which contains 14% ethanol, also providesa cooling effect on the skin. It may be claimed as an OTC drug product astringent under theSkin Protectant Monograph (2), but both the distillate and extracts forms are morefrequently used as a cosmetic ingredient in skin toners. Isoflavones, such as soy extract,known for their phytoestrogen content, are beneficial to more mature and dry skins.

70 Smith Other beneficial ingredients used in toners are allantoin and panthenol forconditioning and soothing of the skin, and free radical scavenging antioxidants, such asalpha lipoic acid, superoxide dismutase, and vitamins A, C, and E. Vitamin E and itsderivative, tocopheryl acetate, can also be used to protect the product and its constituentsfrom oxidization. Alpha-hydroxy acids (AHAs) such as glycolic, lactic, malic, citric, and mixed fruitacids are used for exfoliation and/or pH adjustment. While they are not marketed as toners,the toner product form has been used by aestheticians and dermatologists to deliver highlevels of hydroxy acids in chemical peels for years, and more recently chemical peels withlower levels of AHAs have been introduced through the retail market. AHAs at efficaciousexfoliating levels of pH !5 may cause skin stinging and redness, so the addition of anti-inflammatory and soothing botanical extracts is recommended. Although neutral pHranges offer less irritation potential, they do not offer the same exfoliation activity.Polyhydroxy acids (PHAs), larger molecular weight variants of AHAs, are designed to beless irritating (7). Both AHAs and PHAs may be used in both aqueous and hydroalcoholicsolutions. When used as a pH adjuster, AHAs are added at levels of 0.01–0.20%. The betahydroxy acid (BHA), salicylic acid, is used for its keratolytic/exfoliating activity and ismonographed as an OTC anti-acne drug (3). Whitening agents have a long history of use in Asia. They are highly regulated inAsia as quasi-drugs. They have gained popularity in the rest of the world for the cosmeticclaim of even skin tone, where the term whitening is considered a drug claim. Licorice,mulberry, and bearberry are popular skin lightening botanical extracts. The oil-solubleform of licorice at 0.05% is regulated as a functional drug in Korea (8). The water-solublevitamin C derivatives, magnesium ascorbyl phosphate (MAP) used at 3%, and ascorbylglucoside at 2%, are recognized as quasi-drugs in most of Asia (9). MAP is highly unstableand turns brown readily with time, high temperatures, and exposure to light. Ascorbylglucoside is preferred for its acceptable stability profile. Thickening ingredients are added when a slightly viscous and/or film formingproperty is desired. They also provide a more lubricious application and afterfeel than asolution. Xanthan gum, polyacrylic acids such as carbomer, and cellulose gum derivatives,such as methylcellulose, hydroxypropylcellulose, and hydroxyethylcellulose, are used. Fragrance oils or naturally derived extracts and oils may be added to impart a pleasantscent to the formula or cover off-odors that develop when the product is exposed toexcessive heat, light, or other parameters associated with shelf life. They also can be usedto support a toner’s marketing position and enhance the message that the toner is soothingor refreshing or, in the case of anti-acne toners, medicinal. Rose and lavender extracts canbe used for soothing and dry skin formulas. Rosemary, peppermint, and citrus extracts maybe added to toners designed for oily and combination skins or when a refreshing,stimulating signal or scent is desired. Menthol, peppermint, and eucalyptus odors areassociated with a medicinal benefit. Like fragrance, color is included to deliver a sensorial signal, such as soothing,refreshing or therapeutic, or to enhance the product’s appearance, or to cover product colorstability issues. Water-soluble Food, Drug, and Cosmetic (FD&C) and Drug and Cosmetic(D&C) colorants are used.New and Patented Ingredients/ApplicationsToners have historically contained plant-derived key ingredients. With recentcontroversies in the cosmetic industry concerning the use of animal-derived ingredients,the use of collagen and other animal-derived ingredients has diminished, and they are very

Toners and Astringents 71rarely found in toners outside of Japan. A recent U.S. patent discloses the use ofextensions, plant-derived hydroxyproline-rich glycoproteins that can be incorporated intotoners as substitutes for animal collagen (10). The use of Morinda Citrifolia or Noni fromthe Indian Mulberry plant in a toner is disclosed in a recent patent. Noni providesantioxidant benefits and is high in linoleic acid to nourish the skin (11). Sanguisorba,a plant native to Korea, China, and Japan, produces a root extract widely used in Asiancosmetics for its astringent effect. It is said to offer antimicrobial and anti-inflammatoryeffects as well, and it functions much like superoxide dismutase as an antioxidant (12).A recent patent discloses the preparation zinc glycyrrhizinate for use as an astringent inmedical and cosmetic preparations (13). A mixture of butylene glycol and mushroomextract is used as an astringent additive for its skin tightening benefits (14). Pycogenol orpine bark extract and blueberry extract exhibit potent antioxidant and anti-inflammatoryactions. They are useful as soothing and antioxidant agents in toners (15). Another recentpatent (16) discloses the use of solvent extracts of plants including Spondias mombin,Maprounea guianesis, Waltheria indica, Gouania blanchetiana, Cordia schmoburgkii,Randia armata, and Hibiscus furcellatus to stimulate autosynthesis of reduced glutathione.A skin toner formulation patent (17) covers the use of butylene oxide-based ethers andpropylene oxide-based ethers. It is purported to remove sebum from the skin withoutsignificant removal of moisture-retaining intercellular lipids.Formulation ChallengesSkin TypesToners have two key formulating challenges—formulating for specific skin types andvehicle/ingredient stability and compatibility. Varying skin types, including dry, normal,oily, combination, sensitive, and acne-prone, require different and skin-type specificingredients and vehicles. Free radical scavenging antioxidants are used regardless of skintype. Most toners are used within a skin care regimen. The patient’s concern about tonersbeing drying or harmful may be mitigated by using a regimen and toner appropriate forskin type. Alcohol-free formulas with humectants, emollients, and soothing agents are mostsuitable for the dry and sensitive skin patient (Table 2). This, in conjunction with the use ofa moisturizer, allays the concern of a toner being drying. The addition of humectants andemollient agents will help maintain moisture balance. Soothing ingredients are beneficialto alleviate the redness and irritation often experienced with these skin types. SensitiveTable 2 Skin Toner for Dry SkinIngredients % FunctionWater QS to 100% VehicleSodium PCA 5.0 HumectantGreen tea extract 3.0 Botanical extract with soothing, anti-inflamma-Soy extract 2.0 tory, mild astringency, free radical scavengerXanthan gum 0.2 benefitsFragrance, color, As needed Botanical extract with moisturizing benefits Film former, thickener preservative

72 Smithskin toners are formulated similar to dry skin formulas with the addition of anti-irritantssuch as allantoin, green tea, or licorice extract. Toners designed for normal to combination skin types typically contain low levels ofethanol, humectants, and appropriate key ingredients. Botanical extracts with high tanninlevels offer skin tightening effects without stripping the skin of its natural oils to mitigatethe potentially drying effect of ethanol. It is recommended that soothing agents andhumectants be added and that toner use be followed by a moisturizer designed fornormal skin. Oily skin toners, such as the formula in Table 3, are designed to provide a highdegree of astringency and to control and/or remove excess sebum. This is achieved byusing higher levels of ethanol and highly astringent and oil-absorbing ingredients. Levelsof 20–50% ethanol may be used. The sebum removing and cooling effects of ethanol arehighly desirable to the oily skin patient. High tannin-containing ingredients provideastringency. Astringent botanicals to consider include extracts of witch hazel, rosemary,lemon, grapefruit, horse chestnut, and stinging nettle. Natural sources of glycolic acidfound in sugar cane extract, lactic acid found in milk, and salicylic acid found in willowbark extracts are often added for exfoliation. If a stimulating sensation is desired,peppermint, menthol, or eucalyptus is added. Kaolin, polyamides (nylon-6 and -12),methylmethacrylate crosspolymer, and silica absorb skin oil and minimize the appearanceof oily shine on the skin. Silica settles slowly and gives the product a hazy appearance. Theother oil-absorbing particulates settle readily, so a shake-well instruction prior to use isrequired. Soothing botanical agents and allantoin may be added to lessen any irritatingdryness associated with higher ethanol concentrations. Toners formulated for acne-prone skin typically contain high levels of ethanol,salicylic acid, and naturally derived antibacterials such as cinnamon, neem, and tea treeoil. Recently, there have been several references on the allergenic characteristics of teatree oil (18–21). The ethanol level should be kept to the minimum necessary to solubilizethe salicylic acid in order to minimize excessive drying to the skin. The FDA OTC AcneMonograph (3) dictates levels of salicylic acid from 0.5–2.0% as well as the acnetreatment claim that may be listed on the product. A pH !4 is needed to assure delivery ofthe acid form. Formulations containing salicylic acid typically use 35–60% ethanol tomaintain its solubility and stability. Levels as low as 20% ethanol in conjunction with thehumectants glycerin and butylene glycol as cosolvents have been shown to provideacceptable salicylic acid solubility at room-temperature and low-temperature (58C)conditions (22). To further enhance the perception of medicinal benefits of an anti-acnetoner, scent and skin sensorial-stimulating agents such as menthol, eucalyptus,peppermint, or camphor may be added. Soothing botanical extracts and humectants arebeneficial to minimize the potentially irritating and drying effects of high alcohol levels.Table 3 Skin Toner for Oily SkinIngredients % FunctionWater QS to 100% VehicleEthanol 20.0 Vehicle, astringent, preserva-Witch hazel distillate 20.0 tive, oil removal Astringent, cooling andGlycerin 5.0Fragrance, color As needed soothing effect Humectant

Toners and Astringents 73 Alcohol-free toners may be used as a last step in cleansing, a preparation step tomoisturizing, or as a whitening treatment product in the Far East. Toners are frequentlysold under the “softener” nomenclature in Asia. Asian consumers have a negativeperception of alcohol in terms of both skin reactions and odor of ethanol. They exhibita higher degree of sensitivity to the skin effects of alcohol (23). It is advisable to avoid theuse of alcohol and sensorial-stimulating agents to minimize the chance of irritation.Botanical extracts and the quasi-drug ascorbyl glucoside are used for whitening effects intoners. Another popular toner form in Asia is the lightweight, low-viscosity milky lotion.These are frequently used to prepare the skin as the first step of the moisturizing regimen.The milky lotions are alcohol-free. Collagen, hyaluronic acid, and whitening agents arepopular in these products.Ingredient and Vehicle Stability and Compatibility ConsiderationsRequirements of pH, ingredient solubility and compability, and product stability influencethe choice of ethanol-to-water ratios, humectants, and cosolubilizers. Hydroxy acidsrequire low pH to be effective as exfoliants. Fortunately, they also act as pH adjusterswhen a low pH is desired. This low pH limits the choice of film formers and thickeners.There are also pH and concentration limitations when using AHAs in retail products soldin the U.S. The Cosmetic, Toiletry, and Fragrance Association’s Cosmetic IngredientReview (CIR) Expert Panel recommends that cosmetic products containing glycolic andlactic acids and their salts and esters be formulated at pH R3.5 and at concentrations%10% (24). Oil-soluble ingredients such as emollients, fragrance oils, and vitamins A andE require cosolubilizers to assure ingredient solubility to maintain product clarity andstability. The use of these cosolubilizers may cause product foaming during productionfilling and consumer use. This foaming can be minimized by adding an ingredient such assimethicone to reduce surface tension. Tea tree oil, found in many anti-acne and oily skintoners for its antibacterial activity, requires solubilizing agents for a clear solution, hasa distinctive odor and its terpene constituents are highly susceptible to oxidation. Theoxidation potential impacts the safety of the product (18–21); therefore, a recent EuropeanCosmetic Toiletry and Perfumery Association (COLIPA) report recommended thatmanufacturers add antioxidants and/or packaging that minimizes the product’s exposure tolight (25). High levels of ethanol in a toner can solubilize oil-soluble ingredients without theneed for additional cosolubilizers. Easier to use water-soluble botanical extracts are morecommonly used to provide antioxidant, anti-irritant, and soothing benefits, thus negatingthe need for cosolubilizers and mitigating any drying effects of alcohol. Alcohol-freetoners or toners with less than 20% alcohol require preservatives to maintainmicrobiological quality.PRODUCT CLAIMSToners on the market tout a plethora of skin benefit claims. It is these benefits that offera prime opportunity for toner acceptance. The benefit most frequently associated withtoners is a reduction of apparent pore size. Although no cosmetic product can alter theactual size of the pores, this claim is achieved because the pores appear less prominent dueto an astringent effect that results in swelling of the skin surrounding the pore or removalof oil and dirt from the pore. “Purifies skin by removing dirt and oils” and “removing (or)

74 Smithcontrolling oil” are claims used in oily skin toners. The toner claims, “restores theacid/alkali balance of the skin” and “pH balanced,” still resonate well with consumersalthough they go back to the days of highly alkaline cleansers. Sensorial claims include“skin looks healthy,” “even skin tone,” “softens,” “soothes,” “refreshes,” “energizes,”“cools skin,” “warms skin,” and “tightens.” Lightening and whitening claims such as“whitens (or lightens) the skin” and “reduces dark spots” are popular in Far East whiteningtoners. These claims may be quasi-drug or cosmetic depending on the country, ingredient,and claims. The “evens skin tone” claim is gaining popularity in the rest of the world.CLAIMS TESTING METHODSToner claims are substantiated by subjective and objective measurements. Many claimsare substantiated by using both measurements. These tools are useful in the screening ofingredients and final product efficacy. Subjective measurements include consumerperception testing and panelists self-assessment on clinical trials. These tests includeyes/no, like/dislike, agree/disagree, and point scales to rate consumer perception. Pointscales may be a three-, five-, seven-, or 10-point scale. For example, using a five-pointscale of “much worse,” “slightly worse,” “no change,” “slightly improved,” or “muchimproved” would offer the panelists the option to rate the skin’s appearance and condition.Another method is the use of a line marked in units from one to 10 designating least tomost, where the panelists mark product attribute agreement. Objective measurements include expert grading, photography, and instrumentmeasurements. The expert grader is trained in visually assessing the skin for changes incolor for evenness of skin tone, reduction of pore size for tightening and astringent claims,and reduction of the appearance of fine lines and wrinkles for anti-aging claims.Photography and more recently VISIA CRe is used to capture these same measures ona permanent record. Instrumental measures include the Sebumetere and Sebutape(CuDerm Corporation, Dallas, TX) (Fig. 1) to measure oil control. The Gas BearingElectrodynamometere assesses skin softness, and the Minolta chromameter measuresskin tone and color. Chromameter measurements are useful in measuring skin tone andcolor in products claiming evenness of skin tone or skin whitening as well as the reductionof redness when measuring anti-irritant and anti-inflammatory benefits.USES IN DERMATOLOGYUntil recently, the use of astringents and toners in dermatology was primarily limited totheir anti-acne and astringent properties, although some also functioned as mild antisepticagents suitable for mild or limited bacterial infections of the skin surface (24). Todaysoothing toners are increasingly being used by dermatologists and aestheticians for theiranti-inflammatory and anti-irritant benefits as part of a post-cosmetic surgery regimensuch as laser, chemical peel, or light-modulated procedures. The perceptual attributes ofclean and refreshing for oily and acne-prone skins and soothing and calming for dry andsensitive skins in a cosmetically acceptable toner formulation assure patient compliancewhen compared with traditional drug vehicles that lack the aesthetic characteristicspreferred by patients (26).

Toners and Astringents 75Figure 1 Macroscopic view of Sebutapes taken from oily skin surface before (left) and after(right) toner treatment. The fewer and smaller black spots on the right indicate a reduction in sebumafter treating the skin with an oily skin toner. The number of pores and amount of sebum secreted canalso be determined via image analysis.ADVERSE REACTIONSAdverse reactions in toners include transient contact irritation, contact allergy, andsensitization. Contact allergy is most often seen with more pharmacologically complexproducts, such as those containing multiple botanical extracts and penetration enhancers(27). Propylene glycol is often used as a humectant and sometimes as a solvent in toners. It isapproved for use in concentrations up to 50% by the CIR (28), but caution is advised in usingit above 10% as it can act as a penetration enhancer and cause irritation which, in patchtesting, is often confused with comedones. Although tea tree oil is not recognized by theFDA as an anti-acne, antiseptic or antibacterial active ingredient, it is found in many anti-acne and oily skin toners. It also has a distinctive odor, and recently there have been severalreports on the allergic, sensitization, and irritation potential of tea tree oil (18–21,29).COLIPA recommended that it not be used in cosmetic products at concentrations greaterthan 1% (25). Increased sun sensitivity occurs from topical application of AHA-containingproducts. Recently, the FDA issued industry guidance for labeling these products witha sunburn alert to minimize this risk (30). Toners have very low rates of reported adversereactions compared to other skin care products. FDA statistics for the years 1991–1994show 7.07 reported adverse reactions to toners and fresheners per million units sold, (31)and no consumer complaints were reported from 1995–2003 (32).SUMMARYToners have a beneficial role in a patient’s skin care regimen. They reduce the appearance ofpore size; exfoliate; remove or control sebum; soothe skin aggravated by the environment,

76 Smithdryness, or dermatological procedures, and provide a clean, refreshing skin feel. Whenproperly formulated for skin type and skin benefits, they offer a cosmetically acceptablevehicle for delivery of ingredients used in cosmetic, cosmetology, post-cosmetic surgery,and acne treatment applications.ACKNOWLEDGMENTSThe author is grateful to Dawn Burke-Colvin of Mary Kay Inc., and Laurie Pan, PhD, fortheir technical expertise, Gopa Majmudar, PhD, for providing Figure 1, and to Regina Lee,Mary Kay Inc., for research assistance.REFERENCES 1. Skin Care: Cosmetics and Toiletries, In: Integrated Marketing Information System, Euromonitorw International: London, 2005. 2. Skin Protectant Drug Products for Over-the-Counter Human Use: Astringent Drug Products; Final Rule, Federal Register, 2004. 3. Topical Anti-microbial Drug Products for Over-the-Counter Human Use: Acne Drug Products; Final Rule, Federal Register, 1991. 4. Dweck A. Natural extracts and herbal oils: concentrated benefits for the skin. Cosmet Toilet 1992; 107:89–98. 5. Accessed April, 2005, at http://www.drugdigest.org/DD/DVH/Herbs/0,3913,,00.html. 6. Accessed April, 2005, at http://www.mskcc.org/mskcc/html/11571.cfm?searchZtannin&tab. 7. Draelos Z. Topical Agents Used in Association with Cosmetic Surgery. Semin Cutan Med Surg 1999; 18(2):112–118. 8. Notice No. (2000-33) of the Korea Food and Drug Administration [Functional Cosmetic Regulations]: Attachment A, 2000. 9. Taiwan: Law for the Control of Cosmetic Hygiene in the Republic of China. Bureau of Pharmaceutical Affairs, Department of Health, The Executive Yuan, Republic of China, 2004.10. Wolf B, Tietjen M. Patent US5443855-A (to Revlon), 1995.11. Patent 2002187168 (to Jensen C, Robinson H.), 2002.12. Lee O, Kang H, Han S. Oriental herbs in cosmetics. Cosmet Toilet 1997; 112:57–64.13. Patent JP7149787-A (to Toyo Beauty), 1995.14. Patent 6803032 (to Cognis Corporation), 2004.15. Baumann L. Cosmeceutical Critique: Pycnogenol. Skin and Allergy News, 2004.16. Patent 6,406,720 (to Pauly G, Fleury M.), 2002.17. Patent 5133967 (to The Dow Chemical Company), 1992.18. Southwell IA, Freeman S, Rubel D. Skin irritancy of tea tree oil. J Essent Oil Res 1997; 9:47–52.19. Crawford GH, Sciacca JR, James WD. Tea tree oil: cutaneous effect of the exracted oil of Melaleuca alternifolia. Dermatitis 1992; 27:279–280.20. Knight TE, Hausen BM. Melaleluca oil (tea tree oil) dermatitis. J Amer Acad Dermatol 1994; 30:423–427.21. Rubel DM, Freeman S, Southwell IA. Tea tree oil allergy: What is the offending agent? Report of three cases of tea tree oil allergy and review of the literature. Aust J Derm 1998; 39:244–247.22. Herrera L. Solubility of salicylic acid with and without co-solvents. Unpublished data presented to Mary Kay Inc., Dallas, TX, in fulfillment of the University of Texas College of Pharmacy internship, 1999.23. Stephens TJ, Oresajo C. Ethnic sensitive skin: a review. Cosmet Toilet 1994; 109(2):75–79.24. Cosmetic Ingredient Review Expert Panel (CIR), Andersen FA, ed. “Final Report on the Safety Assessment of Glycolic Acid, Ammonium, Calcium, Potassium, and Sodium Glycolates,

Toners and Astringents 77 Methyl, Ethyl, Propyl, and Butyl Glycolates, and Lactic Acid, Ammonium, Calcium, Potassium, Sodium, and TEA-Lactates, Methyl, Ethyl, Isopropyl, and Butyl Lactates, and Lauryl, Myristyl, and Cetyl Lactates.” Int J Toxicol 1998; 17:1–241.25. SCCP Opinion on Tea Tree Oil. Scientific Committee on Consumer Products Adopted by the SCCP during the 2nd plenary meeting of 2004.26. Barker MO. Masks and astringents/toners. In: Baran R, Maibach H, eds. Textbook of Cosmetic Dermatology. 3rd ed. London; New York: Taylor and Francis, 2003:229–237.27. Pittz E. Skin barrier function and use of cosmetics. Cosmet Toilet 1984; 99:30–35.28. Cosmetic Ingredient Review Expert Panel (CIR). Final Report on the Safety Assessment of Propylene Glycol and Polypropylene Glycols. J Am Coll Toxicol 1994; 13:437–491.29. Human studies Draize method, study no. DT-029. Skin and Cancer Foundation Australia, 1997.30. Guidance for Industry: Labeling for Topically Applied Cosmetic Products Containing Alpha Hydroxy Acids, U.S. Department of Health and Human Services. College Park, MD: Food and Drug Administration, 2005.31. Participation Status Report for Cosmetic Voluntary Registration Program, Office of Cosmetics and Colors, Division of Program and Enforcement Policy. Washington, DC: Food and Drug Administration, 1995.32. Accessed April, 2005, at http://www.cfsan.fda.gov/wdms/cos-comp.html. Consumer Com- plaints about Cosmetic Products, 1995-2003, Office of Cosmetics and Colors, U.S. Department of Health and Human Services. College Park, MD: Food and Drug Administration.

6The Dry Skin CyclePaul J. MattsP&G Beauty, Rusham Park Technical Center, Egham, Surrey, U.K.Anthony V. RawlingsAVR Consulting Ltd., Northwich, Cheshire, U.K.INTRODUCTIONIn 1994 two key publications summarized the knowledge on the state of the art of stratumcorneum biology and dry skin, namely: “Stratum corneum moisturization at the molecularlevel” (1) and “The correlation of water content with ultrastructure in the stratumcorneum.” Since then, significant advances have been made in our understanding of thepathophysiology of dry skin. This chapter will review these recent findings and from thesepropose a new model of a dry skin cycle (Fig. 1). First, however, we need to consider the role of water loss through the stratumcorneum (SC). Under normal circumstances, the SC must be as impermeable as possibleexcept for a small amount of water loss to (i) hydrate the outer layers of the SC to maintainits flexibility and (ii) to provide enough water to allow enzyme reactions that facilitate SCmaturation events, together with corneodesmolysis and ultimately desquamation (Fig. 2)(4–6). This inbuilt water loss is vital for the normal functioning of the SC. This does,however, generate water gradients within the tissue. Key in precipitating the condition wecall “dry skin” is a perturbation of these water gradients within the SC. Scientists at Procterand Gamble were the first to demonstrate changes in SC water gradients in dry skin (7)where about one-third of the outer layers of the SC are reported to contain less than 10%water content (Fig. 3). At this level of water content the SC will be dysfunctional andbrittle (8). The SC uses three main mechanisms to hold onto water: -the intercellular lamellar lipids whose physical conformation, predominantly an orthorhombic laterally-packed gel and 13 nm long periodicity (LPP) lamellar phase induced by linoleate containing long chain ceramides, provide a tight and semi-permeable barrier to the passage of water through the tissue -the presence of fully matured, rigid, corneodesmosome-bound, and ceramide hydrophobed corneocytes which influence the tortuosity of the SC and thereby the diffusion path length of water 79

80 Matts and RawlingsFigure 1 Typical photographs of cosmetic dry skin. Source: From Ref. 2. -the presence of both intracellular and extracellular hygroscopic materials called “natural moisturizing factors” (NMF)STRATUM CORNEUM AND EPIDERMAL STRUCTUREOur original concept of the SC with a “basket weave” appearance at the histological leveland a stratum compactum–stratum disjunctum at the electron microscope level has comeunder scrutiny over the last decade. For instance, Pfeiffer et al. (9) developed new high-pressure freezing followed by freeze substitution techniques for electron microscopymethods and visualized an SC that appeared more compact with smaller intercellularFigure 2 Typical structure of the epidermis and critical steps in formation of the stratum corneum.Source: From Refs. 1, 3.

The Dry Skin Cycle 81 80% water 70 60 (B) Dry skin 50 40 (A) Normal skin 30 20 10 Stratum corneum Stratum granulosumFigure 3 Water profile averaged over a single rectangular region of a cryosection obtained froman individual with (A) good skin, grade 0.5. The horizontal axis is distance across the SC with theSC/granulosum junction indicated by a vertical line. Water profile averaged over a single rectangularregion of a cryosection obtained from an individual with (B) dry skin, grade 4. Source: From Ref. 7.spaces and hence tighter cell-cell interactions. More controversial, however, was the lackof presence of keratohyalin granules in the epidermis. Lars Norlen (10) has also developednovel cryo-transmission electron microscopy techniques to image vitreous sections of skinwithout the use of cryo-protectants and, again, more densely-packed SC cells wereapparent compared with conventional images and new organelles or tubular structureswere observed in the epidermis. Norlen (11) has further proposed a cubic rod packingmodel for SC keratin structures. However, even with a more compacted SC, several SCswelling regions have been established by Bouwstra et al. (12) and Richter et al. (13) uponskin hydration which appear to be related to loss of barrier function and loss of NMF in theouter layers of the SC, hydrolysis of filaggrin to NMF, and lysis of non-peripheralcorneodesmosomes, allowing greater intercorneocyte freedom and transglutaminase-mediated maturation of corneocytes towards the surface layers of the SC. As will bediscussed, all of these events become aberrant in dry skin.STRATUM CORNEUM LIPID CHEMISTRY AND BIOPHYSICSAll SC lipids are important for barrier function of the skin but due to their uniqueproperties and structure the ceramides have been of most interest in recent years.Ceramides constitute (on a weight basis) approximately 47% of the SC lipids (14). Giventhis diversity, together with the identification of new ceramides, a new nomenclature basedon structure, rather than the original chromatographic migration characteristics, wasproposed by Motta et al. (15). In this system, ceramides are classified in general as CERFB, where F is the type of fatty acid and B indicates the type of base. When an ester linkedfatty acid is present, a prefix of E is used. Normal fatty acids (saturated or unsaturated),alpha-hydroxy fatty acids, and omega-hydroxy fatty acids are N, A, O respectively,whereas sphingosines, phytosphingosines, and 6-hydroxysphingosine are indicated by S,P, and H. Sphinganine (not previously classified) is proposed to be SP in this nomenclature

82 Matts and Rawlingssystem. A novel long-chain ceramide containing branched chain fatty acids is also foundin vernix caseosa (16). Typical structures of human ceramides are given in Figure 4.Newly identified ceramides have also been found attached to the corneocyte envelope(CE). In addition to ceramide A (sphingosine) and ceramide B (6-hydroxysphingosine),Chopart et al. (17) recently identified covalently-bound omega hydroxyl fatty acidcontaining sphinganine and phytosphingosine ceramides. These covalently-boundceramides should now be named CER OS, CER OH, CER OSP, and CER OP. Ceramides are synthesised from either glucosylceramides, epidermosides, orsphingomyelin. Epidermosides are glycated precursors of omega, hydroxyl–containingceramides. The studies of Hamanaka et al. (18) have demonstrated that sphingomyelinprovides a proportion of CER NS and CER AS whereas the glucosylceramides areprecursors to ceramides and epidermosides are precursors to the covalently boundceramides, together with CER EOS, CER EOH, and CER EOP. It is the packing states, however, and not only the structures of the SC lipids that areimportant for barrier function. Lipids in vivo appear to exist as a balance between a solidcrystalline state (orthorhombic packing) and gel (hexagonal packing) or liquid crystallinestates. The orthorhombically-packed lipids are the most tightly packed conformation andhave optimal barrier properties. However, a greater proportion of hexagonally-packedlipid conformations are observed in the outer layers of the SC (19). This is consistent witha weakening of the barrier towards the outer layers of the SC. It is believed that short chainfatty acids from sebum contribute to the crystalline to gel transition in the upper stratumcorneum layers (20). Bouwstra et al. (21) recently proposed a new sandwich model consisting of twobroad lipid layers with a crystalline structure separated by a narrow central lipid layer with == ==O O O HN OH CER EOS OHCER NS O CER NP O O HN OHCER AS HN OH CER AP HN OHCER AH OH CER NH OH OH O OH OH O OH O CER EOH HN OH OH OH O OH HN OH OH O OH HN OH O OH HN OH OH OH OH == = O O O CER EOP HN OH OH OHFigure 4 Structures of human stratum corneum ceramides.

The Dry Skin Cycle 83fluid domains (Fig. 5). Cholesterol and ceramides are important for the formation of thelamellar phase, whereas fatty acids play a greater role in the lateral packing of the lipids.Cholesterol is proposed to be located with the fatty acid tail of CER EOS in the fluid phase.CER EOS, EOH, and EOP play an essential role in formation of the additional lamellararrangements. The repeated distances were found to be 13 nm in dimension, composed oftwo units measuring approximately 5 nm each and one unit measuring approximately3 nm in thickness. These repeat lamellar patterns were also observed by X-ray diffractionstudies and were named the “LPP” and “short periodicity” (SPP) phases respectively. Mostly hexagonal phases are also observed for total lipid mixtures in the absenceof CER EOS. Equally no LPP phase is formed. Moreover, the importance of ceramide 1 orCER EOS in facilitating the formation of the LPP has been further elaborated byFigure 5 (A) “Sandwich model,” the characteristics of which are: (1) the liquid sublattice islocated in the central lipid layer of this phase, and in this layer mainly unsaturated linoleic acid andcholesterol are present; (2) in the sublattice adjacent to the central layer a gradual change in lipidmobility occurs due to the presence of less mobile long saturated hydrocarbon chains; (3) onlya small fraction of lipids forms a fluid phase in the SC, and therefore one can assume that this centrallipid layer is not a continuous phase. (B) The liquid phase parallel to the basal layers of the lamellaefacilitates transport and therefore communication between the desmosomes. Source: From Ref. 21.

84 Matts and Rawlings Lamellar Phases Not presentLPP SPP LPP SPP LPP SPP LPP SPP Moderately present Predominantly present HCER(1-8) HCER(1-ste, 2-8) HCER(1-ol, 2-8) HCER(1-Lin, 2-8)Figure 6 A summary of the lamellar phases and CER EOS in various lipid mixtures. HCER (1–8)mixtures in which HCER (EOS) is replaced with either synthetic stearate-containing CER (EOS),oleate-containing CER (EOS), or linoleate-containing CER (EOS). Source: From Ref. 22.understanding the influence of the type of fatty acid esterified to the omega-hydroxyl fattyacid (Fig. 6) (22). As a consequence, the LPP is seen mainly with linoleate-containingCER EOS, less with oleate-containing CER EOS and is absent if only stearate-containingCER EOS is present in the lipid mixtures. These studies indicate that for formation of theLPP, a certain fraction of the lipids has to form a liquid phase. If the liquid phase is toohigh (as with the oleate-containing CER EOS) or too low (as with stearate-containing CEREOS), the levels of the SPP increase at the expense of the LPP. It is important to rememberin vivo that the fatty acid composition of CER EOS is highly complex but contains a largeproportion of linoleic acid. Changes to the composition of the SC lipids could, therefore, dramatically influencethe condition of the skin. In this respect, using electron microscopy of tape strippings fromthe outer layers of normal healthy skin, Rawlings et al. (23) reported complete loss oflamellar ordering in the outer layers of the SC (Fig. 7). These results have been confirmedby Warner et al. (24) and more recently by Berry et al. (25).STRATUM CORNEUM CORNEODESMOSOMESAND CORNEODESMOLYSISThe “brick and mortar” model of the SC has been known for many years. However, a morecomplete description of this model includes “corneodesmosomes.” Corneodesmosomes(26) are macromolecular glycoprotein complexes incorporated into the CE and consist ofthe cadherin family of transmembrane glycoproteins, desmoglein 1 (Dsg 1) anddesmocollin 1 (Dsc 1). These glycoproteins span the cornified envelope into the lipid-enriched intercellular space between the corneocytes and provide cohesion by bindinghomeophilically with proteins on adjacent cells. Within the corneocytes, Dsg 1 and Dsc 1arelinked to keratin filaments via corneodesmosomal plaque proteins such as plakoglobin,desmoplakins, and plakophilins. The corneodesmosomal protein, corneodesmosin (Cdsn),after secretion by the lamellar bodies with the intercellular lipids and certain proteases,becomes associated with the desmosomal proteins just before transformation ofdesmosomes into corneodesmosomes. As these proteins are cross-linked into the complexby transglutaminase, their controlled disruption must occur by proteolysis to allow

The Dry Skin Cycle 85Figure 7 Organization of stratum corneum lipids in tape strippings of individuals with clinicallynormal skin. Transmission electron micrographs of tape strippings. Ultrastructural changes in lipidorganization towards the surface of the stratum corneum: (A) First strip; absence of bilayers andpresence of amorphous lipidic material. (B) Second strip; disruption of lipid lamellae. (C) Thirdstrip; normal lipid lamellae. x200,000. Source: From Ref. 23.desquamation to proceed. Indeed, Rawlings et al. (Fig. 8) (23) demonstrated degradation ofthe corneodesmosomes towards the surface of the SC in humans. Desquamation is facilitated by the action of specific hydrolytic enzymes in the SC thatdegrade the corneodesmosomal linkages. Currently, several serine, cysteine, and asparticenzymes are believed to be involved in this process, namely stratum corneum chymotrypticenzyme (SCCE), stratum corneum tryptic enzyme (SCTE), stratum corneum thiol protease(SCTP, now known as Cathepsin L-2), cathepsin E, and the aspartic protease cathepsin D.SCCE and SCTE are alkaline-optimal enzymes whereas the latter ones are acidic-optimumenzymes (27–31). Cathepsin L has also recently been implicated in Cdsn hydrolysis (32).Only SCTE and not SCCE, however, was capable of degrading Dsg 1 (33). This enzyme wasalso reported to be involved in the processing of pro-SCCE. Bernard et al. (34) have alsoidentified an endoglycosidase, heparanase 1, within the SC, thought to play a role in the pre-proteolytic processing of the protecting sugar moieties on corneodesmosomal proteins.

86 Matts and RawlingsFigure 8 Electron micrographs of tape strippings of normal skin (grade 1). Degradation ofcorneodesmosomes (CD) toward the surface of the stratum corneum: (A) First strip; CD fullydegraded. (B) Second strip; CD partially degraded and encapsulated by lipid lamellae. (C) Thirdstrip; CD partially degraded, vaculation of structure. (D) Third strip, normal CD in contact withlamellar lipids. Source: From Ref. 23.Cdsn undergoes several proteolytic steps. Cleavage of the N terminal glycine loop domainoccurs first at the compactum disjunctum interface (48–46 KDa to 36–30 KDa transition),followed by cleavage of the C terminal glycine loop domain in exfoliated corneocytes(36–30KDa to 15KDa transition) (35). The last step appears to be inhibited by calciumresulting in residual intercorneocyte cohesion. Nevertheless, the presence of oligosacchar-ides did not protect Cdsn against proteolysis by SCCE (33). A complete list of the putuativedesquamatory enzymes is given in Table 1. These enzymes largely exist as proforms, and as they are secreted with the lamellarbodies, they have been immunolocalized to the intercorneocyte lipid lamellae. Sondellet al. (36) used antibodies that immuno-react precisely with pro-SCCE to confirm that thisenzyme is transported to the SC extracellular space via lamellar bodies. In later studies,using antibodies to both pro-SCCE and SCCE, Watkinson et al. (37) demonstrated that theprocessed enzyme was more associated with the corneodesmosomal plaque. Morerecently, Igarashi et al. (38) have immunolocalized cathepsin D to the intercellular space,

The Dry Skin Cycle 87Table 1 Desquamatory EnzymesSphingoid hydrolases Cermidase GlucocerebrosidaseSulphatases SphingomylinaseGlycosidases Sphingomyelin deacylaseSerine proteases GlucosylceramidedeacylaseCysteine proteases Steroid sulphataseAspartic proteases Heparanase 1 Stratum corneum chymotryptic-like enzyme (SCCE/KLK7) Stratum corneum tryptic-like enzyme (SCTE/KLK5) Stratum corneum thiol protease (SCTP/L2) Stratum corneum cathepsin L-like enzyme (SCCL) Stratum corneum cathepsin D-like enzyme (SCCDE) Stratum corneum cathepsin E-like enzyme (SCCEE) Skin aspartic protease (SASPase) Caspase 14whereas cathepsin E was localized within the corneocytes. Finally, KLK8 has also beenreported to be localized to the intercellular spaces of the SC (39). As the desquamatory enzymes are present in the intercellular space, the physicalproperties of the SC lipids, together with the water activity in this microenvironment, willinfluence the activity of these enzymes. Interestingly, however, SCCE appears to have agreater tolerance to water deprivation than other proteolytic enzymes, and this may be anadaptation to maintain enzyme activity even within the water-depleted SC intercellularspace (40). However, a variety of inhibitors are also present to attenuate their activities,cholesterol sulphate being one of them. Other protein and peptide inhibitors are present suchas elfin, covalently bound to the CE, antileukoproteinase, alpha-1-antitrypsin, alpha-1-antichymotrypsin, and the SPINK5-derived peptides (41). Nevertheless, anti-leukoproteaseis believed to be the major physiological inhibitor of SCCE; the serpins are too low inconcentration to be physiologically relevant (42). Caubet et al. (33) recently speculated in anew model of desquamation that SPINK5 may also inhibit SCTE. Currently, little is understood of the molecular activation mechanisms of SCCE orother enzymes within the SC, but Brattsand et al. (43) has proposed a model recently forthe activation of the kallikreins (Fig. 9). Clearly, SC pH and water content will influenceenzymic activity. As the SC pH declines towards the surface of the skin, the activity ofSCTE and SCCE may be reduced and perhaps the acid optimal cathepsin enzymes mediatethe final desquamatory steps. The role of the newly identified skin aspartic protease andcaspase 14 in this process is still awaiting clarification.CORNEOCYTE ENVELOPE MATURATION AND THE ROLEOF TRANSGLUTAMINASESThe CE is an extremely stable and insoluble proteinaceous layered structure. The stabilityof the envelope is attributed to the degree of cross-linking of envelope proteins by eitherdisulphide, glutamyl-lysine isodipeptide bonds, or glutamyl polyamine cross-linking ofglutamine residues of several CE proteins (44). The enzymes, responsible for catalysingthe gamma-glutamyl-epsilon-lysine isodipeptide bond formation, are the calcium-dependent transglutaminases (TGase; glutamyl-amine aminotransferases EC 2.3.2.13),

88 Matts and Rawlings hK14 Acidic pH(skin surface) pro-hK7 hK7 + prohK14 hK14 pro-hK5 + hK5pro-hK7 + – pro-hK5 + Neutral pHFigure 9 Proposed kallikrein activation cascade in human stratum corneum. Source: FromRef. 43.of which four are expressed in the epidermis: TGase 1, 2, 3, and 5. However, only TGase 1,3, and 5 are thought to be involved in keratinocyte differentiation. At early time points in the keratinocyte differentiation process, envoplakin andperiplakin are expressed and become associated with desmosomes in the viableepidermis. Subsequently, involucrin (the glutamyl-rich protein that covalently-boundlipids become attached to) is expressed at the same time as TGase 1 (45–47). TGase 1then cross-links involucrin to the other early expressed proteins, such as members of thesmall proline-rich family of proteins. Subsequently, other plasma membrane proteinsbecome cross-linked, and these form a scaffold for further reinforcement and maturationevents (48). By Normarski microscopy, CEs (CE’s) were shown to have a crumpled surfacewhen isolated from the lower layers of the SC and a smoother, more flattened surface whenisolated from the upper SC. These two populations of CEs were named fragile (CEf) andrigid (CEr). Mils et al. (49) reported that about 80% of corneocytes from volar forearmskin were smooth and rigid, whereas 90% from foot sole were rough or fragile cells. Theycan also be further differentiated by their binding of tetra-methyl rhodamineisothiocyanate (TRITC), with the rigid envelopes staining to a greater extent (Fig. 10)(50). However, Hirao et al. (51) have used a more elegant method to identify CEs basedupon their hydrophobicity (staining with Nile red) and antigenicity (to anti-involucrin)(Fig. 11). It is clear from these studies that immature envelopes (CEf) occur in the deeperlayers of the SC (involucrin-positive and weak staining to Nile red or TRITC) and thatmature envelopes occur in the surface layers of healthy skin (apparent involucrin staininglessened and increased staining with Nile red or TRITC). More recent work fromKashibuchi et al. (52) using atomic force microscopy confirmed these structural changes incorneocytes from the deeper layers of the SC. The classification of fragile and rigid envelopes has subsequently been found to be apertinent classification system as, mechanically, they have fragile and rigid characteristics

The Dry Skin Cycle 89Figure 10 Fluorescence and Normaski phase contrast microscopy of TRITC stained cornifiedenvelopes demonstrating increased fluorescence labelling of CEr compared with CEf. Source: FromRef. 50.under compressional force (Fig. 12) (50). Supporting this concept of increasing CEstrength, gamma glutamyl-lysine cross-links also increase in the subsequent layers of theSC, due to enhanced TGase activity. Three pools of TGase activity have been identified inthe SC which have been classified based upon their solubility characteristics: a water-soluble TGase (mainly TGase 1 and 3), a detergent-soluble TGase (TGase 1), and aparticulate form that cannot be liberated from the corneocyte. Whether all enzymefractions are active in this maturation process of CEf to CEr is currently not known.STRATUM CORNEUM NATURAL MOISTURIZING FACTORS (NMF)A historical perspective on filaggrin biology was given by Rawlings et al. (1).Biologically, NMF allows the outermost layers of the SC to retain moisture against theFigure 11 Double staining of CEs with Nile red and anti-involucrin (shown here in gray scale).(A) Face and (B) upper arm. Source: From Ref. 51.

90 Matts and Rawlings CEr Population mean = 832.94µN% probability 0.16 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0 250 350 450 550 650 750 850 950 1050 1150 1250 1350 1450 1550 CEf force range (µN) 0.40 Sample mean = 135.1µN 0.35% probability 0.30 700.25 900.20 1100.15 1300.10 1500.05 170 1900 210 force range (µN)Figure 12 Distribution profile of the maximal compressional forces (uN) of individual CEs. Toppanel shows the force range for CEr and the bottom for CEf. The maximal compression force wassignificantly different between the corneocytes. Source: From Ref. 50.desiccating action of the environment. Traditionally, it was believed that this waterplasticized the SC, keeping it resilient by preventing cracking and flaking which mightoccur due to mechanical stresses. The general mechanisms by which these NMFcomponents influence SC functionality have been studied extensively. From a physicalchemistry perspective, the specific ionic interaction between keratin and NMF,accompanied by a decreased mobility of water, leads to a reduction of intermolecularforces between the keratin fibers and increased elastic behavior. Recent studies haveemphasized that it is the neutral and basic free amino acids (53), in particular, that areimportant for the plasticization properties of the SC. The generation of NMF issummarized by Mechin et al. (Fig. 13) (54) which also highlights the importance ofpeptidylarginine deminases involved in the processing of filaggrin and thereby allowing itshydrolysis to NMF. Recently, hyaluronic acid has been shown to be present naturally in the SC (55) ashas glycerol. Glycerol will also be derived from sebaceous triglyceride breakdown and

The Dry Skin Cycle 91again, to emphasize the importance of this molecule, studies by Fluhr et al. (56) haveindicated that topically-applied glycerol can completely restore the poor quality of SCobserved in asebic mice (that are lacking sebaceous secretions) to normal. The importanceof glycerol as a natural skin moisturizing molecule has also been shown by Elias et al. (57)However, typically, these two molecules have been largely ignored in descriptions ofNMF composition (1). Recent data also indicates that lactate plays a critical role ininfluencing the physical properties of the SC. Lactate and potassium were found to be theonly components of the NMF analyzed that correlated significantly with the state ofhydration, stiffness, and pH in the SC (58). The generation and maintenance of an acid pH within the SC, the so-called “acidmantle,” is critical to the correct functioning of this tissue. Studies point to an essential roleof free fatty acids generated through phospholipase activity as being vital for SCacidification (59), while Krein and Kermici (60) have recently proposed that urocanic acidplays a vital role in the regulation of SC pH. Although this is in dispute, it is likely that allNMF components contribute significantly to the overall maintenance of pH. Other components of NMF are also not derived from filaggrin, and urea, like lactate,may also be derived in part from sweat. However, the presence of sugars in the SCrepresents primarily the activity of the enzyme beta-D-glucocerebrosidase, as it catalyzesthe removal of glucose from glucosylceramides to initiate lipid lamellae organization inthe deep SC (1). New measurement tools have been developed in the last decade for the measurementof such compounds in vivo. Caspers et al. (61) have pioneered the use of confocalRaman microspectroscopy to determine the concentration of defined NMF components,non-invasively, in vivo within the SC. Typical depth-concentration profiles can be seenin Figure 14.Figure 13 Schematic representation of profilaggrin catabolism and filaggrin hydrolysis to NMFand activation of peptidylarginine deiminase. Source: From Ref. 54.

92 Ser Gly Matts and Rawlings 1.0 1.0 1.0 Pca 0.5 0.5 0.5 0.0 0.0 0.0 0 20 40 60 0 20 40 60 0 20 40 60 1.0 Arg+Orn+Cit 1.0 HisNormalized concentration Ala 1.0 0.5 0.5 0.5 0.0 0.0 0.0 0 20 40 60 0 20 40 60 0 20 40 60 1.0 Urea 1.0 Lactate Uca 1.0 0.5 0.5 0.5 0.0 0.0 0.0 0 20 40 60 0 20 40 60 0 20 40 60 Depth (μm)Figure 14 Semiquantitative in vivo concentration profiles of NMF and sweat constituents in thestratum corneum of the thenar as determined by Raman spectroscopy. Source: From Ref. 61.THE EFFECT OF HUMIDITY ON EPIDERMAL DIFFERENTIATIONAND STRATUM CORNEUM QUALITYBefore considering the biology of dry skin and the dry skin cycle, it is important to reviewthe effect of environmental conditions on the SC, as these are the primary initiating eventsfor the precipitation of the condition. In studies conducted in the different seasons of theyear in the U.K., Rogers et al. (62) demonstrated that there was a significant reduction inthe levels of SC ceramides and fatty acids, together with linoleate-containing CER EOS insubjects in winter. Similar differences in scalp lipid levels have been observed between thewet and dry seasons in Thailand (63). Nevertheless, more importantly, Declercq et al. (64)have reported an adaptive response in human barrier function, where subjects living ina dry climate such as Arizona (compared with a humid climate in New York) had muchstronger barrier function and less dry skin due to increased ceramide levels and increaseddesquamatory enzyme levels (SCCE and SCTE). Several animal studies have been conducted that support these findings. TEWL wasreduced by approximately 30% in animals exposed to a dry (!10%RH) environment due toincreased lipid biosynthesis, increased lamellar body extrusion, and a slightly thicker SClayer, whereas, in animals exposed to a high humidity environment (80%RH), this inductionof lipid biosynthesis was reduced (65). However, abrupt changes in environmental humidity

The Dry Skin Cycle 93can also influence stratum corneum moisturization (66). After transferring animals froma humid (80%RH) to dry (!10%RH) environment, a six-fold increase in TEWL occurred.Barrier function returned to normal within seven days due to normal lipid repair processes.These changes did not occur in animals transferred from a normal to dry humidityenvironment. These changes in barrier function have also recently been reported in a groupof Chinese workers who are exposed to very low humidity conditions. However, thechanges in barrier function take longer to reach equilibrium than anticipated from the animalstudies (Fig. 15) (67). Similarly, findings were reported for the water-holding capacity and free amino acidcontent of the SC. Katagiri et al. (68) demonstrated that exposure of mice to a humidenvironment, and subsequent transfer to a dry one, reduced skin conductance and aminoacid levels even after seven days following transfer; after transfer from a normalenvironment, however, decreased amino acid levels recovered within three days. Exposure to low humidity conditions also increases epidermal DNA synthesis andamplifies the DNA synthetic response to barrier disruption (69). Equally, when in a dryenvironment epidermal IL-1 levels increased and increased levels of this cytokine weregreater when the barrier was experimentally-challenged (70). More recently, the samegroup also reported increased numbers of mast cells and increased dermal histamine levels(but unchanged epidermal histamine levels) (71). These changes in barrier properties ofthe SC are attributable to changes in SC moisture content and provide evidence thatchanges in environmental humidities contribute to the seasonal exacerbation oramelioration of xerotic skin conditions which are characterized by a defective barrier,epidermal hyperplasia, and inflammation.THE PATHOPHYSIOLOGY OF WINTER- ANDSOAP-INDUCED DRY SKINThe differences in SC water concentration profiles between normal and dry skin influencethe enzymic reactions in the SC. In dry flaky skin conditions, corneodesmosomes are not 11.0 10.5TEWL (g m–2h–1) 10.0 9.5 * 9.0 * 8.5 8.0 * * 7.5 7.0 6.5 6.0 control <0.5 m -1.0 m -10.0 m -20.0 m >20.0 m 1.1 10.1 0.5 1.5%RH & 23.6 C for 12hrs TEWL adaptation as result of several Externally approximately months conditioning 78%RH and 24 CFigure 15 Time course of TEWL adaptation in humans working in an ultra-low humidityenvironment (1.5%RH). Source: From Ref. 67.

94 Matts and Rawlingsdegraded efficiently and corneocytes accumulate on the skin’s surface layer leading toscaling and flaking. Increased levels of corneodesmosomes in soap-induced dry skin werefirst reported by Rawlings et al. (23) but have been confirmed more recently by Simonet al. (72). Many corneodesmosomal proteins are now also reported to be increased in thesurface layers of xerotic skin. Increased SC corneodesmosomal proteins have also beenreported (23,71–73). Interestingly, however, in winter xerosis, the accumulation of thecorneodemosomal proteins, Dsg 1 and plakoglobin, correlate with each. Cdsn proteinlevels, which were also increased, do not, however, have such an association, suggestingthat different proteolytic mechanisms occur for the different corneodesmosomalcomponents during desquamation. As suggested by Simon et al. (72), as plakoglobin isa cytoplasmic protein, this would indicate that at least the cytoplasmic domain of Dsg 1may be cleaved. In fact, immunoreactivity to the carboxy terminal tail of the cytoplasmicportion of Dsg 1 was observed. Perhaps the intracellular portions of Dsg 1 are alsodegraded within the corneocyte (for example, plakoglobin by the trypsin-like activity orcathepsin E activity reported within the corneocyte matrix). Conversely, Cdsn might bedegraded by SCCE, SCTE, or cathepsin D in the lamellar matrix. This is consistent withthe early electron microscope images of Rawlings et al. (23) showing thatcorneodesmosomes become internally vacuolated, followed by complete detachment ofthe protein structures from the CE (Fig. 8). The lamellar lipid matrix is also perturbed dramatically in dry skin (Fig. 16) (23). Asthe main desquamatory enzymes are found within this lipid matrix, the physical propertiesof the lamellar lipids will, therefore, influence enzyme activity. Rawlings et al. (5) originally reported that SC SCCE levels were reduced in the outerlayers of xerotic SC compared with normal skin. This has been confirmed recently in moreextensive studies by Van Overloop et al. (74) who also found that the equally important SCSCTE activities were also reduced. Conversely, in SLS-induced dry skin, increasedactivities of these enzymes were reported (28). More recently, the over-activation of theplasminogen cascade has been associated with dry skin. Normally, only observed in theepidermal basal layers, skin plasmin is widely distributed through the epidermis in dryskin. Interestingly, a urokinase-type plasminogen activator also exists in the SC (75).Clearly these and other enzymes are potentially involved in the inflammatory andhyperproliferative aspects of dry skin. It has been well established that, in hyperproliferative disorders such as dry skin,there is a change in SC lipid composition. In particular, the composition of the ceramidesubtypes change and a predominance of sphingosine-containing ceramides (at theexpense of the phytosphingosine-containing ceramides) has been observed in the SC ofsubjects with dry skin. Fulmer and Kramer (76) first identified these changes in SDS-induced dry skin (increased levels of ceramide 2 and 4, and reduced levels of ceramide3). However, Saint-Leger et al. (77) could not find any changes in ceramide levels in dryskin, but found increased fatty acid levels. Rawlings et al. demonstrated the reducedlevels of ceramides at the surface of the SC in winter xerosis (23). At this time, the fullcomplexity of the different ceramide structure was not known, but, more recently,Chopart et al. (78) observed dramatic reductions in the levels of phytosphingosine-containing ceramides in dry skin (approximately 50%), together with a shortening andlengthening of the acyl sphingoid bases sphingosine and 6-hydroxysphingosine,respectively. Van Overloop et al. (74) also clearly demonstrated that the phyto-sphingosine-containing ceramides were reduced to a greater extent than other ceramides,with increasing dryness levels. Fulmer and Kramer at P&G also observed dramaticreductions in the levels of long chain fatty acids in dry skin (76). Imokawa et al. (79) did

The Dry Skin Cycle 95Figure 16 Organization of stratum corneum lipids in tape stripping of subjects with winterxerosis. Transmission electron micrographs of tape strippings of individuals with severe xerosis.Perturbation in lipid organization towards the surface of the stratum corneum. (A) First strip;disorganized lipid lamellae. (B) Second strip; disorganized lipid lamellae. (C) Third strip; normallipid lamellae (x200,000). Source: From Ref. 23.not find reduced ceramide levels in xerotic skin (but only average levels, rather thansuperficial levels, were measured). These changes in lipid composition will, of course, influence the lamellar packing ofthe lipids. In fact, Schreiner et al. (80) established a reduction of CER EOS and EOH withincreased concentrations of sphingosine-containing ceramides (CER NS and CER AS) andcrystalline cholesterol in association with a loss of the LPP. However, although the lipidultrastructure is clearly aberrant in the outer layers of dry skin (23), more work is neededto ascribe a particular lipid phase. The proportions of the different CE phenotypes also change in subjects with dry skin(43,50). Soap washing leads to a dramatic increase in the levels of the fragile envelopephenotype at the expense of the rigid phenotype (Fig. 17). It is known that SCtransglutaminase activities increase towards the surface of the SC, particularly thedetergent-soluble and particulate fractions. Although the same trend of the relativeincrease in TGase between the inner and outer corneum is true of dry skin, TGase activities

96 Matts and RawlingsPercentage of Corneocyte Phenotype Normal Soap-Dried 100 80 60 * 40 * 20 0 Fragile RigidFigure 17 Percentage distribution of CEr and CEf in normal and soap-dried dry skin. *p!0.05.Source: From Ref. 50.are dramatically lowered in dry skin compared with healthy skin, particularly thedetergent-soluble fraction, which contains mainly TGase 1. Reduced NMF levels are also implicated in dry skin conditions. The loss of NMFgenerally reported with increased aging, however, is not consistent with the recentobservations of Takahashi and Tezuka (81) of increased NMF in subjects with senilexerosis, and suggests that our understanding of this process is far from complete.THE “DRY SKIN CYCLE” MODEL: A NEW WAY TO DESCRIBEINDUCTION AND PROPAGATION OF THE XEROSISClassically, dry skin has been described in two ways—(1) as a condition that is simplyeither present or not or (2) as a linear progression of sequelae, resulting in the concomitantdevelopment of clinical tools such as linear visual grading scales, etc. While not refutingthe validity of these, it is proposed that the induction and propagation of dry skinconditions may be best and most intuitively expressed as a cyclical model, dependent onSC integrity and particularly upon barrier function and homeostasis. A cyclical model implies a spiralling deterioration in outcome that, withoutintervention, would lead to a progressive worsening in model endpoints. Additionally, it isimplicit that intervention at one, or preferably multiple, points within this cycle isnecessary to arrest the progression of this continuing downward spiral. This is indeed thecase with most dry skin conditions and, moreover, reflects extremely well consumerperception of dry skin—the seeming repetitive cycle of product usage, re-usage,disappointment with treatment outcome, and, often, a corresponding loss of compliance.The model described below describes several phases within this cycle and, therefore,possible targets against which treatments could be directed. Reference to the graphicaldepiction of the model below (Fig. 18) may facilitate complete understanding of therelationship of these phases, one with another. As discussed the induction phase can be mediated by a variety of different factors: -low environmental temperature and humidity -abrupt changes in environmental conditions which includes the effect of modern indoor climate-controlled environments -surfactant dissolution of SC lipid and NMF -chronological aging and genetics

The Dry Skin Cycle 97 Once the skin has been provoked by one or more of these mechanisms, there is aninevitable sequence of events that may be described conveniently as a cycle. Initially a mini-cycle of barrier deterioration is initiated and perpetuated. Blankestimated that the SC loses its flexibility once its water content falls below approximately 10%(8), the provocation for which may constitute one or a combination of the factors noted above.Without intervention, this quickly leads to a steeper SC hydration gradient, a decrease in netrecondensation on the SC surface, a corresponding increase in evaporative water loss from theSC surface, a consequent further drop in SC water concentration, and so on. The inevitablerapid consequence of this series of events is a decrease in the plastic or viscous properties ofthe SC (commonly interpreted as skin “softness” or “suppleness”), an increase in SCfragility/brittleness, and an impairment of SC barrier function (82–85). This surfacedehydration is the first step in the development of the dry skin cycle and is further exacerbatedby destruction of the normal barrier lipid lamellae in the outer layers of the SC during bathing(23). The impaired barrier in the superficial layers of the SC allows leaching of NMF from theoutermost skin cells, thereby reducing SC water activity. Whiteness between thedermatoglyphics (caused by backscatter from multiple tissue-air interfaces) and minorscaling due to the dehydration of individual corneocytes are the first visible steps in the cycle.Perturbation to the barrier then leads to further development of dry skin. Due to the cyclical nature of these processes, therefore, it becomes virtuallyimpossible to distinguish between dry skin conditions that are provoked initially by barrierdisruption or by dehydration of the SC. However, once the barrier has been disrupted, evensuperficially, a new cascade of events is started primarily through the induction of ahyperproliferative state. Induction SC barrier dehydration AF Scaling TEWL increases, SC water content falls further, ingress of exogenous B materials, loss of superficial NMF, and denaturation of SC enzymesFunctionally impaired Cytokine releaseSC desquamation andmaturation C E Dysfunctional kertainocyte differentiation DFigure 18 Schematic diagram showing pivotal events within the “dry skin cycle.” Source: FromRef. 2.

98 Matts and Rawlings Acute and chronic insults to the SC barrier will lead to enhanced keratinocyteproliferation, consequent hyperkeratosis, and mild inflammatory changes, one of the hall-marks of dry skin conditions, as the skin attempts to repair itself. This response is mediatedvia production and secretion of cytokines and growth factors, many researchers citing theratio between interleukin 1 receptor antagonist protein and interleukin-1 alpha (IL-1 alpha)as a key marker of this process (86–89). The degree of hyperprofileration has been shownto be dependent upon the corresponding degree of barrier perturbation (90), probablyreflecting both the ingress of exogenous irritants through the impaired barrier and thegrowing realization that the SC barrier is itself a biosensor and that corneocytes andkeratinocytes themselves participating in the release of these messengers. Thehyperproliferation of the epidermis probably occurs as a result of the double paracrinesignaling events between the epidermis and dermis. IL-1 acts on fibroblasts which in turnsecrete KGF and GMCSF inducing hyperproliferation and dysfunctional differentiation ofkeratinocytes (91). The induction of this inflammatory hyperproliferative state is absolutely key in thecycle of dry skin as it fundamentally leads to aberrant differentiation and the over-hastyproduction of a variety of poor quality materials and structures vital to the properfunctioning of the SC barrier and normal healthy skin. These include: 1. the production of smaller and immature CEs 2. changes in epidermal lipid and particular ceramide biology 3. reduced transglutaminase activity 4. reduced filaggrin synthesis and NMF levels Finally a loss in efficiency of desquamation, due to reduced activity of desquamatoryenzymes at the surface of the SC, and ensuing scaling, thickening, and loss ofhygroscopicity of the SC occurs. Marked scaling is, of course, one of the obviousconsumer-noticeable expressions of “dry skin.” The formation of a thicker SC withimpaired desquamation has, again, immense biophysical importance. The water gradientacross the thicker SC becomes steeper, leading to further increases in evaporative waterloss, reducing further water concentration in the outer SC, and propagating directlyanother round of the dry skin cycle. Corneocytes that should be in a mature fully hydrophobed format are now replacedby fragile corneocytes. The resulting barrier protecting these corneocytes and theircontents is now weaker due to changes in barrier lipid profiles and surface hydrophobicity.Equally, the hygroscopic (though highly water-labile) NMF present within corneocytes ofnormal SC, are depleted gradually through normal everyday activities such as cleansingand/or occupational duties (1,61). The corneocytes of dry SC are, therefore, subjectto exaggerated insult such due to their changed biochemical and biophysical properties.The dry skin cycle, thus, is propagated further by an increased loss of NMF relative tonormal skin and a corresponding loss in SC hygroscopicity. Finally and most importantly, the development of an increasingly thick, dry SCresults in a layer characterized, from a biomechanical viewpoint, by a dramatic increase inhardness and brittleness. The consumer perceives this as tightness. These properties createan SC barrier inherently susceptible to mechanical stress and fracture, another factordriving the impairment in barrier function cyclical nature of the dry skin cycle. The clinical endpoint of “dry skin” cannot be regarded as static but rather is mostfully described as a cycle that, without intervention, tends to perpetuate itself. Pivotal toevery stage of this cycle and its propagation is a compromised SC barrier. Interventionsthat truly break the dry skin cycle, therefore, by definition need not only to treatsymptomatic manifestations, but repair and augment SC barrier function. This will yield a

The Dry Skin Cycle 99skin that is inherently better able to cope with the constantly changing externalenvironment of the modern world.MANAGEMENT OF DRY SKINAlthough a major analysis of dry skin treatments are outside of the scope of this review it isworth mentioning just briefly the biology that needs to be corrected in cosmetic dry skinconditions and some key examples of suitable treatments. Traditionally, humectants, occlusives, and emollients have been, and will continueto be, the mainstay of cosmetic treatments (92): Arguably, the most widely used and effective humectant used in cosmetic treatmentsfor xerotic skin is glycerol, due to its excellent safety profile, cost, and simply outstandingwater-retaining (humectant) and hygroscopic properties. There is now much evidence,however, that glycerol is not only a “mere” humectant, but also (i) is a lipid fluidizer (93),modulating the temperature-dependent rheology of SC lipid, thus preventing a loss offluidity of their lamellar structure at low relative humidities and (ii) has corneodesmolyticactivity, facilitating the proteolytic digestion of superficial corneodesmosomes in dryskin (94). Humectants are also an essential requirement for most of the additionalapproaches. In O/W creams occlusives and bilayers-forming lipids (described below) alsorequire glycerol to alleviate dry skin. Moreover, humectants are required for thetransglutaminase-mediated CE maturation that is required for a healthy SC (95). In thisrespect, combinations of humectants including glycerol have been shown to be moreeffective than just using glycerol alone. Glycerol has also been shown to enhance thebarrier function of the SC (96). Like glycerol, urea is a natural component of the SC NMF and has been used as ahumectant in creams since 1943 (97). Ten-percent urea has been shown to be moreefficacious than salicylic acid and petroleum jelly. Urea-containing moisturizers have beenreported to improve barrier function and reduce TEWL, increase skin capacitance, andreduce irritation reactions (98–101). As a principal component of NMF, considerable interest has been paid to the abilityof PCA and its derivatives to moisturise the SC. Creams and lotions containing the sodiumsalt of PCA are widely reported to help hydrate the SC and improve dry flaky skinconditions (102–106). Petroleum jelly acts primarly as an occlusive agent having been shown to reduceTEWL by over 98%, whereas other oils only manage a 20–30% reduction. Yet this agentdoes not simply act as an occlusive film over the surface of the skin; it has been shown todiffuse into the SC intercellular domains which may add to its efficacy. On penetratingthe epidermis it was also shown to accelerate lipid biosynthesis, thereby aiding barrierrepair (107). Recent years, however, have seen a dramatic increase in the development andinclusion of novel technologies that complement these mainstays of moisturization.Bilayer-Forming LipidFrom the current understanding of the compositional changes in dry skin five aspects ofstratum corneum lipid biochemistry need to be corrected: The lowered levels of ceramides generally. The phytosphingosine-containing ceramide insufficiency.

100 Matts and Rawlings The ceramide one linoleate (CEOS) insufficiency. The lowered covalently bound ceramides. The precise chain length of the ceramide sphingoid bases and free fatty acids. Overall, however, the lipid lamellar architecture in the outer layers of the stratumcorneum needs to be normalized in dry flaky skin conditions. Evidence also indicates that areduction in long chain fatty acids also occurs in SLS-induced dry skin. As these lipids areimportant for inducing an orthorhombic lateral packing state, these will also need to besupplied to the skin to more effectively correct barrier function. Moreover correction of thereduction of SC NMF levels, correction of the aberration of CE maturation, and theimpaired corneodesmolysis are needed for dry skin treatments. Several clinical studies evaluating the effects of ceramides have been conductedrecently. However, it is important to remember that to derive the full benefits of ceramidetechnology formulation into heavy emulsions where other emollients dominant theformulation will be difficult to discern unless the ceramides are at a high enoughconcentration. Nevertheless, two studies investigating the properties of Locobase Repaircream have found opposite effects on barrier recovery. Barany et al. (108) could not findany improvements to placebo whereas Kucharekova et al. (109) found that the CER NP-containing cream significantly reduced TEWL, erythema, and epidermal proliferationcompared with placebo cream. Nevertheless, further improvements in function areobserved with complete lipid mixtures. De Paepe et al. (110) have demonstratedimprovements in barrier functionality and SC hydration from a lipid mixture of CER NP(0.2%), CER AS (0.1%), and CER UP (0.2%) together with cholesterol (0.25%), linoleicacid (0.25%), and phytosphingosine (0.5%) compared with placebo lotions and a lotioncontaining only CER NP (0.6%) and CER UP (0.4%). The percentage increases in TEWLand SC hydration are shown in Figure 15. Berardesca et al. (111) have also established thatbalanced lipid mixtures containing CER NP are effective in improving the barrierproperties and clinical condition of skin in subjects with contact dermatitis. Equallyconvincing are the studies of Chamlin et al. (112) showing that a ceramide dominantbarrier repair lipid cream alleviates childhood atopic dermatitis. Over the six-weektreatment period TEWL values decreased by 50% and the number of D-squame tapestrippings required to break the barrier increased from approximately 12 to 22 strippings,indicating a stronger SC barrier function. In addition to ceramides, which have been introduced to supplement the SC barrier,(113) phospholipids are also bilayers-forming lipids and when combined with glycerolhave been demonstrated to be clinically superior to petroleum jelly in relieving dryskin (114).Hydroxy AcidsHydroxy acids are being used to facilitate desquamation and improve lipid biosynthesistogether with barrier function. The influence of alpha-and beta-hydroxy acids (115) ondesquamation is now well established, but new lipophillic variants of salicylic acid appearto influence corneodesmolysis differently. Whereas lactic and salicylic acid act on allcorneodesmosomes, LSA only acted in the stratum disjunctum corneodesmosomes. Theselipophillic variants appear to act on the whole structure of the corneodesmosomes whereasthe “ordinary” acids fractionate the corneodesmosomes. Fartarsch et al. (116) alsodemonstrated that the action of glycolic acid on corneodesmolysis was restricted to thestratum disjunctum suggesting a targeted action without compromising barrier function.Medium chain fatty acids have also been reported to not only improve SC flexibility but

The Dry Skin Cycle 101also assist in the relief of dry skin in combination with barrier lipids. Further enhanced dryskin relief was observed in the presence of barrier lipids (117), and the L isomer, inparticular, increased SC extensibility and keratinocyte proliferation as reported byRawlings et al. (118). Rawlings et al. also reported that longer chain hydroxy acids weremore effective than short chain fatty acids at facilitating corneocyte cell release in thepresence of several calcium chelators. This may be due to a fluidizing effect of these longerchain fatty acids on the lamellar lipids as in SC extensibility studies using extensionswhere only lipids are believed to being extended longer chain alpha-hydroxy acidsplasticize the corneum (119). SC turnover time measured by dansyl chloride (a measure of epidermal proliferationmatched by desquamation) increased by 15% by applying a moisturizing cream at pH 3.8.However, further increases were observed with increasing concentration of the free acid ofglycolic acid or by decreasing the pH of the base. At 8% glycolic acid concentration (4%free acid) Johnson (120) reported approximately 30% increase in SC turnover time. Theincreased turnover time needs to be matched by increased desquamation; otherwise,retention hyperkeratosis would occur, which clearly it does not. In fact, the oppositeoccurs. So desquamation must also be enhanced by further activating acidic optimumenzymes or by also chelating calcium, which is known to reduce the final processing stepsinvolved in Cdsn degradation. Nevertheless, not all hydroxy acids perform equally, and, in fact, some appear toenhance the skin’s sensitivity to UV irradiation, especially glycolic acid. However,glucanolactone and tartaric acid have been shown to be not only superior to glycolic acidand lactic acid in improving barrier function but have been shown to not increase insunburn cell formation (121).SC Barrier Augmentation by Inducing Epidermal DifferentiationLigands for nuclear receptors such as the peroxisomal proliferator activated receptorhave been shown to improve epidermal differentiation, increasing ceramide and filaggrinlevels (122). This superfamily of nuclear transcription receptors includes the retinoicacid receptors, the steroid receptors, the thyroid receptors, and the vitamin D receptors andalso the peroxisome proliferator activated receptor (PPAR), together with farnesolactivated receptor (FXR) and the liver activated receptor (LXR). These transcriptionfactors bind their respective ligands and regulate many of the aspects of cellularproliferation and differentiation. Fatty acids are important ligands for the PPAR receptor,farnesol for the FXR, and hydroxylated cholesterol derivatives or cholestenoic acid for theLXR. All of these pathways stimulated epidermal differentiation and increased thesynthesis of involucrin, filaggrin, and enzymes of the ceramide synthesis pathway. The transcription factor most intensively investigated is the PPAR. There are threemain PPAR isoforms: alpha, beta/delta, and gamma. Nevertheless, PPAR delta wasrecently observed to be the predominant PPAR subtype in human keratinocytes, whereasPPAR alpha and gamma were only induced during epidermal differentiation, suggestingnon-redundant functions during differentiation (123). Respective ligands for all of theseisoforms increased epidermal differentiation. Pharmaceutical ligands for the PPARreceptors increase ceramide synthesis in vitro by increasing the expression of SPT,glucosyl ceramide synthase, and glucocerebrosidase but not sphingomyelinase (124).More recently PPAR delta ligands were found to be the most potent in inducing epidermaldifferentiation (tetrathioacetic acid) by increasing involucrin and transglutaminase whiledecreasing proliferation.

102 Matts and Rawlings Petroselinic acid (125) and conjugated linoleic acid (126) have been identifiedas potent PPAR alpha activators improving epidermal differentiation, reducinginflammation, increasing extracellular matrix components, and eliciting skin lightening.In vitro increased levels of transglutaminase, involucrin, filaggrin, and CE formationwere observed in keratinocytes after treatment with petroselinic acid. These effects wereconfirmed in vivo by short-term patch testing studies over three weeks and increases ininvolucrin and filaggrin were also observed. Using this technology, improvements in thesigns of photodamage, skin tone and dry skin were observed in a 12-week clinical study onforearm skin (127). Octadecenedioic acid has also recently been identified as a pan-PPARagonist (with a preference for PPAR gamma) and has been shown to reduce skinhyperpigmentation, but with its PPAR agonist activities it is also expected to improveepidermal differentiation (128).SC Barrier Augmentation by Inducing Epidermal LipogenesisChanges in lipid levels and types can be corrected by topically applying agents to manipulatethe lipid synthesis process within the viable epidermis. However, as described above, in dryskin conditions the epidermis makes less phytosphingosine-containing ceramides, changesthe carbon chain lengths of other sphingoid bases and synthesis less long chain fatty acids.These results suggest that changes in the levels or activities of the different fatty acidsynthetases, as well as the enzymes involved in phytosphingosine synthesis, occur in dry skin.The biology of these enzymes is yet to be described in these conditions. Elias et al. (129), however, has used lipid mixtures to aid barrier recovery in acetonedamaged barrier studies. Cholesterol itself was shown to aid barrier recovery in a tapestripping model in aged skin but not young skin. In fact any incomplete mixture of one ortwo of the three major lipid species slows barrier recovery in this model. The equimolarmixture of the three dominant SC lipids allows normal rates of barrier recovery in normalskin, whereas its further adjustment to a 3:1:1 molar ratio accelerates barrier recovery.As expected the requirements for optimal barrier recovery in aged skin is different, andit has been shown that a cholesterol dominant lipid mixture accelerates barrier recovery inaged skin whereas a fatty acid dominant mixture delays barrier recovery. In young skinany of the lipid species can be the dominant lipid and the barrier will recover more quicklywith one exception, and that is in atopic dermatitis where a ceramide dominant mixture isrequired (130). Further studies on the use of long chain fatty acids are recommended.Exploiting these facts it has been shown that (131) mevalonic acid, the product of the ratelimiting enzyme HMGCoA reductase, increases cholesterol biosynthesis. Several other routes have been shown to increase ceramide synthesis in vivo andimprove barrier function. As described above alpha-hydroxy acids well known for theirdesquamatory properties also stimulate lipid biosynthesis. Lactic acid, and especially theL isomer, increases ceramide biosynthesis in vitro and in vivo. Presumably lactic acidachieves this by acting as a general lipid precursor by providing acetate and providingmore reducing power in the form of NADH or NADPH (132). Correspondingimprovements in barrier function were reported. Interestingly, lactic acid also increasedthe levels of linoleate-containing CER EOS which may be contributing to theseimprovements in skin functionality. The pleotropic skin benefits of niacinamide have been the subject of intense study byProcter & Gamble and have been excellently reviewed by Matts et al. (133). Niacinamidehas been reported to stimulate the synthesis of glucosylceramides, sphingomeylin,cholesterol, and fatty acids by keratinocytes in vitro (127). The increases in ceramidesynthesis were achieved by enhancing the activity of SPT together with the expression of

The Dry Skin Cycle 103Table 2 Agents That Increase Ceramide BiosynthesisLipids Optimized mixtures of ceramides, cholerterol & fatty acidsLipid precursors Phytosphingosine, tetra-acetylphytosphingosine, omega-hydrosy-fattyAlpha-hydroxy acids acides, linoleic acidHumectants L-Lactic acidVitamins Glycerol, ureaProtease inhibitors Niacinamide, lipoic acid, ascorbic acidMonerals Aminocyclohexanecarboxylic acid, egg white lysozymeHistamine receptor Magnesium, calciumAntagonists H1 receptor antagonistPPAR H2 receptor antagonistElectrical potential PPAR alpha agonistsTriterpenoids Negative potentialGABA agonists Ursolic acidPurinergic receptor GABA type A agonists (musimol, isoguvacine)Fragrances P2Y antagonistsGC receptor Fragrances Glucocorticoid receptor antagonistsLCB 1 and 2. In vivo, however, increased levels of stratum corneum fatty acid (67%) andceramide (34%) levels were observed. Similar to studies with lactic acid, increases in thelevels of stratum corneum cholesterol seem to be refractory to change. In their furtherstudies Tanno et al. (134) at Kanebo have also been researching the changes in skinfunctionality with presence of sensitive skin. In their most recent studies topicalapplication of niacinamide improved the barrier of the most severely affected subject with N A D K G A NTVisual Dryness 3 2.5 2 1.5 1 0.5 0 0 1 3 5 7 10 14 21 N is significantly (P<0.05) different to all other products at days 3, 5, 7, 10 and 14Figure 19 Results from the treatment phase of a Kligman-type regression study (products appliedtwice-daily at 2 mg/cm2 to randomized sites on the outer, lower leg of female subjects [nZ36] withinclusion of a no-treament control). Products represented high-efficacy commercial moisturizerswith ingredients of differing dry skin relief mechanism. Abbreviations: NT, no treatment control; N,niacinamide-containing lotion; A, lactic acid-containing moisturizer; other product codes representcommercial products with high loadings of traditional humectants and emollients (including glycerinand petrolatum). Source: From Ref. 2.

104 Matts and RawlingsChange in capacitance vs. baseline (Corneometer units)14 12 10 8 HEBM 6 Product V2 Product D 4 Product K Product G 2 Product A No treatment 0 0 2 4 6 8 10 12 14 −2 −4 DayFigure 20 Change in capacitance during treatment with several moisturizers expressed asdifference from baseline. Source: From Ref. 144.sensitive skin with a concomitant improvement in stinging score. Ertel et al. (135)observed similar improvements in barrier functionality together with an increased SCturnover rate using a 2% niacinamide cream. Draelos et al. (136) similarly observed asignificant improvement in SC barrier function and improvement in global skin conditionin subjects with stage 1/11 Rosacea. Topical application of phytosphingosine and its derivatives have also been shown toincrease SC ceramide levels and barrier function (137). This is especially important as thephytosphingosine-containing ceramides are deficient in dry skin. Although increases in thetotal levels of ceramides were observed, greater increases in CER EOS and CER AS werefound when combined with juniperic acid and linoleic acid. Linoleic acid on its own hasChange in TEWL vs. baseline (gH2O.m2.h−1) 0.5 0 5 10 15 20 25 30 35 0 −0.5 −1.0 −1.5 HEBM Product V2 −2.0 Product D Product K −2.5 Product G Product A −3.0 No treatment DayFigure 21 Change in TEWL during treatment and regression phases expressed as difference frompre-treatment baseline. Regression starts at day 28. Source: From Ref. 144.

The Dry Skin Cycle 105(A) 20 Mean diff. in TEWL vs. baseline (gH2O.m2.h−1) HEBM 18 Product V2 16 Product D 14 Product K 12 Product G 10 Product A 8 No treatment 6 4 1 23 45 6 2 0 0 Days after SLS insult(B) 5Change in TEWL vs. baseline (gH2O.m2.h−1) 4 HEBM Product V2 3 Product D Product K 2 Product G Product A No treatment 1 0 01 23 4 56 −1 DaysFigure 22 (A) Change in TEWL in post-treatment phase after SLS patch chemical insultexpressed as difference from pre-treatment baseline. (B) Change in TEWL in post-treatment phaseafter tape stripping mechanical insult expressed as difference from pre-treatment baseline. Source:From Ref. 144.also been proven to be incorporated into CER EOS in vivo (138) which is obviouslyimportant for the lipid phase behavior and skin properties. Lipid fractions fromunsaponifiable fractions of avocado (furanyl-8-11- cis heptadecadiene) and sunfloweroleodistillates (mainly linoleic and oleic acids) also increase ceramide and cholesterolbiosynthesis ex vivo (139). The effects of increasing SC lipid levels by stimulating ceramide biosynthesis havebeen investigated extensively by Denda et al. (140). Histamine antagonists and certainfragrances stimulate lipid biosynthesis. Mixtures of magnesium and calcium salts havealso been shown to accelerate skin barrier recovery and improve surfactant-induced ortape stripping-induced dry skin. Although these studies indicate the importance of theseions for epidermal homeostasis, more work is needed with cosmetic formulations. Morerecently, it has been demonstrated that gamma-aminobutyric acid (GABA) type A

106 Matts and RawlingsChange in fluorescence vs. pretreatment baseline (units) 0 45 −0.02 −0.04 HEBM −0.06 Product N −0.08 Product J −0.10 Product V −0.12 Product J2 −0.14 Product L Product V2 No treatment DayFigure 23 Change in absolute dansyl chloride fluorescence over five days following staining.Source: From Ref. 144.receptor agonists, musimol, and isoguvacine accelerate barrier recovery following barrierdisruption. Conversely, ATP (purinergic) receptor (P2X) agonists delay barrier recoverywhereas P2Y antagonists accelerate it. These also reduced the epidermal hyperprolifera-tive response induced by acetone treatment under low environmental humidity (Table 2). Other agents have been shown to stimulate ceramide synthesis in vitro. Lipoic acidand N-acetylcysteine were also reported to increase ceramide synthesis in vitro (141).Recently vitamin C has been shown to activate PKC and increase ceramide synthesisand improve the ceramide subspecies profile in epidermal skin equivalents (142). Yaroshand Brown (143) also demonstrated that Ursolic acid increased ceramides in human skin.For a complete analysis of agents that stimulate lipid biosynthesis see Table 2. Very recently, exploiting its lipogenesis and differentiation enhancing effects,niacinamide has been introduced into lotions, together with glycerol and other NMFcomponents, that effectively alleviate dry skin and provide a significant improvement inSC barrier function (144). These lotions have been shown to be more effective thantraditional emollient and lactic acid-containing moisturisers in relieving dry skin in thetreatment phase of a typical Kligman-type regression study (Fig. 19), together with thechanges in moisturization (Fig. 20) and barrier function (Fig. 21) as well as improvingresistance to SLS and tape stripping-induced barrier perturbation (Fig. 22) (101). Theimprovement in desquamation was also proven with a dansylchloride exfoliationtest (Fig. 23).SUMMARY AND CONCLUSIONSNew and exciting discoveries have been made in SC biology over the last decade, but moreimportantly the understanding of the aberration of the normal functioning of the SC in dry,flaky skin conditions has become clearer and a new model of dry skin has been described.On perturbation of SC barrier function, a futile cycle of events begins first with thesuperficial dehydration of the SC and subsequent release of inflammatory mediators,induction of hyperproliferation of epidermal keratinocytes, and disruption of epidermal

The Dry Skin Cycle 107(A) e CCEELLL D= Corneodesmosome E= Stratum corneum enzymes Enzyme mediated E degradation of e=Intracellular enzymes e CELL corneodesmosome and lipids, SURFACE LAYERS weakening of barrier EE DD OF and loss of NMF e FRAGILE CELL STRATUM CORNEUM Enzyme diffuses towards corneodesmosomes to begin their E DD INNER LAYERS e OF degradation and encapsulation FRAGILE CELL with barrier lipids, STRATUM CORNEUM transformation of fragile to resilient corneocyte Intact corneodesmosomes and normal lipid bilayers, filaggrin hydrolysis dependent on water activity(B) e FRAGILE CELL D= Corneodesmosome Intact corneodesmosomes, E= Stratum corneum enzymes reduced enzyme activity, ED lipid disruption, decreased e e=Intracellular enzymes lipids leading to abnormal FRAGILE CELL barrier function, excessive SURFACE LAYERS loss of NMF and retention ED OF e of fragile corneocyte phenotype FRAGILE CELL STRATUM CORNEUM Intact corneodesmosomes ED INNER LAYERS and lipid disruption, e OF FRAGILE CELL lack of maturation of corneocytes STRATUM CORNEUM reduced Tgase activity Intact corneodesmosomes and normal lipid bilayersRELEASE OF INFLAMMATORY MEDIATORS AND PROTEASESFigure 24 Summary of stratum corneum maturation and corneodesmolysis in (A) normal and (B)dry skin. Source: From Ref. 2.differentiation, leading to an inferior SC. As has become apparent, reductions in SC waterand NMF levels, changes in lipid ultrastructure, and reductions in enzyme activitiescontribute to the reduced corneodesmolysis known to occur in these conditions. SeeFigure 24 for a schematic summary of the differences in SC biology in normal and dryskin. As a result, new therapies for the treatment of dry skin have been developed thattarget all aspects of the aberrant biology described by the “dry skin cycle.”REFERENCES 1. Rawlings 0AV, Scott IR, Harding CR, Bowser PA. Stratum corneum moisturization at the molecular level. J Invest Dermatol 1994; 103:731–740. 2. Rawlings AV, Matts PJ. Stratum corneum at the molecular level: an update in relation to the dry skin cycle. J Invest Dermatol 2005; 124:1099–1110.

108 Matts and Rawlings 3. Rawlings AV, Harding CR. Moisturization and skin barrier function. Dermatol Ther 2004; 17:43–48. 4. Rawlings AV. Skin waxes: their composition, properties, structures and biological significance. In: Hamilton RJ, ed. Waxes: Chemistry, Molecular Biology and Functions. New York: The Oily Press, 1994:221–256. Chapter 6. 5. Harding CR, Watkinson A, Rawlings AV. Dry skin, moisturization and corneodesmolysis. Int J Cosmet Sci 2000; 22:21–52. 6. Rawlings AV, Harding CR, Watkinson, Scott IR. Dry and xerotic skin conditions. In: Leyden JJ, Rawlings AV, eds. Skin Moisturization. New York NY: Marcel Dekker 2002:119–143. 7. Warner RR, Lilly NA. Correlation of water content with ultrastructure in the stratum corneum. In: Elsner P, Berardesca E, Maibach HI, eds. Bioengineering of the Skin: Water and the Stratum Corneum. Boca Raton: CRC Press Inc, 1994:3–12. 8. Blank IH. Factors which influence the water content of the stratum corneum. J Invest Dermatol 1952; 18:433–440. 9. Pfeiffer S, Vielhaber G, Vietzke JP, Wittern KP, Hintze U, Wepf R. High-pressure freezing provides new information on human epidermis: simultaneous protein antigen and lamellar lipid structure preservation. Study on human epidermis by cryoimmobilization. J Invest Dermatol 2000; 114:1030–1038. 10. Norlen L. Skin barrier structure and function: the single gel phase model. J Invest Dermatol 2001; 117:830–836. 11. Norlen L, Al-Amoudi A. Stratum corneum keratin structure, function, and formation: the cubic rod-packing and membrane templating model. J Invest Dermatol 2004; 123:715–732. 12. Bouwstra JA, de Graaff A, Gooris GS, Nijsse J, Wiechers JW, van Aelst AC. Water distribution and related morphology in human stratum corneum at different hydration levels. J Invest Dermatol 2003; 120:750–758. 13. Richter T, Peuckert C, Sattler M, et al. Dead but highly dynamic—the stratum corneum is divided into three hydration zones. Skin Pharmacol Physiol 2004; 17:246–257. 14. Downing DT, Stewart ME. Epidermal composition. In: Loden M, Maibach HI, eds. Dry Skin and Moisturizers Chemistry and Function, 2000:13–26. 15. Motta SM, Monti M, Sesana S, et al. Ceramide composition of psoriatic scale. Biochem Biophys Acta 1993; 1182:147–151. 16. Oku H, Mimura K, Tokitsu Y, Onaga K, Iwasaki H, Chinen I. Biased distribution of the branched-chain fatty acids in ceramides of vernix caseosa. Lipids 2000; 35:373–381. 17. Chopart M, Castiel-Higounenc I, Arbey E, Schmidt R. A new type of covalently bound ceramide in human epithelium. Stratum Corneum 2001; III. 18. Hamanaka S, Hara M, Nishio H, Otsuk F, Suzuki A, Uchida Y. Human epidermal glucosylceramides are major precursors of stratum corneum ceramides. J Invest Dermatol 2002; 119:416–423. 19. Pilgram GSK, Engelsma-van Pelt AM, Bouwstra JA, Koerten HK. Electron diffraction provides new information on human stratum corneum lipid organisation studied in relation to depth and temperature. J Invest Dermatol 1999; 113:403–409. 20. Brancaleon L, Bamberg MP, Sakamaki T, Kollias N. Attenuated total reflection-fourier transform infrared spectroscopy as a possible method to investigate biophysical parameters of stratum corneum in vivo. J Invest Dermatol 2001; 116:380–386. 21. Bouwstra J, Pilgram G, Gooris G, Koerten H, Ponec M. New aspects of the skin barrier organization. Skin Pharm Appl Skin Physiol 2001; 14:52–62. 22. Bouwstra J, Gooris GS, Dubbelaar FER, Ponec M. Phase behavior of stratum corneum lipid mixtures based on human ceramides: the role of natural and synthetic ceramide 1. J Invest Dermatol 2002; 118:606–617. 23. Rawlings AV, Watkinson A, Rogers J, et al. Abnormalities in stratum corneum structure lipid composition and desmosome degradation in soap-induced winter xerosis. J Soc Cosmet Chem 1994; 45:203–220.

The Dry Skin Cycle 10924. Warner RR, Boissy YL. Effect of moisturizing products on the structure of lipids in the outer stratum corneum of humans. In: Loden M, Maibach HI, eds. Dry Skin and Moisturisers. Boca Raton: CRC Press Inc, 2000:349–372.25. Berry N, Charmeil C, Gouion C, et al. A clinical, biometrological and ultrastructural study of xerotic skin. Int J Cosmet Sci 1999; 21:241–249.26. Serre G, Mils V, Haftek M, et al. Identification of late differentiation antigens of human cornified epithelia, expressed in re-organized desmosomes and bound to cross-linked envelope. J Invest Dermatol 1991; 97:1061–1072.27. Lundstorm A, Egelud T. Cell shedding from human plantar skin in vitro: evidence that two different types of protein structures are degraded by a chymotrypsin-like enzyme. Arch Dermatol Res 1990; 282:237–243.28. Suzuki Y, Nomura J, Koyama J, Horii T. The role of proteases in stratum corneum: involvement in stratum corneum desquamation. Arch Dermatol Res 1994; 286:249–253.29. Horikoshi T, Igarashi S, Uchiwa H, Brysk H, Brysk MM. Role of endogenous cathepsin D-like and chymotrypsin-like proteolysis in human epidermal desquamation. Br J Dermatol 1999; 141:453–459.30. Horikoshi T, Arany I, Rajaraman S, et al. Isoforms of cathepsin D human epidermal differentiation. Biochimie 1998; 80:605–612.31. Watkinson A. Stratum corneum thiol protease (SCTP): a novel cysteine protease of late epidermal differentiation. Arch Dermatol Res 1999; 291:260–268.32. Bernard D, et al. Analysis of proteins with caseinolytic activity in a human SC extract revealed a yet unidentified cysteine protease and identified the so called ‘SC thiol protease’ as Cathepsin L2. J Invest Dermatol 2003; 120:592–600.33. Caubet C, et al. Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family. J Invest Dermatol 2004; 122:1235–1244.34. Bernard D, Mehul B, Delattre C, Simonetti L, Thomas-Collignon A, Schmidt R. Purification and characterization of the endoglycosidase heparanase 1 from human plantar stratum corneum: a key enzyme in epidermal physiology. J Invest Dermatol 2001; 117:1266–1273.35. Simon M, Jonca N, Guerrin M, et al. Refined characterization of corneodesmosin proteolysis during terminal differentiation of human epidermis and its relationship to desquamation. J Bio Chem 2001; 276:20292–20299.36. Sondell B, Thornell LE, Stigbrand T, Egelrud T. Immunolocalization of SCCE in human skin. Histo Cytom 1994; 42:459–465.37. Watkinson A, Smith C, Coan P, Wiedow O. The role of Pro-SCCE and SCCE in desquamation. 21st IFSCC Congress 2000; 16–25.38. Igarashi S, Takizawa T, Yasuda Y, et al. Cathepsin D, degrades desmosomes during epidermal desquamation. Brit J Dermatol 2004;151:355.39. Ishida-Yamamoto A, Simon M, Kishibe M, et al. Epidermal lamellar granules transport different cargoes as distinct aggregates. J Invest Dermatol 2004; 122:1145–1153.40. Watkinson A, Harding C, Moore A, Coan P. Water modulation of stratum corneum chymotryptic enzyme activity and desquamation. Arch Dermatol Res 2001; 293:470–476.41. Komatsu N, Takata M, Otsuki N, et al. Elevated stratum corneum hydrolytic activity in netherton syndrome suggests an inhibitory regulation of desquamation by SPINK5-derived peptides. J Invest Dermatol 2002; 118:436–443.42. Franzke CW, Baici A, Bartels J, Christophers E, Wiedow O. Antileukoprotease inhibits stratum corneum chymotryptic enzyme. J Biol Chem 1996; 271:21886–21890.43. Brattsand M, Stefansson K, Lundh C, Haasum Y, Egelrud T. A proteolytic cascade of kallikreins in the stratum corneum. J Invest Dermatol 2005; 124:198–203.44. Watkinson A, Harding CR, Rawlings AV. The cornified envelope: its role on stratum corneum structure and maturation. In: Leyden JJ, Rawlings AV, eds. Skin Moisturization. New York NY: Marcel Dekker 2002:95–117.

110 Matts and Rawlings 45. Candi E, et al. Transglutaminase cross linking properties of the small proline rich 1 family of cornified envelope proteins. J Biol Chem 1999; 274:7226–7237. 46. Kim IG, Gorman JJ, Park SC, Chung SI, Steinert PM. The deduced sequence of the novel protransglutaminase-E (TGase 3) of human and mouse. J Biol Chem 1993; 268:12682–12690. 47. Nemes Z, Marekov LN, Steinert PM. Involucrin cross linking by transglutaminase 1. J Biol Chem 1999; 274:11013–11021. 48. Cabral A, Voskamp P, Cleton-Jansen M, et al. Structural organisation and regulation of the small proline rich family of cornified envelope precursors suggest a role in adaptive barrier function. J Biol Chem 1923; 26:19231–19237. 49. Mils V, Vincent C, Croute F, Serre G. The expression of desmosomal and corneodesmosomal antigens shows specific variations during the terminal differentiation of epidermis and hair follicle epithelia. J Histochem Cytochem 1992; 40:1329–1337. 50. Harding CR, Long S, Richardson J, et al. The cornified cell envelope: an important marker of stratum corneum maturation in healthy and dry skin. Int J Cosmet Sci 2003; 25:1–11. 51. Hirao T, Denda M, Takahashi M. Identification of immature cornfield envelopes in the barrier-impaired epidermis by characterization of their hydrophobicity and antigenicities of the components. Exp Dermatol 2001; 10:35–44. 52. Kashibuchi N, Hirai Y, O’Goshi K, Tagami H. Three-dimensional analyses of individual corneocytes with atomic force microscope: morphological changes related to age, location and to the pathologic skin conditions. Skin Res Technol 2002; 8:203–211. 53. Jokura Y, Ishikawa S, Tokuda H, et al. Molecular analysis of elastic properties of the stratum corneum by solid-state C-13-nuclear magnetic resonance spectroscopy. J Invest Dermatol 1995; 104:806. 54. Mechin MC, Enji M, Nachat R, et al. The peptidylarginine deiminases expressed in human epidermis differ in their substrate specificities & subcellular locations. CMLS DO1 2005;1–12. 55. Sakai S, Yasuda R, Sayo T, et al. Hyaluronan exists in the normal stratum corneum. J Invest Dermatol 2000; 114:1184. 56. Fluhr JW, Mao-Qiang M, Brown BE, et al. Glycerol regulates stratum corneum hydration in sebaceous gland deficient (Asebia) mice. J Invest Dermatol 2003; 120:728. 57. Choi EH, Man MQ, Wang F, et al. Is endogenous glycerol a determinant of stratum corneum hydration in humans. J Invest Dermatol 2005;1–6. 58. Nakagawa N, et al. Relationship between NMF (potassium and lactate) content and the physical properties of the stratum corneum in healthy subjects. J Invest Dermatol 2004; 122:755. 59. Fluhr JW, et al. Generation of free fatty acids from phospholipids regulates stratum corneum acidification and integrity. J Invest Dermatol 2001; 117:44. 60. Krein PM, Kermici M. Evidence for the existence of a self-regulated enzymatic process within the human stratum corneum- an unexpected role for urocanic acid. J Invest Dermatol 2000; 115:414. 61. Caspers PJ, Lucassen GW, Carter EA, Bruining HA, Puppels GJ. In vivo confocal raman microspectroscopy of the skin: non-invasive determination of molecular concentration profiles. J Invest Dermatol 2001; 116:434–442. 62. Rogers J, Harding CR, Mayo A, Banks J, Rawlings AV. Stratum corneums lipids: the effect of ageing and the seasons. Arch Dermatol Res 1996; 288:765–770. 63. Meldrum H. The characteristic decrease in scalp stratum corneum lipids in dandruff is reversed by use of a ZnPTO containing shampoo. IFSCC Mag 2003; 6:3–6. 64. Declercq L, Muizzuddin N, Hellemans L, et al. Adaptation response in human skin barrier to a hot and dry environment. J Invest Dermatol 2002; 119:716. 65. Denda M, Sato J, Masuda Y, et al. Exposure to a dry environment enhances epidermal permeability barrier function. J Invest Dermatol 1998; 111:858–863. 66. Sato J, Denda M, Chang S, et al. Abrupt decreases in environmental humidity induce abnormalities in permeability barrier homeostasis. J Invest Dermatol 2002; 119:900–904.

The Dry Skin Cycle 11167. Chou TC, Lin KH, Wang SM, et al. Transepidermal water loss & skin capacitance alterations among workers in an u;tra-low humidity environment. Arch Dermatol Res 2005; 296:489–495.68. Katagiri C, Sato J, Nomura J, et al. Changes in environmental humidity affect the water- holding capacity of the stratum corneum and its free amino acid content, and the expression of filaggrin in the epidermis of hairless mice. J Dermatol Sci 2003; 31:29–35.69. Denda M, Sato J, Tsuchiya T, Elias PM, Feingold KR. Low humidity stimulates epidermal DNA synthesis and amplifies the hyperproliferative response to barrier disruption: implication for seasonal exacerbation of inflammatory dermatoses. J Invest Dermatol 1988; 111:873–878.70. Ashida Y, Ogo M, Denda M. Epidermal interleukin-1 generation is amplified at low humidity: implications for the pathogenesis of inflammatory dermatoses. Br J Dermatol 2001; 144:238–243.71. Ashida Y, Denda M. Dry environment increases mast cell number and histamine content in dermis in hairless mice. Br J Dermatol 2003; 149:240–247.72. Simon M, Bernard D, Minondo AM, et al. Persistence of both peripheral and non-peripheral corneodesmosomes in the upper stratum corneum of winter xerosis skin versus only peripheral in normal skin. J Invest Dermatol 2001; 116:23–30.73. Long S, Banks J, Watkinson A, Harding C, Rawlings AV. Desmocollins: a key marker for desmosome processing in stratum corneum. J Invest Dermatol 1996; 106:872.74. Van Overloop L, Declercq L, Maes D. Visual scaling of human skin correlates to decreased ceramide levels and decreased stratum corneum protease activity. J Invest Dermatol 2001; 117:811.75. Kawai E, Kohno Y, Ogawa K, et al. Can inorganic powders provide any biological benefit in stratum corneum while residing on the skin surface. 22nd IFSCC Congress Edinburgh P10, 2002.76. Fulmer AW, Kramer GJ. Stratum corneum lipid abnormalities in surfactant-induced scaly skin. J Invest Dermatol 1986; 86:598–602.77. Saint-Leger D, Francois AM, Leveque JL, Stoudemayer TJ, Kligman AM, Grove G. Stratum corneum lipids in skin xerosis. Dermatologica 1989; 178:151–155.78. Chopart M, Castiel-Higounenc C, Arbey E. Quantitative analysis of ceramides in stratum corneum of normal and dry skin. Stratum Corneum 2001; III.79. Imokawa G. Ceramides as natural moisturizing factors and their efficacy in dry skin. In: Leyden JJ, ed. Skin Moisturization. New York NY: Marcel Dekker 2002:267–302.80. Schreiner V, Gooris GS, Pfeiffer S, et al. Barrier characteristics of different human skin types investigated with x-ray diffraction, lipid analysis and electron microscopy imaging. J Invest Dermatol 2000; 114:600–654.81. Tezuka T. Electron microscopical changes in xerotic senilis epidermis. Its abnormal membrane coating granule formation. Dermatologica 1983; 166:57.82. Matts PJ, Goodyer E. A new instrument to measure the mechanical properties of human skin in vivo. J Cosmet Sci 1998; 49:321–333.83. Matts PJ. In: Elsner P, Beradesca E, Wilhem KP, Maibach HI, eds. Hardware and Measurement Principles: the Gas-Bearing Electrodynamometer and Linear Skin Rheometer, in Bioengineering of the Skin: Skin Biomechanics. Boca Raton: CRC Press, 2002.84. Cooper ER, Missel PJ, Hannon DP, Albright GB. Mechanical properties of dry, normal and glycerol-treated skin as measured by the gas-bearing electrodynamometer. J Cosmet Sci 1985; 36:335–348.85. Christensen MS, Hargens CW, III, Nacht S, Gans EH. Viscoelastic properties of intact human skin: instrumentation, hydration effects, and the contribution of the stratum corneum. J Invest Dermatol 1977; 69:282–286.86. Denda M, Wood LC, Emami S, et al. The epidermal hyperplasia associated with repeated barrier disruption by acetone treatment or tape stripping cannot be attributed to increased water loss. Arch Dermatol Res 1996; 288:230–238.87. Kikuchi K, Kobayashi H, Hirao T, Ito A, Takahashi H, Tagami H. Improvement of mild inflammatory changes of the facial skin induced by winter environment with daily

112 Matts and Rawlings applications of a moisturizing cream. A half-side test of biophysical skin parameters, cytokine expression pattern and the formation of cornified envelope. Dermatology 2003; 207:269–275. 88. Terui T, Hirao T, Sato Y, et al. A increased ration of interleukin-1 receptor antagonist to interleukin-1 in inflammatory skin diseases. Exp Dermatol 1998; 7:327–334. 89. Proksch E, Jensen J, Elias PM. Skin lipids and epidermal differentiation in atopic dermatitis. Clin Dermatol 2003; 21:134–144. 90. Proksch E, Feingold KR, Man MQ, Elias PM. Barrier function regulates epidermal DNA synthesis. J Clin Invest 1991; 87:1668–1673. 91. Angel P, Szabowski A. Function of AP-1 target genes in mesenchymal-epithelial cross-talk in skin. Biochem Pharmacol 2002; 64:949–956. 92. Rawlings AV, Canestrari DA, Dobkowski B. Moisturizer technology versus clinical performance. Dermatol Ther 2004; 17:49–56. 93. Mattai J, Froebe CL, Rhein LD, et al. Prevention of model stratum corneum lipid phase transitions in vitro bu cosmetic additives. J Soc Cosmet Chem 1993; 44:89–100. 94. Rawlings AV, Watkinson A, Hope J, Sabin C, Harding R. The effect of glycerol and humidity on desmosome degradation in stratum corneum. Arch Dermatol Res 1995; 287:457–464. 95. Hirao T, Takahashi M, Kikuchi K, et al. A novel non-invasive evaluation method of cornified envelope maturation in the stratum corneum provides new insight for skincare cosmetics. 22nd IFSCC Congress, Edinburgh. P51, (2002). 96. Fluhr JW, Gloor M, Lehmann L, et al. Glycerol accelerates recovery of barrier function in vivo. Acta Derm Venereol 1999; 79:418–421. 97. Rattner H. Dermatologic uses of urea. Acta Derm Venereol 1943; 37:155–165. 98. Fredrikkson T, Gip L. Urea creams in the treatment of dry skin & hand dermatitis. Int J Dermatol 1990; 14:442–444. 99. McCallion R, Po AL. Modelling TEWL under steady state conditions & relative humidities. Int J Pharm 1994; 105:103–112.100. Loden M. Urea containing moisturisers influence barrier properties of normal skin. Arch Dermatol Res 1996; 288:103–107.101. Pigatto PD, Bigardi AS, Cannistraci C, et al. 10% urea cream for atopic dermatitis. J Dermatol Treat 1996; 7:171–175.102. Scott IR, Harding CR. A filasggrin analogue to increase natural moisturising factor synthesis in skin. Dermatology 2000; 773:1993.103. Kwoyo Hakko Kogyo. Pyrroliodone carboxylic acid esters compositions to prevent loss of moisture from the skin. Patent JA 4882046, 1982.104. Org Santerre. Pyrolidone carboxylic acid sugar compounds as rehydrating ingredients in cosmetics. Patent FR 2277823, 1977.105. Clar EJ, Foutanier A. L’acide pyrrolidone carboxylique et la peau. J Cosmet Sci 1981; 3:101–113.106. Middelton JD, Roberts ME. Effects of a skin cream containing the sodium salts of pyrrolidone carboxylic acid on dry & flaky skin. J Soc Cosmet Chem 1978; 29:201–205.107. Ghadially R, Halkiersorenson L, Elias PM. Effects of petrolatum on stratum corneum structure & function. J Am Acad Dermatol 1992; 26:387–396.108. Barany E, Lindberg M, Loden M. Unexpected skin barrier influence from non-ionic emulsifiers. Int J Pharm 2000; 195:189–195.109. Kucharekova M, Schalkwijk J, Van De Kerkhof PC, Van De Valk PG. Effect of a lipid-rich emollient. Contact Dermatitis 2002; 46:331–338.110. De Paepe K, Roseeuw D, Rogiers V. Repair of acetone- and sodium lauryl sulphate-damaged human skin barrier function using topically applied emulsions containing barrier lipids. JEADV 2002; 16:587–594.111. Berardesca E, Barbareschi M, Veraldi S, Pimpinelli N. Evaluation of efficacy of a skin lipid mixture in patients with irritant contact dermatitis, allergic contact dermatitis or atopic dermatitis: a multicenter study. Contact Dermatitis 2001; 45:280–285.

The Dry Skin Cycle 113112. Chamlin SL, Kao J, Frieden IJ, et al. Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol 2002; 47:198–208.113. Wollenweber U, Korevaar K, Rawlings AV, Schick. Application of a skin-identical lipid concentrate for enhanced skin moisturization and protection. SOFW-J 2004; 130:9.114. Summers RS, Summers B, Chandar P, Feinberg C, Gurskey R, Rawlings AV. The effect of lipids with and without humectant on skin xerosis. J Soc Cosmet Chem 1996; 47:27–39.115. Leveque JL, Saint-Leger D. Salicylic acid and derivatives. In: Leyden JJ, Rawlings AV, eds. Skin Moisturization. New York NY: Marcel Dekker 2002:353–364.116. Fartasch M, Teal J, Menon GK. Mode of action of glycolic acid on human stratum corneum: ultrastructural and functional evaluation of the epidermal barrier. Arch Dermatol Res 1997; 289:404–409.117. Bowser P, Evenson A, Rawlings AV. Cosmetic composition containing a lipid and a hydroxyl or ketcarboxylic acid. EP0587288B1.118. Rawlings AV, Davies A, Carlomusto M, et al. Effect of lactic acid isomers on keratinocyte ceramide synthesis, stratum corneum lipid levels and stratum corneum barrier function. Arch Derm Res 1996; 288:383–390.119. Rawlings AV, Hope J, Ackerman C, Banks J. Hydroxycaprylic acid improves stratum corneum extensibility at low relative humidity and protects desmosomes against mechanical damage. IFSCC Congress, Yokohama, 1992: P1.120. Johnson AW. Hydroxyacids. In: Leyden AV, Rawlings JJ, eds. Skin Moisturization, 2002:323–352.121. Berardesca E, et al. Alpha hydroxy acids modulate stratum corneum barrier function. Br J Dermatol 1997; 137:934.122. Hanley K, Jiang Y, He SS, et al. Keratinocyte differentiation is stimulated by activators of the nuclear receptor PPAR alpha. J Invest Dermatol 1998; 110:368–375.123. Westergaard M, Henningsen J, Svendsen ML, et al. Maodulators of keratinocyte gene expression and differentiation by PPAR selective ligand tetradecylthioacetic acid. J Invest Dermatol 2001; 116:702–712.124. River M, Castiel I, Safonova I, Ailhaud G, Michel S. Peroxisome proliferator-activated receptor-alpha enhances lipid metabolism in a skin equivalent model. J Invest Dermatol 2000; 114:687–691.125. Alaluf S, Barrett KE, Green MR, Ottey A, Rawlings AV. A cosmetic composition for treating aged wrinkled skin through topical application of a composition containing petroselenic acid. US6042841.126. Alaluf S, Rawlings AV. A topical composition comprising from petroselenic acid and conjugated linoleic acid. US6423325.127. Lee R, Paterson S, Marti V, Ginger R, Watkinson A, Rawlings AV. Peroxisome proliferator activated receptor alpha activators: Petroselenic acid as a novel skin benefit agent for antiperspirants. 22nd IFSCC Congress, Edinburgh P11 (2002).128. Wiechers JW, Rawlings AV, Garcia C, et al. A new mechanism of action for skin whitening agents: binding to the peroxisome proliferator activated receptor. Int J Cosmet Sci 2005; 27:123–132.129. Mao-Qiang M, Feingold KR, Elias PM. Exogenous lipids influence permeability barrier function. Arch Dermatol 1993; 129:729–738.130. Chamlin SL, Frieden IJ, Fowler A, et al. Optimization of physiological lipid mixtures for barrier repair. J Invest Dermatol 1996; 106:1096–1101.131. Haratake A, Ikenaga K, Katoh N, Uchiwa H, Hirano S, Yasuho H. Topical mevalonic acid stimulates de novo cholesterol biosynthesis and epidermal permeability barrier homeostasis in aged mice. J Invest Dermatol 2000; 114:247–252.132. Rawlings AV, Davies A, Carlomusto M, et al. Effect of lactic acid isomers on keratinocyte ceramide synthesis, stratum corneum lipid levels and stratum corneum barrier function. Arch Derm Res 1996; 288:383–390.

114 Matts and Rawlings133. Matts PJ, Oblong JE, Bissett DL. A review of the range of effects of niacinamide in human skin. IFSCC Mag 2002; 5:285–290.134. Tanno O, Ota Y, Hikima R, Matsumoto M, Ota, M, Inoue S. An increase in Endogenous Epidermal Lipids Improves Skin Barrier Function. 20th IFSCC International Congress. P 347–358 (2000).135. Ertel KD, Berge CA, Mercurio MG, et al. New facial moistuizer technology increase exfoliation without compromising barrier function. 58th Annual meeting of the American Academy Of Dermatology, San Francisco (2000).136. Draelos ZD, Ertel E, Berge C, et al. A facial moisturizing product as an adjunct in the treatment of rosacea. 59th Annual meeting of the American Academy Of Dermatology, San Francisco (2001).137. Davies A, Verdejo P, Feinberg C, Rawlings AV. Increased stratum corneum ceramide levels and improved barrier function following treatment with tetraacetylphytosphingosine. J Invest Dermatol 1996; 106:918.138. Conti A, Rogers P, Verdejo P, Harding CR, Rawlings AV. Seasonal influences on stratum corneum ceramide 1 fatty acids and the influence of topical essential fatty acids. Int J Cos Sci 1996; 18:1–12.139. Msika P, Piccirilli A, Chesne C. Effects of two specific lipidic ingredients on the synthesis of epidermal lipids in human skin explants in culture. 21st IFSCC Congress, Berlin. P1-5 (2000).140. Denda M. New stategies to improve skin barrier homeostasis. Ad Drug Del Rev 2002; 54:123–130.141. The effect of thiols on epidermal lipid biosynthesis. Zhang K, Kosturko K, Rawlings AV. Annual Meeting Of Society For Investigative Dermatology, Chicago, USA, 1995. J Invest Dermatol 1995; 104:687.142. Uchida Y, Behne M, Quice D, et al. Vitamin C stimulates sphingolipid production and markers of barrier formation in submerged human keratinocyte cultures. J Invest Dermatol 2001; 117:1307–1313.143. Yarosh DB, Both D, Brown D. Liposomal ursolic acid (merotaine) increases ceramides and collagen in human skin. Horm Res 2000; 54:318–321.144. Matts PJ, Gray J, Rawlings AV. In: The ‘Dryskin Cycle’-A New Model of Dry Skin & Mechanisms for Intervention, Vol. 256. London: The Royal Society Of Medicine Press International congress & symposium series, 2005:1–38.

7Factors Influencing Optimal Skin Careand Product SelectionJames Q. Del RossoDepartment of Dermatology, University of Nevada School of Medicine,Las Vegas, Nevada, U.S.A.Due to consistent marketing influences promoting multiple products that claim “removalof fine lines, wrinkles, and age spots,” consumer demand for products that provide a “freshlook and a more youthful appearance,” television and written advertising mediacampaigns promoting individual product lines, and the myriad of products available forthe consumer to choose from, it is not surprising that patients are confused about whichproducts to use for their skin and how to use them. Despite the high level of confusing“white noise” created by media and advertising promotions, optimal skin care is not rocketscience! Based on a few basic principles and knowledge of appropriate productformulation, the dermatologist or designated skin care professional is trained to match asound skin care regimen with the needs of the individual patient. Prior to product selection, skin type characteristics, history of previous skinsensitivities or allergies, presence of underlying skin disorders, current skin care regimen,and medication history need to be evaluated. A thorough understanding of skin careproduct formulations and their differentiating features affords the clinician greaterknowledge, confidence, and flexibility when recommending products and designing a skincare regimen for patients. Unfortunately, the value of basic skin care practices such as cleansing andmoisturizer use as a component of the management of dermatologic disorders has taken aback seat due to the strong emphasis on management with pharmacologic agents. Greaterattention to basic skin care products and procedures, and maintenance of epidermal barrierfunction, may provide additive therapeutic benefit for patients. The following chapteremphasizes the core significance of maintaining epidermal barrier integrity. The basicfundamentals of optimal skin care, gentle cleansing and moisturization, and their intimatecorrelation with product formulation and selection are discussed.BASIC SKIN CARE PROCESSESProper skin cleansing and moisturization are the two basic processes that must work inharmony to maintain overall skin health and epidermal barrier integrity (1,2). The role of 115

116 Del Rossoskin cleansing is to remove external debris, cutaneous secretions, and microorganisms. Inaddition, the integrity of the epidermal barrier must be consistently maintained to allow forcutaneous homeostasis as the presence of proper skin water content is mandatory forenzymatic functions required for lipid synthesis and barrier restoration. Therefore,moisturization is a vital component of “routine maintenance” of the outer skin barrier. Thisis especially true in conditions where epidermal barrier dysfunction and reduced epidermalwater content are present. Examples of such conditions include low ambient humidity,xerotic skin disorders such as atopic dermatitis, genedermatoses such as ichthyosisvulgaris, underlying systemic disease states such as hypothyroidism and diabetes mellitus,use of skin care products that produce significant epidermal barrier damage such asharsh soaps and cleansers or astringents, and some topical medications such as topicalretinoids (3–5). The plethora of cleanser and moisturizer products available make it difficult for bothprofessionals and consumers when faced with the question, “Which products should beused?” The bottom line is to maintain a “simplest is best approach,” especially as manyproduct claims, special ingredients, and heavily promoted “designer” products aresubstantiated by little to no scientific evidence supporting their purported benefits and highexpense (1,2,5,6).THE EPIDERMAL BARRIER AND WATER CONTENTNormal skin appearance, water balance, and continued barrier integrity necessitate anintact epidermal barrier with maintenance of the proper water content required forphysiologic and enzymatic functions. As the epidermis is a living dynamic unit, severalphysiologic functions continue as an ongoing process, with perturbations of barrierintegrity requiring necessary adjustments and repairs before the epidermal barrier canreturn to its normally functioning physiologic state. The epidermal barrier is comprised oftwo components which work in concert to assure barrier integrity through functions suchas maintenance of proper epidermal water balance, physiologic stratum corneum watercontent (20–35%), optimal lipid synthesis, limitation of transepidermal water loss(TEWL), and orderly corneocyte desquamation (1–4). The first component of theepidermal barrier, the cellular matrix, is comprised of a staggered and layered lattice ofkeratinocytes, referred to as the “bricks.” In its uppermost layer, the flattened stratumcorneum cells are referred to as corneocytes. The second component of the epidermalbarrier, the intercellular lipid bilayer matrix, surrounds the keratinocytes, and is referredto as the “mortar” (1–3). Disturbances of these epidermal barrier components, associatedwith a variety of causes such as use of harsh soaps or underlying “sensitive skin” disorderssuch as atopic dermatitis or rosacea, enhance TEWL, which can lead to xerotic skinchanges. When increased TEWL produces a reduction in stratum corneum water contentto below 10%, this marked loss of epidermal barrier integrity is visibly expressed asdryness, scaling, roughness, and fine fissuring, the clinical features of xerosis (2,3,6–8). The epidermis is in constant flux as keratinocytes traverse from the basal layer, laterflattening as they pass upward into the stratum corneum, leading ultimately to surfaceshedding, or corneocyte desquamation. As referred to above, under normal circumstances,adequate water content allows for enzymatic degradation of the attachments betweencorneocytes (corneodesmosomes), allowing for the physiologic separation and sheddingof superficial corneocytes. Corneocyte moisture content is maintained by a collection ofdiverse intracellular hygroscopic compounds which have been collectively termed“natural moisturizing factor” (NMF). The components of NMF include filaggrin-derived

Optimal Skin Care and Product Selection 117amino acids, pyrrolidone carboxylic acid, lactate, sugars, and several electrolytes (1–3,5).Under abnormal conditions associated with xerosis, corneodesmosomes are not readilydeagraded, leading to clumping of corneocytes. The visible expressions of clumpedcorneocytes with impaired desquamation are flaking and scaling (1–3,5,8,9).EPIDERMAL BARRIER INTEGRITY, FUNCTION, AND REPAIRA pivotal component of epidermal barrier formation is the synthesis within nucleatedkeratinocytes of the intercellular lipid bilayer, a functional permeability barrier composedof specific lipids present in proper ratio. Epidermal barrier lipids are autonomous fromlipids circulating in the bloodstream and are composed predominantly of equimolarconcentrations of free fatty acids, cholesterol, and ceramides (1–3,5,10–12). Withinlamellar bodies (Odland bodies) located within keratinocytes of the upper epidermis,precursor epidermal lipids are used to create newly synthesized lipids which are organizedinto a lipid bilayer referred to as the lamellar unit membrane structure (1,10–17).Ultimately, as cornification occurs in the upper epidermis, a phospholipid-enriched plasmamembrane is converted to a ceramide-rich bilayered membrane by weight (1,8,17). The intercellular lipid bilayer matrix (“the mortar”) functions to control intercellularwater movement, maintain intracellular water content, and limit TEWL. The majorhomeostatic signal stimulating epidermal lipid synthesis is an adverse change in epidermalbarrier status, sensed as an increase in TEWL. In the presence of exogenous (i.e., use of aharsh soap) or endogenous (i.e., underlying dermatologic disease) insults that cause a lossin barrier lipids which comprise the intercellular matrix, an increased TEWL of as little as1% produces a physiologic signal that upregulates lipid synthesis (1–3,5). Depending uponthe degree of barrier insult and several other factors, normalization of barrier function mayoccur over a period of hours to days (1,15,17).IMPACT OF EXOGENOUS MOISTURIZATION ON BARRIER REPAIRIn a state of epidermal barrier disruption characterized by increased TEWL and reducedepidermal water content, a properly formulated moisturizer can act in a manner similar toendogenous epidermal lipids in promoting and restoring epidermal barrier function(1–3,13–24). Lipids applied externally in moisturizer formulations intercalate betweencorneocytes and have been shown to reduce surfactant-induced skin irritation (15–18). Theuse of nonphysiologic lipids such as petrolatum initially restores barrier function byproducing a diffuse hydrophobic interstitium. Importantly, physiologic lipids applied inmoisturizers can be directly incorporated into barrier lipids and lamellar units and do notappear to downregulate physiologic lipid production in skin (16–18). However, it is vitalthat all three lipid components (ceramide, cholesterol, free fatty acids) be incorporated inmoisturizer formulations in optimized concentrations in order to avoid impairment ofbarrier recovery (16,17).CLINICAL IMPLICATIONS OF EXOGENOUS MOISTURIZATIONIn a clinical study of adult and pediatric patients treated for atopic dermatitis twice dailyover a three-week period with a low-potency topical steroid lotion, with or without amoisturizer cream, both regimens exhibited consistent reductions in signs and symptoms

118 Del Rossoof disease, although greater improvement was noted at treated sites where moisturizer wasalso used (25). Importantly, patients recognized the therapeutic benefit of moisturizer useas a component of the combination regimen with preference for the combination reportedby 96% of patients. The significance of repeated application of externally applied moisturizers shouldnot be underemphasized. Factors such as the inherent limitations of product substantivityrelated to formulation characteristics, superficial loss of applied product due to external“wear and tear” effects prior to thorough skin penetration, and the natural consequence ofcontinual corneocyte shedding mandate that repetitive moisturizer application on a dailybasis is required for maintenance of barrier function and repair (3,19). In addition,individual moisturizers may vary in the persistence of their moisturizing properties afterdiscontinuation of application based on regression phase analysis studies (20,24).COMPONENTS OF MOISTURIZER FORMULATIONSWhether or not a moisturizer formulation “makes it in the real world” is ultimatelydependent on recognizable efficacy, cosmetic acceptability, and patient preference. It isimportant to recognize that the term moisturizer does not imply that moisture (water) isbeing added to the skin. A properly formulated moisturizer contains occlusive, humectant,and emollient ingredients that are ultimately formulated to produce an effective productthat is also cosmetically elegant (1–5,8,17,26). Occlusive and humectant ingredients workin a complimentary fashion to maintain epidermal water content and barrier function.Occlusive agents retard water loss via evaporation by forming a hydrophobic film on theskin surface and within the stratum corneum interstitum. Humectant compounds attractwater “from the inside out,” that is, from the dermis with passage into the upper epidermis(3–5,8,17). Emollients include a wide spectrum of compounds ranging from esters to long-chain alcohols which function to fill “the fine cracks and crevices” between corneocytes inthe upper stratum corneum; specific emollients are often incorporated into formulations toenhance efficacy and improve cosmetic elegance by providing a smooth, soft texture to thecutaneous surface (2–5).BALANCING EFFECTS AND COSMETIC ELEGANCEOF PRODUCT COMPONENTSThe greasiness of occlusive agents such as petrolatum and lanolin can limit their clinicalusefulness due to lack of cosmetic elegance (2–5). For example, odor and potentialallergenicity may limit the use of lanolin. Although mineral oil demonstrates lesscapability to reduce TEWL as compared to some other occlusive agents, it is a popularformulation component due to its favorable texture and easy spreadability (5). Siliconederivatives are also popular formulation ingredients as they may serve both occlusive andemollient functions, do not impart a greasy feel to the skin, exhibit a barrier protectanteffect that is often incorporated into “hand creams,” and are used in combination withpetrolatum to achieve greater cosmetic acceptability by reducing the greasiness of theoverall product texture (2,5). Most effective formulations which enhance skin moisturization include humectantagents, such as glycerin, hyaluronic acid, urea, ammonium lactate, and panthenol, whichserve to attract water from the dermis into the epidermis, with some humectants alsoimparting emolliency (1–5). In order to prevent exacerbation of TEWL, a humectant agent

Optimal Skin Care and Product Selection 119should always be combined with an occlusive ingredient. For example, skin application ofglycerin alone without an accompanying occlusive agent results in a significant increase inTEWL (29%) (2,3,5). As referred to above, although emollients may vary in their inherentmoisturization and barrier maintenance properties, the elegant characteristics they impartto the overall product may be appreciated by the user after product application and oftenrelate directly to consumer product preference (5).FORMULATION CHARACTERISTICSMost moisturizers are formulated as creams (water-in-oil emulsion) or lotions (oil-in-water emulsion) (1,2,8,13). The “heaviness” of the final formulation correlates with theinclusion and relative concentration of heavier occlusive agents such as petrolatum andlanolin derivatives, the inherent qualities of individual emollients and humectants that maybe included in some products, and the oil-water ratio (5). Night creams are examples ofproducts that are specifically designed to be heavier formulations. Specific ingredients areoften combined in formulations to correlate with use for individual “skin types” such asdry, normal, or oily complexions. This is achieved by altering the heaviness characteristicof the occlusive agent used through selection of specific emollients that may be eitherprotective, fatting, dry, or astringent in their inherent quality, and through adjustment ofoil-water ratios. Examples of ingredient adjustments designed to correlate with use inspecific skin types include dimethicone, a non-greasy, noncomedogenic emollient agentused in “oil free” facial moisturizers marketed for individuals with “oily skin” or inclusionof oil-absorbent compounds such as kaolin or talc, added to formulations to reduce “facialshine” by absorbing excess sebum (5).SPECIAL ADDITIVES AND INGREDIENTSSpecial ingredients may be added to basic moisturizer formulations to create “targetedmoisturizer products” (1–3). Alpha-hydroxy acids, such as glycolic acid and lactic acid,have been added to many formulations to create exfoliant moisturizers, often marketed asanti-aging preparations (2,3,5). In order to reduce associated irritation, reduction inconcentration or use of neutralizing additives (buffering) is common. However, as clinicalefficacy correlates with availability of free acid, neutralization to a pHO4.8 results in lossof efficacy (2,3,5). Retinol (vitamin A) and retinyl palmitate are added to some anti-agingmoisturizer preparations to improve photodamage by decreasing fine wrinkling and tactileroughness. Both are inactive “precursor retinoids,” requiring enzymatic conversions toproduce retinoic acid from retinol; it is believed that the extent of retinol conversion toretinoic acid in skin is limited (2,3,5). Niacinamide (nicotinamide) is stable andcompatible in moisturizer preparations due to its high water solubility, appears to producean exfoliant effect, and may have anti-aging characteristics (5). The role of niacinamide inprevention of photocarcinogenesis and promotion of antineoplastic changes inkeratinocytes in murine skin models is of considerable interest and is currently a focusof additional research (5,27,28). The addition of effective sunblock or sunscreen agents tomoisturizer formulations is significant as photoprotection is important in the maintainanceof epidermal integrity, dermal infrastructure and support, avoidance of small vesseldamage and formation of telangiectasia, prevention of photocarcinogenesis, and reductionin pigmentation irregularities. Combination moisturizer-sunscreen formulations may

120 Del Rossoenhance compliance as both are applied together, usually early in the day, in a “onestep” process.THE SIGNIFICANCE OF GENTLE SKIN CLEANSINGThe goal of an effective cleanser is to encompass, loosen, and promote easy removal ofaccumulated surface cutaneous debris, inclusive of natural skin secretions (i.e., sebum,desquamating corneocytes), dirt, microorganisms, and externally applied products (i.e.,cosmetics, skin care products, medication residue) (6,29,30). As cleansing is a regular“daily ritual” for many cultures, the choice of an effective and nonirritating cleanser issignificant. Cleansers containing irritant or abrasive components may enhance loss ofepidermal integrity and barrier function. Improper or aggressve cleansing and overbathingare common causes of epidermal insult, irritation, and xerosis (4,6,29–31).BASIC CLEANSER FORMULATIONSSoap is created by a heating process called saponification; an alkali and a long-chainfat compound are combined, producing a fatty acid salt which exhibits detergent proper-ties (6). A surfactant effect from usage of a soap reduces surface tension between waterand surface debris, allowing for separation and removal by a lathering effect. A majordifficulty with basic soap formulation is a pH of O7 (usually pH 9–10); the normal pH ofskin ranges between 4.5–6.5 (6). The use of true soaps commonly leads to unacceptabledryness and irritation. The development of soap-free synthetic detergent (“syndet”) bars and non-lipid liquidcleansers has significantly improved the cosmetic acceptability and tolerability of skincleanser formulations (6,29). Syndet bars are efficacious cleansers formulations, effectivelylimit damage to the epidermal barrier, and are widely accepted and very popular in themarketplace (6,30). These formulations are comprised of !10% soap and sustain anadjusted pH of 5.5–7 by utilizing synthetic detergents (“syndets”) and filler substances thatare associated with effective cleansing and little to no irritation (6). Lipid-free liquidformulations are also effective cleansers which may create a thin moisturizing film andproduce little to no irritation in patients with normal, sensitive, photoaged, or diseasedskin (6). They are also effective in the removal of cosmetics and makeup. Major componentsof non-lipid liquid cleansers include water, cetyl alcohol, stearyl alcohol, and glycerin (6). The terms gentle or mild do imply that irritation is significantly minimized or absentdue to the combination of ingredients and adjusted pH of the formulation, and do not implya lack of efficacy. Several studies support the efficacy, high degree of patient preference,and lack of irritation associated with use of syndet bars and non-lipid liquid cleansers(6,31). Some combination bars (“combars”) utilize additives to improve the “feel” of theformulation and reduce dryness through creation of a superfatted soap or by addition ofhumectants (i.e., glycerin). However, these formulations usually sustain an alkaline pHO9,and some tend to dissolve rapidly during usage (6).CONCLUSIONThe primary goals of skin cleansing and moisturization are to sustain overall skin healthand appearance by maintaining epidermal barrier integrity. This is achieved by selecting

Optimal Skin Care and Product Selection 121products that are formulated to preserve retention of water content, limit damage toepidermal lipids and proteins, minimize TEWL, and contribute to barrier repair duringepisodes of compromise. Optimal product selection is based primarily upon the inherentqualities of the formulation, correlated with the needs and skin type characteristics of theindividual patient. Ultimately, effective products are well designed with regard to theirfundamental skin care characteristics and not dependent on multiple special additives thatare included based on marketing trends rather than scientific validity.REFERENCES 1. Johnson AW. The skin moisturizer marketplace. In: Leyden JJ, Rawlings AV, eds. Skin Moisturization. New York: Marcel Dekker, 2002:1–30. 2. Draelos ZD. Therapeutic moisturizers. Dermatol Clin 2000; 18:597–607. 3. Flynn TC, Petros J, Clark RE, et al. Dry skin and moisturizers. Clin Dermatol 2001; 19:387–392. 4. Rawlings AV, Harding CR, Watkinson A, Scott IR. Dry and xerotic skin conditions. In: Leyden JJ, Rawlings AV, eds. Skin Moisturization. New York: Marcel Dekker, 2002:119–144. 5. Draelos ZD. Moisturizers. In: Draelos ZD, ed. Cosmetics in dermatology. 2nd ed. New York: Churchill-Livingstone, 1995:83–95. 6. Draelos ZD. Skin cleansers. In: Draelos ZD, ed. Cosmetics in Dermatology. 2nd ed. New York: Churchill-Livingstone, 1995:207–214. 7. Kirsner RS, Froehlich CW. Soaps and detergents: understanding their composition and effect. Ostomy/Wound Manage 1998; 44:62S–69S. 8. Wehr RF, Krochmal L. Considerations in selecting a moisturizer. Cutis 1987; 39:512–515. 9. Proksch E, Elias PM. Epidermal barrier in atopic dermatitis. In: Bieber T, Leung DYM, eds. Atopic Dermatitis. New York: Marcel Dekker, 2002:123–143.10. Shurer NY, Plewig G, Elias PM. Stratum corneum lipid function. Dermatological 1991; 183:77–94.11. Grubauer G, Feingold KR, Elias PM. The relationship of epidermal lipogenesis to cutaneous barrier function. J Lipid Res 1987; 28:746–752.12. Yamamoto A, Serizawa S, Ito M, et al. Stratum corneum lipid abnormalities in atopic dermatitis. Arch Dermatol Res 1991; 283:219–223.13. Jackson EM. Moisturizers: adjunct therapy and advising patients. Am J Contact Derm 1996; 7:247–251.14. Imokawa G, Abe A, Jin Y, et al. Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol 1991; 96:523–526.15. Menon GK, Feingold KR, Elias PM. Lamellar body secretory response to barrier disruption. J Invest Dermatol 1992; 98:279–289.16. Zettersten EM, Ghadially R, Feingold KR, et al. Optimal ratios of topical stratum corneum lipids improve barrier recovery in chronically aged skin. J Am Acad Dermatol 1997; 37:403–408.17. Fluhr J, Holleran WM, Berardesca E. Clinical effects of emollients on skin. In: Leyden JJ, Rawlings AV, eds. Skin moisturization. New York: Marcel Dekker, 2002:223–243.18. Mao-Qiang M, Brown BE, Wu-Pong S, et al. Exogenous non-physiologic vs physiologic lipids. Divergent mechanisms for correction of permeability barrier dysfunction. Arch Dermatol 1995; 131:809–816.19. Tabata N, O’Goshi K, Zhen XY, et al. Biophysical assessment of persistent effects of moisturizers after daily applications: evaluation of corneotherapy. Dermatology 2000; 200:308–313.20. Kligman A. Regression method for assessing the efficacy of moisturizers. Cosmet Toil 1978; 93:27–32.21. Lazar AP, Lazar P. Skin, water, and lubrication. Dermatol Clinics 1991; 9:45–51.

122 Del Rosso22. Salka BA. Emollients. Cosmet Toil 1997; 112:101–106.23. Loden M. Barrier recovery and influence of irritant stimuli in skin treated with a moisturizing cream. Contact Dermatitis 1997; 36:256–260.24. Loden M, Andersson A-C, Lindberg M. Improvement in skin barrier function in patients with atopic dermatitis after treatment with a moisturizer cream. Br J Dermatol 1999; 140:264–267.25. Hanifin JM, Hebert AA, Mays SR, et al. Effects of a low-potency corticosteroid lotion plus a moisturizing regimen in the treatment of atopic dermatitis. Curr Ther Res 1998; 59:227–233.26. Presland RB, Jurevic RJ. Making sense of the epithelial barrier: what molecular biology and genetics tell us about the functions of oral mucosal and epidermal tissues. J Dental Ed 2002; 66:564–574.27. Ludwig A, Dietel M, Schafer G, et al. Nicotinamide and nicotinamide analogues as antitumor promoters in mouse skin. Cancer Res 1990; 50:2470–2475.28. Gensler HL. Prevention of photoimmunosuppression and photocarcinogenesis by topical niacinamide. Nutr Cancer 1997; 29:157–162.29. Rawlings AV, Harding CR. Moisturization and skin barrier function. Dermatol Ther 2004; 17:43–48.30. Rawlings AV, Canestrari DA, Dobkowski B. Moisturizer technology versus clinical performance. Dermatol Ther 2004; 17:49–56.31. Del Rosso JQ. Understanding skin cleansers and moisturizers: the correlation of formulation science with the art of clinical use. Cosmet Dermatol 2003; 16:19–31.

8AntiperspirantsJohn E. WildHill Top Research, Miamiville, Ohio, U.S.A.A. C. Lanzalaco and D. F. SwaileP&G Beauty, Sharon Woods Technical Center, Cincinnati, Ohio, U.S.A.INTRODUCTIONPersonal care has been a concern of both men and especially women since the beginning ofrecorded history and most likely prior to those times as well. The ancient Egyptians usedperfumes while bathing and for their hair and clothing (1). The art of making the body smell better was evident in the early civilizations ofBabylon, Assyria, Persia, China, Greece, and Rome (2). Although this chapter topic isrelated to antiperspirants it is difficult to separate the fact that the antiperspirant market hasgrown to its sales level in the market place because an antiperspirant delivers not onlywetness control but, as a secondary benefit, imparts deodorant efficacy as well.HistoryWhile deodorizing or masking of unpleasant body odor has been in practice for much ofrecorded history, controlling underarm wetness has only become a personal care practicein the past 100 or so years. Underarm products began to appear in the market place in theUnited States in the late 19th century with the introduction of a product called MUM in1888. At the dawn of the 20th century the first brand name antiperspirant appeared on theU.S. market as EverDry. It was followed in a few years by a product called Odo-RO-No(3). These early products lacked the aesthetic qualities of today’s brands. Aluminumchloride solutions were wet and runny and had very little cosmetic appeal but managed tosell at a reasonable rate and therefore had enough potential for their manufacturers to keepthem in the market. The greatest shortcomings of these products were their irritatingeffects on the skin and the damage they caused to clothing materials (3). During the early part of the 20th century the antiperspirant market progressedslowly. Following World War II the antiperspirant market expanded very rapidly. The 123

124 Wild et al.technology advancements that occurred because of the war could now be applied to non-war related applications. The ball point pen led to the idea for roll-on applicators.Aerosolized packaging led to aerosol antiperspirants and deodorants. Radio and, the most impactful communication system of our time, televisionprovided a medium for commercial advertising that captured the attention of millions ofconsumers with both verbal and visual displays. Manufacturers of antiperspirants and deodorants were quick to buy into TVadvertising to extol the virtues of their new products. TV watchers were provided a dailybarrage of how to control offensive body odor and underarm wetness. The fact that peoplethemselves can experience their own odor and wetness, as well as notice these attributes inothers, reinforced the commercial appeal of these products. Antiperspirants and deodorants, which in earlier days had been formulated as creamsand solutions, now became available in all types of product forms. There were pads,daubers, pump sprays, squeeze bottles, powders, stick creams, solids, roll-ons, andaerosols. The aerosol market grew rapidly and created “family use” products that were anaesthetically as well as hygienically pleasing way of delivering the product. The aerosolmarket captured the greatest market share until late in the 1970s when the use of aerosolsbecame severely impacted by the concerns for the atmospheric ozone layer depletion andthe ultimate ban on chloroflurocarbon propellants for aerosols. New propellant technologyhas preserved the aerosol but the solid cream and gel sticks came to the forefront of theUnited States market in the 1980s and remain as a large market share of the currentformulation market place.ANTIPERSPIRANTSDefinitionAn antiperspirant, as defined by the Department of Health and Human Services in the finalantiperspirant monograph published in 2003, reads as follows: “A drug product applied topically that reduces the production of perspiration (sweat)at that site” (4). There has always been some confusion in the industry that consumers do not alwaysrelate to the basic difference between antiperspirant and deodorant products.Antiperspirants, because of their ability to reduce perspiration and thus diminish themedium that is a factor in the development of axillary odor, can also claim to be adeodorant. However, because a deodorant product only reduces the body odor and doesnot reduce perspiration it can only be labeled as a deodorant. Delivering that message to the consumer has been difficult because of that dualcapability of the antiperspirant product. This problem may have been more prevalentduring the earlier history of these products than now. In the European market the problemcontinues as labeling allows products containing antiperspirant actives to be labeled asdeodorants. More recently some manufacturers have begun marketing these products asantiperspirants within Europe and these have started to reduce deodorant market share.The United Kingdom was the only one of the European markets that was always open tothe use of antiperspirants and now the remaining countries in the common market areshowing greater market share with antiperspirants. Japan seems to categorizeantiperspirants with deodorants and suggests that their mode of action is the reductionof body odor by way of suppression of perspiration.

Antiperspirants 125Regulatory StatusThe regulatory status of antiperspirants is somewhat different in various regions of theworld market place.United StatesIn the United States an antiperspirant is categorized as an over-the-counter (OTC) drugproduct and therefore subject to regulations by the Food and Drug Administration (FDA).In 1972 the FDA announced a proposed review of the safety, effectiveness, and labeling ofall OTC drugs by an independent advisory panel. In 1978 the FDA announced theestablishment of a monograph and notice of proposed rulemaking that would establishconditions under which OTC antiperspirants are generally recognized as safe and effectiveand not misbranded. In 1982 the FDA issued a tentative final monograph for antiperspirants. In 1990 theFDA issued a rule that certain active ingredients which were used in antiperspirants are notgenerally recognized as safe and effective and are misbranded. Then in 2003 the FDAissued the final monograph for antiperspirant products. The final antiperspirant monographbecame effective in December of 2004 and did not address foot antiperspirancy claims. Inaddition the monograph did not identify any OTC antiperspirant products to be effective inreducing problem or especially troublesome perspiration. However, there was no datasubmitted to support those claims. The agency remains open to those potential claimsif data are submitted with individuals who perceive themselves to have problemperspiration (4).European UnionIn the European Common Market antiperspirants are considered to be cosmetic productsand are therefore subject to the European Cosmetic Directive. The definition of a cosmeticproduct is “any substance or preparation intended to come in contact with the varioussurface areas of the body (epidermis, hair, and capillaries, nails, lips, and external genitalorgans) or with the teeth and buccal mucosae, solely or principally for cleansing,perfuming, or protective purposes in order to maintain them in good condition, modifytheir appearance, and/or improve body odor, and/or protect or maintain them in goodorder” (5). The European Cosmetic Directive has three essential objectives: (i) to ensureconsumer safety, (ii) to harmonize legislation between the different Member States of theEuropean Union, and (iii) to respond to the consumer’s need for information (5). The overall impact of the Cosmetics Directive is to deliver safe products to theconsumer. There is also the implication that the manufacturers should possess data thatsupports the product’s efficacy. However, unlike the OTC monograph for antiperspirantswhich sets a minimum standard of 20% reduction in axillary perspiration for anantiperspirant, there is no minimum level of efficacy stipulated.JapanIn Japan antiperspirant products are controlled under the system of the Ministry of Healthand Welfare (MHW). The regulation governing them is Japan’s Pharmaceutical AffairsLaw (PAL). Antiperspirant products in Japan are regulated and classified as quasi-drugs. Aquasi-drug is an article used only for certain purposes that are specifically designated bythe MHW. Antiperspirants are categorized under body deodorant quasi-drugs based upontheir indication of effects against body odor, perspiration odor, and suppression of

126 Wild et al.Table 1 Data Required in Applications for Approval of Cosmetics and Quasi-DrugsData required Scope Quasi-drug CosmeticOrigin, background of Origin and details of discovery X X discovery; use in foreign countries Use in foreign countries X X Characteristics and comparison with X XPhysical and chemical properties, specifications, other quasi-drugs or cosmetics X X testing methods, etc. Determination of structure X X X XStability Physical and chemical properties XSafety Specification and testing methods X X Long term storage XIndications or effects Severe test X X Acceleration test X Acute toxicity a Subacute toxicity a Chronic toxicity a NA Reproductive effects NA Skin sensitization, X X photosensitization, etc. Mutagenicity X X Carcinogenicity NA Skin irritation, mucosa a X irritation, etc. Absorption, distribution, X X metabolism, and excretion Laboratory tests supporting indi- X NA cations or effects Use test in humans X NA Xa May not be required under certain conditions.Abbreviations: X, required; NA, not applicable.perspiration (6). Quasi-drugs and cosmetics are clearly stipulated to be articles whosebiological activities are gentle and mild. Table 1 presents a tabular summary of the datarequired in an application for approval of cosmetics and quasi-drugs. The practical result of the U.S., EU, and Japanese regulatory control of antiperspirantsis that to be in a global market place, such products require a high level of formulation andmanufacturing expertise to ensure safety and efficacy.ANTIPERSPIRANT EFFICACYIn the U.S. the FDA has included in the OTC Antiperspirant Final Monograph guidelinesthat the manufacturer may use in testing for effectiveness. The agency does not require thatthese guidelines be used but requests that alternate methods and statistical evaluations aresubject to FDA approval (4). The FDA has established in the monograph the minimum standard for effectivenessat 20% sweat reduction to allow a product to be labeled as an antiperspirant. There are noguidelines suggested in the European Cosmetics Directive, however, because there are

Antiperspirants 127many publications on this topic concerning antiperspirant efficacy, and techniques forproving efficacy are well known and readily available in the testing market place. In Japan, Tagami indicates that the MHW does not specify in the PAL any specificstandard test methodology for evaluating the clinical effects of quasi-drugs. It only makesreference to the use of a clinical use test in humans, under conditions simulating actualdaily usage, for supplying data to assess the effects and safety of such products (6).Recommended and Approved UsesThe antiperspirant monograph provides very specific labeling requirements for anantiperspirant drug product as follows: 1. A statement that the product be identified as an antiperspirant and that the product contains a drug identified by its established name, if a drug is present. 2. Under a heading titled “uses” the following language may be used by selecting one of the following phrases: “decreases,” “lessens,” or reduces underarm: “dampness,” “perspiration,” “sweat,” “sweating,” or “wetness.” Other language can be appended to the phrase if it is truthful and not a misleading statement describing an established use as follows: “decreases, lessens or reduces” underarm “dampness, perspiration, sweat, sweating or wetness due to stress.” For products that demonstrate the minimum standard of 20% sweat reduction over a 24-hour period the label may state either “all day protection,” “lasts all day,” “lasts 24 hours,” or “24-hour protection.” For products that demonstrate extra effectiveness of 30% sweat reduction the labelmay state “extra effective.” In addition for products that demonstrate the extra effectivereduction over a 24-hour period the language for the standard reduction may be used orcombined with any one of these statements: “24-hour extra effective protection,” “all dayextra effective protection,” “extra effective protection lasts 24 hours,” or “extra effectiveprotection lasts all day.” The product label must also contain the following items listed under “Warnings:” “Do not use on broken skin.” “Stop use if rash or irritation occurs.” “Ask a doctor before use if you have kidney disease.” If the product is aerosolized: “When using this product keep away from face and mouth to avoid breathing it.” The label must also contain the following under the heading of “Directions:” “Apply to underarms only” (4). The regulatory agencies in other countries have not been as specific in as manydetails as the FDA.Function of AntiperspirantsAntiperspirant products are relatively unusual drug formulations. Unlike most drugs, theirmechanism of action is physical rather than pharmacological. Figure 1 illustrates how theantiperspirant actives form a shallow plug near the opening of an eccrine sweat duct on theskin surface (7). These blockages prevent the eccrine excretion from reaching the skinsurface in the axilla without creating a significant systemic effect on the thermal regulatorysystem. These blockages can remain within the sweat duct for seven to 14 days dependingon the rate of skin desquamation, consumer’s hygiene regime, activity type, and quality.

128 Wild et al. HHoowwAAnnttiippeersrspiprairnatsnWtsoWrk.o.. rk... antiperspirant matrix with actives1) Antiperspirant 2) Moisture grabs 3) Active particles matrix applied to and dissolves solidify to form skin carries active particles... a temporary active particles. which descended gel plug inside into the sweat the duct. duct. Underarm wetness is prevented, limiting the malodor caused by production of bacteria on the skin. sweat ducts in the skinFigure 1 Graphic showing the formation of the shallow plug in the sweat duct demonstrating themechanism of action for current antiperspirant products.Function of DeodorantsHistorically, there has been some confusion among the public when distinguishingbetween the benefits provided by commercial antiperspirant and deodorant products (8).While antiperspirants are designed to reduce both axillary sweating and malodor,deodorants provide only malodor control. The most effective deodorants are typicallyglycol-based products containing odor-masking fragrances. The use of a glycol base isespecially effective as it augments the masking fragrance by providing microbial controlof the odor causing bacteria (9). However, these products do not impact axillary sweatingin any way. In contrast, OTC antiperspirant products provide the dual benefits of axillarywetness and malodor control. Antiperspirants reduce malodor through a combinatorialeffect that includes the microbial inhibition of the aluminum and zirconium salts; thedeleterious effect on the odor causing bacterial ecosystem of a drier axillary vault and theability of skin substantive antiperspirant products to extend the residence time of maskingfragrances (10). For perspective, in a head-to-head clinical comparison, a fragrance-freealuminum zirconium tetrachlorohydrex glycine-containing antiperspirant was shown to besuperior to a fragrance-free glycol-based deodorant at reducing axillary malodor (11).FORMULATIONApproved Active IngredientsThe final OTC antiperspirant monograph itemized the 18 active ingredients that areapproved for use in antiperspirant products in the U.S. Table 2 shows each of the approved

Antiperspirants 129Table 2 Antiperspirant Active Ingredients Dosage form Only aqueous solutionActive ingredient Concentration (must be nonaerosol)Aluminum chloride Up to 15% (calculated Aerosol or nonaerosol on hexahydrate Aerosol or nonaerosolAluminum chlorohydrate form) Aerosol or nonaerosolAluminum chlorohydrex Aerosol or nonaerosol Up to 25% Aerosol or nonaerosol polyethylene glycol Up to 25% Aerosol or nonaerosolAluminum chlorohydrex Aerosol or nonaerosol Up to 25% Aerosol or nonaerosol propylene glycol Aerosol or nonaerosolAluminum dichlorohydrate Up to 25% NonaerosolAluminum dichlorohydrex Up to 25% Nonaerosol Nonaerosol polyethylene glycol Up to 25% NonaerosolAluminum dichlorohydrex Nonaerosol Up to 25% Nonaerosol propylene glycol Up to 25% NonaerosolAluminum sesquichlorohydrate NonaerosolAluminum sesquichlorohydrex Up to 25% polyethylene glycol Up to 20%Aluminum sesquichlorohydrex Up to 20% propylene glycolAluminum zirconium Up to 20% octachlorohydrate Up to 20%Aluminum zirconium Up to 20% octachlorohydrex glyAluminum zirconium Up to 20% pentachlorohydrate Up to 20%Aluminum zirconium Up to 20% pentachlorohydrex glyAluminum zirconium tetrachlorohydrateAluminum zirconium tetrachlorohydrex glyAluminum zirconium trichlorohydrateAluminum zirconium trichlorohydrex glyingredients, concentration limits, and dosage forms/types in which the approved active canbe formulated. There are no specific active ingredient lists specified by the EU or Japan.Formulation VariationsAs with all treatment programs, the key to achieving maximum benefit is compliance.Antiperspirant products can require up to 10 consecutive days to reach maximum efficacyand benefits can be completely eliminated within 14 days of treatment termination.Barriers to compliance are typically associated with products’ aesthetics rather than skinirritation. Refer to Table 3 for details on formulation and compliance. Erythema and

130 Wild et al.Table 3 Formulation and ComplianceProduct types Active types Carrier system Barriers to Comments compliance Only form avail-Water-based Aluminum chloride Water Skin irritation able with alumi- roll-on num chloride in Aluminum Oil in water (aluminum mass marketPowder-based roll-on chlorohydrate Emulsion chloride) Most common product form inGels Aluminum Wet sticky mass marketStick zirconium skin feel Generally the mostCreams efficacious form tetrachlorohy- in mass market drate gly Aluminum zirco- Anhydrous Wet skin feel at nium tetrachlor- emollients application ohydrate gly Aluminum zirco- Water in silicone Sticky skin feel nium tetrachlor- emollient ohydrate gly emulsion Aluminum chloro- Silicone emolli- White residue hydrate ent system on skin and Aluminum zir- solidified with clothes conium trichlor- wax ohydrate gly Aluminum zirconium tetrachlorohy- drate gly Aluminum zirco- Silicone emolli- Skin feel at nium trichloro- ent system application hydrate gly thickened with Aluminum wax zirconium tetrachlorohy- drate glystinging can still be common for products containing Aluminum Chloride and/or highlevels of glycol or fragrance but are not common on most commercial antiperspirants.Unscented products based on the emollients cyclopentasiloxane and dimethicone havevery good skin compatibility. Most common barriers to compliance are associated with the skin feel of product,product appearance on skin, product transfer to clothes, and fragrance. Typically,consumers view antiperspirant application as part of their total grooming process andoften create application behaviors that reduce product efficacy. Behaviors such asremoving the product shortly after application, not applying the dose of productrecommended by the manufacturer, or only applying it to a portion of the axilla willreduce efficacy. Encouraging consumers to identify a product form that allows them tocomply with a daily application routine will maximize their observed benefit. Efficacycan further be improved by placing the user on a nighttime application to remove issueswith the user’s morning grooming routine. Night time application allows the active toenter the duct during a time of low sweating rates and allows for more efficientplug formation.

Antiperspirants 131FORMULATING FOR THE CONSUMERThe approach taken by manufacturers to encourage compliance has been to offer a widechoice in product form and aesthetics. Today’s consumers are accustomed to a variety ofchoices in their antiperspirant selection. It is clear, from even a cursory glance at theantiperspirant/deodorant shelves in any supermarket or pharmacy, that there is a widerange of aesthetic experiences acceptable to people. The desired experiences aredelivered through a multitude of packaging presentations, both in size variation andproduct type. These include aerosol sprays, silicone/wax sticks, aqueous clear gels, andlotion-like creams. In addition, most antiperspirant brands provide a variety of fragranceoptions for their consumers. All of these variations cater to the consumer’s demands forboth gender and ethnic preferences. Manufacturers long ago discovered that people tendto gravitate to the form that they are most comfortable with, which in turn ensurescompliance leading to effective axillary wetness control. Importantly, the drive to meetthe consumer’s demand for aesthetically appealing products applies globally to theantiperspirant market place.INTRODUCING NEW ANTIPERSPIRANT ACTIVE FORMULATIONSIn the U.S. the introduction of any new antiperspirant actives into the market will require aNew Drug Application (NDA) or an Abbreviated New Drug Application (ANDA). Theseprocedures will no doubt inhibit bringing new actives into the market place unless there isa strong inclination by the manufacturer to believe their new active will bring a largereturn from the market place. The submission of an NDA or ANDA requires a majorcommitment of time and capital by the manufacturer. When consumers demand new andmore effective products, industry will usually respond as long as there will be the hope fora return on its investment.MEDICAL APPROACHES TO HYPERHIDROSISHyperhidrosis is defined as excessive sweating. The profusion of sweat may be in theaxillae, the palms, the feet, the face, on the trunk, or a combination of any or all of theabove body parts. The excessive sweat is beyond the person’s physiological requirementto regulate the body’s temperature and is largely under emotional control (12). In a culture where the personal hygiene and social standards are established to notemit unpleasant odors and/or exhibit underarm wetness, clammy skin, etc., ahyperhidrodic condition can be devastating in social environments. The condition canadversely affect the person’s ability to attain a normal and healthy quality of life. Personssuffering with hyperhidrosis have reported both physical and emotional impairment anddifficulty in their professional and social lives. Approximately 0.5% of the U.S. populationsuffers from axillary hyperhidrosis and report that their excessive sweating is barelytolerable to intolerable and interferes in some way with their daily activity (12,13).TreatmentAntiperspirantsThe treatment of hyperhidrosis with OTC antiperspirant products is usually the first methodemployed by those who suffer with this condition. There are no currently marketed

132 Wild et al.antiperspirants that are explicitly designed or claim to have a beneficial effect on excessivesweating. As stated earlier the FDA has not approved any marketed OTC antiperspirantproduct for an excessive sweating condition. In addition, all the currently marketed OTCantiperspirant products are explicitly labeled to be used only in the axilla and are notapproved for any other body location. The FDA has, however, remained open to a claim forthe treatment of excessive sweating if data are submitted for their review for this claim (12). The currently marketed OTC antiperspirant products most likely offer only marginaleffectiveness to those who suffer from hyperhidrosis. Because this condition is so sociallydevastating, a large number of those who suffer with hyperhidrosis seek the advice of ahealth professional (12,14). There are prescription drug solutions available for those who seek medical treatmentfor their condition. These prescription products usually contain aluminum chlorideconcentrations greater than those which have been established as safe and effective in thefinal OTC antiperspirant monograph. These higher concentration products are usuallyrecommended to be used at bedtime to allow for maximum absorption at a time whensweating may be at a minimum for the day. They are typically applied nightly for threenights under the occlusion of plastic wrap. The plastic wrap occlusion traps perspiration inthe armpit and hydrates the skin enhancing penetration of the aluminum chloride solution,which increases efficacy. After this initial treatment period, the plastic wrap occlusion isdiscontinued and the aluminum chloride solution is only applied every other night for a weekand then twice weekly for a week. Patients are advised to keep decreasing the frequency ofaluminum chloride application until the minimum application frequency to maintainsweating control has been determined. Applications at this frequency are continuedindefinitely as the aluminum chloride only decreases axillary sweating temporarily. The higher concentrations of aluminum chloride can be more irritating to the skinthan OTC antiperspirant products. These higher concentrations have also been known tobe harmful to fabrics, and therefore caution should be used about clothing worn duringtreatment (12). Other treatment options are also available to those who suffer with hyperhidrosis.These treatments include some of the following.IontophoresisThis procedure employs the use of weak electric current to slow down sweat production. Itrequires the purchase of a battery-operated device with a removal pad. The pad is soakedeither with tap water or a dilute solution of aluminum chloride in tap water. The device isplaced in the armpit and turned on for approximately 20–30 minutes. During this time, thelow voltage electric current is used to drive the tap water with or without aluminumchloride into the duct of the eccrine sweat gland to create a plug. This plug prevents therelease of the sweat into the armpit. Devices are also available for the palms of the handsand the soles of the feet. The primary drawback to this technique is the time required to administer thetreatments. With continued use, it is possible to cut back on the frequency or sessions fromdaily, to twice weekly, to once weekly. It is key to maintain the plug in the sweat duct forefficacy. Once the plug is gone, the previous rate of sweating will return. Unfortunately,iontophoresis can only decrease the amount of sweating, not stop it completely (12).Endoscopic Thoracic Sympathectomy SurgeryEarly surgical techniques that were used to treat hyperhidrosis were invasive, risky,scarring, and sometimes unsuccessful. Endoscopic thoracic sympathectomy (ETS) surgery

Antiperspirants 133is less invasive, since it is performed with the aid of a small endoscope that is introducedinto the body. This surgery is designed to interrupt the transmission of nerve signals to thesweat glands. This procedure carries with it the usual risks that can be encountered duringsurgery, such as nerve damage, as well as other side effects, such as chronic painsyndrome. The most notable of these side effects may be compensatory sweating, that is,increased sweating may occur at a new body location. In addition, the cut nerves mayreconnect, rendering the procedure completely unsuccessful (12).Prescription MedicationsAnticholinergic drugs, such as Robinal, may help prevent the stimulation of the sweatglands and thus inhibit sweat output. The FDA has not approved any drug for the treatmentof hyperhidrosis. Although these drugs may be effective in inhibiting excessive sweat,there are significant side effect risks with these medications. These include such effects asdry mouth, blurred vision, urine retention, constipation, impaired swallowing, taste, etc.Medications such as these are usually taken only for special occasions when sweat controlis important. Most persons cannot tolerate the side effects on a daily basis (12).Botulinum Toxin A Injections (Contributed by Zoe Diana Draelos, M.D.)Botulinum toxin A (Botox, Allergan) is the most effective method of reducing axillaryhyperhidrosis. It is classified as a method of chemodenervation, since it interrupts thenerve signal to sweat. As mentioned previously, axillary hyperhidrosis is largely undercentral control. The brain must send a signal to the nerves in the armpit to initiatesweating. If the nerve signal is never received by the sweat gland, sweating does not occur.This is how botulinum toxin works. Unfortunately, it cannot be applied to the skin surface,but must be injected with a small insulin syringe just beneath the skin surface where thesweat glands lie. Botulinum toxin A treatment for hyperhidrosis is typically administered as a medicalprocedure in the office of a dermatologist. The armpit is first cleaned thoroughly to removeall sweat and antiperspirants. It is then painted with an iodine solution and dusted withcornstarch. The reaction between the sweat and iodine will turn the cornstarch black onceperspiration has begun. An indelible marker is then used to draw a line around the area ofmaximum sweating. This is the location for the botulinum toxin A injections. Once the area of maximum sweating has been determined, the botulinum toxin A isremoved from the freezer, where it must be keep until just before use. The freeze-driedbotulinum toxin bottle containing 100 units is then reconstituted with 2 cc of unpreservedsterile saline. Approximately 10 units are drawn up into 20 insulin syringes for injectionwith 10 syringes used in each armpit. The injections are made just under the skin surface toraise a tiny wheal at 2 cm intervals in a whirl configuration from the central armpitoutward until the entire area outlined by the indelible marker has been injected. As mightbe imagined, this is a painful and tedious procedure. Fortunately, the sweat reduction induced by the botulinum toxin A lasts forapproximately six months, or longer in some individuals. The treatment does not completelyeradicate axillary sweating, but significantly diminishes its amount. Any remaining sweatingcan usually be controlled with traditional nonprescription antiperspirants. Botulinum toxin Acan also be injected into the hands and feet for purposes of sweat reduction.Other Surgical Treatment OptionsThere are a variety of other treatment options that have been tried with limiteddocumented success. These treatments include such surgeries as excision of sweat glands

134 Wild et al.and liposuction. It is very difficult to excise the sweat glands without creating movementproblems in the armpit. The hair bearing skin typically denotes the location of the sweatglands in the armpit, but removal of this quantity of skin is both scarring and restrictive.A better alternative is liposuction. Liposuction can be performed under a form of locallidocaine anesthesia known as tumescent anesthesia. Here a dilute solution of water andlidocaine is introduced into the fat just below the armpit skin. The lidocaine provides painrelief and raises the armpit skin away from the underlying nerves and vessels that must notbe damaged during surgery. A 2 mm opening is made in the armpit and a metal tube,known as a cannula, is inserted. The cannula has a cutting edge just below the tip and isvigorously pulled against the undersurface of the skin to intentionally damage and scar thesweat glands. The cannula is attached to a negative pressure vacuum suction device thatcollects the removed tissue and anesthesia. Tumescent liposuction of sweat glands iseffective at reducing axillary sweat in some individuals.REFERENCES 1. Miller J. The H & R Book of Perfume. London: Johnson, 1984. 2. Parisee AJ. Antiperspirants. In: Waggoner WC, ed. Clinical Safety and Efficacy Testing of Cosmetics. New York: Marcel Dekker, 1990:163–223. 3. Laken K. Introduction and History of Antiperspirants and Deodorants. In: Laden K, Felger CB, eds. Antiperspirants and Deodorants. New York: Marcel Dekker, 1988:1–13. 4. Federal Register, Antiperspirant Drug Products for Over-the-Counter Human Use. Final Monograph, Food and Drug Administration 21 CFR Parts 310, 350 and 369, U.S. Vol. 68. Rockville, Md: Department of Health and Human Services, 2003:34273–34293. 5. Masson, Ph. The Contribution of the European Cosmetic Directive Towards International Harmonization: Impact on the Evaluation of Safety and Efficacy. In: Elsner P, Merk HF, Maibach HI, eds. Cosmetics: Controlled Efficacy Studies and Regulations. Berlin: Springer, 1999:20–35. 6. Tagami H. Claim Support in Japan: Legal Aspects. In: Elsner P, Merk HF, Maibach HI, eds. Cosmetics: Controlled Efficacy Studies and Regulations. Berlin: Springer, 1999:36–49. 7. Swaile DF. Variation in efficacy of commercial antiperspirant products based on differences in active composition and manufacturing method. In: 61st Annual Meeting of the American Academy of Dermatology. San Francisco, CA: American Academy of Dermatology, March 21–26, 2003:P337. 8. Laden K. Preface. In antiperspirants and deodorants. 2nd ed. Revised and Expanded. New York: Marcel Dekker Inc, 1999: preface. 9. Karabit MS, Juneskans OT, Lundgren P. Studies on the evaluation of preservative efficacy. In the determination of antimicrobial characteristics of some pharmaceutical compounds in aqueous solutions. Int J Pharm 1989; 54:51–56.10. Benohamian A. Antiperspirants and deodorants. Clin Dermatol 2001; 19:398–405.11. Lanzalaco AC, Rocchetta M, Snyder M, Chabi G. In the absence of fragrance, both deodorants and antiperspirants show effective control of underarm odor. J Am Acad Dermatol 2005; 52:91.12. Accessed May 2005 at http://sweathelp.org.13. Lowe NJ, Glaser DA. Botulinum toxin type A in primary axillary hyperhidrosis. In: A 52-week, Multi-Center, Double-Blind, Randomized, Placebo-Controlled Trial; 62nd Annual Meeting of the American Academy of Dermatology, Feb. 6–11, 2004:P195.14. Kowalski JW, Eadie N, Dagget S, et al. Validity and reliability of the Hyperhidrosis Disease Severity Scale (HDSS). In: 62nd Annual Meeting of the American Academy of Dermatology. Washington, DC: American Academy of Dermatology, Feb. 6–11, 2004:P195.

PART III: ACTIVE INGREDIENTS FOR SKIN TREATMENT9SunscreensJ. F. Nash and Paul R. TannerP&G Beauty, Sharon Woods Technical Center, Cincinnati,Ohio, U.S.A.INTRODUCTIONThere is consensus among the scientific and medical communities that exposure tosunlight is a major factor in the etiology of the progressive unwanted changes in theappearance of skin, i.e., photoaging, and in the risk of skin cancers (1–3). The evidencesupportive of this view comes from epidemiology, clinical studies, and experimentalstudies in humans, laboratory animals, and in vitro systems. It is well established that acuteexposure of unprotected skin to ultraviolet (UV) radiation in sunlight produces numerousphysiological effects beyond the most obvious which is sunburn (4). Such insults ordamage following repeated, lifetime exposure to solar UV lead to skin cancers (5–8), andas presented in Table 1, a myriad of degenerative events responsible for the visible signs ofskin aging (10,11). Recent years have seen a very rapid increase in knowledge concerningthe etiology and prevention of solar damage (12–14). Since exposure to UV radiation insunlight is associated with deleterious dermatological events, it is logical that reducingsolar UV exposure will diminish such damage to the skin. Arguably, the complete avoidance of solar UV is neither achievable nor entirelyhealthy. For example, it is known that exposure to sunlight has health benefits includingproduction of vitamin D (15). As such, moderation seems prudent when considering thebalance between the established damage and benefits of solar exposure. To this end,a “safe sun” strategy has been developed and promoted by healthcare professionalsworldwide (16–18). An important part of this “safe sun” strategy is the use of sunscreens. Once the energy from UV is absorbed in the skin, it may produce new chemicalentities, e.g., 60,40-DNA photoproducts, free radicals, etc., or dissipate the excess energy asheat or phosphorescence. This absorption and subsequent conversion of energy contributeto the processes involved in the etiology of skin cancer and photoaging. Preventing solarUV from interacting with skin chromophores is the primary function of sunscreens. To thisend, sunscreen products are quite simple; they absorb/reflect/scatter UV radiation fromsunlight before this energy can be absorbed by chromophores residing in the skin. As itturns out, sunscreen products are technically complex. Moreover, such products must beapplied to be effective, and as with any other preventative measure, compliance is the keyto achieving health benefits. 135

136 Nash and TannerTable 1 Features of Chronological (Intrinsic) and Photo-Induced Skin Aging Chronological Photo-inducedClinical Physiological/histological Clinical Physiological/histologicalFine wrinkles Increase variability Varying degrees of Epidermal acanthosisSkin laxityDry skin in epidermal thickness thickness Thickened stratumEven skin tone corneum Decrease in epidermal Coarse wrinklesImpaired wound Marked cellular healing filaggrin dysplasia Reduction in the number Marked dryness Variability in size and shape of keratinocytes of melanocytes and scaliness Pronounced flattening Reduction in number Uneven pigmenta- of epidermal-dermal junction of Langerhans cells tion and lenti- Reduction in number of gines Langerhans cells Decrease in dermal Benign, premalig- Solar elastosis resulting from hyperplasia of thickness nant, and malig- abnormal elastic tissue nant skin lesions Blood vessels dilated and on the face called Increase in cross-linkage telangiectasias and disorganization of Sebaceous gland hyperplasia and collagen fibers pore size Decrease in number of eccrine, apocrine, and sebaceous glands Flattened dermoepidermal junctionSource: Modified from Ref. 9.SUNSCREENSUnquestionably, the safety and efficacy of sunscreen products is of paramount importance.To this end, the function, UV filters, and product design will be discussed.FunctionAs stated, the function of sunscreen products is to absorb/scatter/reflect solar UV, therebyreducing the dose of such harmful radiation to the skin. This is accomplished through theuse of a combination of UV filters (Table 2) and an appropriate film-forming vehicle.Whereas for most products, such as cosmetics or over-the-counter (OTC) drugs, it mightbe enough to simply include ingredients that have an established effect, i.e., cough/coldpreparations with antihistamines, decongestants, etc., for sunscreens, the protectiveeffectiveness is communicated directly to consumers as the sun protection factor (SPF).Recently, it has been recognized that SPF is incomplete and some additional measure ofprotection against long wavelength UV, i.e., UVA-I (340–400 nm), is needed. None-theless, the SPF is meaningful to consumers and the single most important in vivo measureof sunscreen product efficacy. For consumers, the most recognized and understood skin response to sunlightexposure is erythema or “sunburn.” This can occur in most Fitzpatrick Skin Types and can

Sunscreens 137Table 2 Approved UV Filters Up to % concentrationUV filter 15 3Aminobenzoic acid or PABA 3Avobenzone or butyl methoxydibenzoylmethane 3CinoxateDioxybenzone 15Homosalate 5Menthyl anthranilate or meradimateOctocrylene 10Octyl methoxycinnamate or octinoxate 7.5Octyl salicylate or octisalate 5Oxybenzone or benzophenone-3 6Octyl dimethyl PABA or padimate O 8Phenylbenzimidazole sulfonic acid or ensulizole 4SulisobenzoneTitanium dioxide or TiO2 10Trolamine salicylate 25Zinc oxide or ZnO 12 25Source: From Ref. 19.be produced in a clinical setting following exposure to an artificial light source. Mostimportant, the erythema action spectrum, i.e., erythemal response as a function of UVwavelength, is nearly identical to the action spectrum for DNA damage (20–22) andnonmelanoma skin cancer as evaluated in hairless mice and predicted for humans (23).Thus, the current in vivo test used to evaluate the functional efficacy of sunscreens is basedon an endpoint that is meaningful to consumers, e.g., sunburn protection, and a surrogatefor clinically relevant acute and longer term skin damage. The SPF is a ratio of the response to solar-simulated UV exposure in protected skinversus unprotected skin. Specifically, the minimum erythema dose (MED) is determined foreach panelist in an SPF test. This is the time/dose of solar-simulated UV needed to produce auniform, barely perceptible redness in the skin. The MED will vary depending onFitzpatrick Skin Type (24,25). To determine the SPF, a product is applied at a fixed dose of2 mg/cm2 over a 50–100 cm2 area of the lower back. Five to seven “spots” are exposed tovarying doses of solar-simulated UV, two/three above, two/three below, and one at the“expected” product SPF. The “expected” SPF is a predicted value from in vitro estimates orthe experience of the sunscreen product formulator. At 16–24 hours after UV exposure, thesites are evaluated and the one receiving the lowest UV dose in which a uniform, barelyperceptible redness was produced is recorded (26). The “UV-dose/time” is used to calculatethe SPF using the following equation: SPFZMED protected skin/MED unprotected skin.According to the methods stipulated by FDA, the SPF is determined in 20 panelists. There has been much effort to make the SPF test reproducible and reliable, mostrecently with the introduction of an International SPF Test coordinated by the EuropeanCosmetic Toiletry and Perfumery Association (COLIPA). However, there are severalshortcomings of the SPF test and resulting label which should be pointed out. First, it must beclearly understood that the SPF test measures a biological effect using an artificial light source,fixed dose, and an endpoint, i.e., erythema, that is weighted for short wavelengths of UV,namely 290–340 nm (27). Unfortunately, it is overly convenient to refer to SPF as a measureof UVB protection even though it is determined using full spectrum, 290–400 nm, solar-simulated UV and that the UVA-II region (320–340 nm) contributes significantly to high SPF

138 Nash and Tannervalues. Moreover, because it is a “number,” even knowledgeable individuals overemphasizethis quantitative index of what is most certainly a qualitative response. For example, an SPF 12is quantitatively different than an SPF 17, yet from a biological standpoint, the protectionafforded by proper use of an SPF 12 or 17 is indistinguishable. As well, the SPF determinedunder controlled laboratory conditions is dependent on the light source and may be different ifthe light source changes, e.g., solar-simulated light versus natural sunlight. Finally, the SPFratio is “nonlinear” since an SPF 15 is not half of an SPF 30 based on the ability to reduceerythemally-weighted UV. That is, the SPF is determined by the erythema action spectrumwhich, as stated previously, is weighted for short wavelengths of UV. The SPF can berepresented as a percent of erythemally-weighted UV transmitted, i.e., 1/SPF ! 100, orblocked, i.e., ½1Kð1=SPFÞ !100Š. Thus, an SPF 15 blocks 93.3% and SPF 30, 96.7% of theerythemally-weighted UV or a mere 3% difference. Finally and perhaps the most significantlimitation of SPF is the failure to provide assurance of protection against long wavelengths ofUV, 340–400 nm, or the so-called UVA-I. Whereas it is now established that protection of long wavelength UVA is essential(28–30), as of December 2005 there is no agreed to, regulatory-mandated means ofmeasuring or communicating UVA protection of sunscreen products to consumers in theUnited States. To further complicate the situation, there are currently no known surrogatesfor long wavelength UVA damage that can be measured in the skin following acuteexposure to filtered solar-simulated UV. This fact has profound implications for any in vivohuman study measuring a UVA protection factor, i.e., the ratio of response to a filtered,artificial light source at a fixed dose in protected versus unprotected skin. The mostprominent concern is that any such UVA protection factor based on a response which has nodirect relationship to a human health concern, e.g., photoaging or skin cancer, is nothingmore than misleading at best. Further, the resulting UVA protection factor is meaningless toconsumers since the skin response, e.g., persistent pigment darkening or “color change,” isnot a response to which protection is considered when purchasing a sunscreen product.Finally, it is possible to measure a UVA protection factor without protecting againstthe breadth of UVA. Nonetheless, there are numerous proponents of such an approach andtests including persistent pigment darkening (PPD) (31) and protection factorUVA (PFA) (32,33). Since any in vivo test is without merit, there have been several in vitro methodsproposed (34,35). In general, the in vitro approach is based on measurement of absorbance/transmittance of UV through a sunscreen product applied to a substrate (36). The resultingdata can be used to calculate a “metric” from which some labeling designation can be derived(37–39). This general approach has been used successfully in several countries includingAustralia (AS/NZS 2604 Sunscreen products, evaluation, and classification), U.K. (Boots StarRating), and Germany (DIN draft standard 67502 whereas the UVA-protection is nowcalculated as UVA-balance). The stated objection to such in vitro approaches is that they arenot done on human skin and, as such, cannot provide quantitative information regarding“protection.” Despite this concern, substrate spectrophotometric measures of absorption haveseveral advantages including cost, reproducibility, and human subjects are not intentionallyexposed to an artificial filtered light source the health consequences of which are unknown.Moreover, the results from in vitro substrate spectrophotometric studies can providecomplimentary information to the in vivo derived SPF. In sum, the function of sunscreen products is to reduce the dose of solar UV therebymitigating or reducing damage to the skin. The SPF test provides meaningful, in vivoinformation regarding the protection against solar UV which is weighted for shortwavelengths based on the erythema action spectrum. The SPF “number” is recognized byconsumers as the measure of sunscreen product efficacy. In vitro substrate

Sunscreens 139spectrophotometric measures of sunscreen product absorbance and calculation of a metricsuch as Critical Wavelength can serve as an independent, complementary measure of longwavelength, UVA, sunscreen product efficacy. The American Academy of Dermatologyhas provided a recommendation (40) which may serve as the basis for a regulatory-mandated testing and labeling for UVA efficacy of sunscreen products.Active Ingredients: UV FiltersIn the U.S., there are 16 UV filters which are approved for use in sunscreen products andare listed in Table 2. Of these 16, there are nine which appear in most currently marketedsunscreen products in the U.S. (41). There is much overlap in the use of such ingredientsbetween U.S. and other regions throughout the world such as Europe (42), the latter havinga larger number of UV filters available for use. The human safety of UV filters has beenreviewed (39,43–45). In general, the human safety profile of UV filters used in U.S.sunscreen products is favorable based on extensive toxicological data and marketinghistory. This view is reflected in the appearance of these ingredients on either positive listsin various regions of the world such as Europe and Australia or as Category I ingredients,i.e., safe, and effective, according to the U.S. FDA. Detailed information regarding thehuman safety of individual UV filters can be found in the review by Nash (39). The UV filters in sunscreen products are primarily, if not solely, responsible for theabsorption/reflection/scattering of solar UV. To achieve the SPF and breadth of UVprotection, a combination of UV filters is selected based on their individual absorption profilesand other physiochemical characteristics. For example, to create a sunscreen product with anSPF 15, nearly any combination of UV filters listed in Table 2 can be used. The selection offilters must absorb wavelengths from 290–340 nm to achieve the desired SPF 15. If protectionagainst long wavelength UV is to be achieved, then in the U.S. the options are much morelimited. Specifically, one must select either avobenzone or zinc oxide, both of which absorblong wavelength UVA-I (340–400 nm). As the SPF of the product increases so too does theconcentration and number of UV filters. This is represented in Figure 1. The percentconcentration of UV filters in a hypothetical SPF 15 product ranges from 10–15% and for anSPF 45, up to 30% and beyond. Net, the higher the SPF, the higher the concentration ofUV filters.ProductsUV filters are the functional component of sunscreens while the formulation is the “art.”The general goal in formulating modern sunscreens is to design the best product that meetsthe desired UV efficacy targets of SPF, UVA/broad spectrum protection, and substantivity,i.e., water/wear resistance. Typically, the best product is the one that most effectivelymanages factors such as cost, skin compatibility, and aesthetics/skin feel (46). From an ingredient standpoint, most sunscreen products are typically very similar toconventional lotions or creams, with the key difference being the addition of 4% to 40%sunscreen actives (Fig. 1). From a formulation perspective, the current list of UV filters(Table 2) can be categorized into one of four groups based on the physical properties of theactive: † Polar oils, e.g., octinoxate, octisalate, homosalate, and octocrylene † Oil soluble crystalline solids, e.g., avobenzone, and the benzophenones † Water soluble salts, e.g., ensulizole † Insoluble powders/particulates, e.g., zinc oxide and titanium dioxide

140 Nash and Tanner SPF 8 SPF 15SPF 30 water UV filters solvents/emollients/humectants thickeners emulsifiers preservatives/color/fragrance SPF 45Figure 1 Hypothetical sunscreen products ranging from SPF 8–45. As the SPF increases thepercent of UV filters increases. Importantly, given the concentration of UV filters used in sunscreen products, i.e.,up to 40% for high SPF products, and their physical properties, by far the greatest factorinvolved in managing cost, skin compatibility, and aesthetics/skin feel in formulating newsunscreen products is the selection and combination of these sunscreen actives.CostCurrent sunscreen actives are expensive relative to the key ingredients utilized in mostlotion and cream vehicles, typically ranging from $10 to $100 per kilogram. Thus, thehigher the level of sunscreen actives in a formulation, the greater the formula cost, andhence the more marketers charge for the product. In turn, and perhaps as a directconsequence, one might expect that the more expensive the sunscreen product the moresparingly, i.e., lower dose and reduced frequency, it will be used by consumers (47).Skin CompatibilityAlong with fragrances and dyes, UV filters, particularly organic moieties, are known toelicit irritant responses in subjects predisposed to such skin reactions (48,49). It isgenerally desirable, therefore, to reduce to a minimum the concentration and number ofUV filters present in a sunscreen product formulation to minimize risk of these typesof incompatibilities.Aesthetics/Skin FeelEach type of sunscreen active described above can have a negative impact on sunscreenproduct skin feel, with higher levels having a corresponding larger effect. Specifically, thegeneral skin-feel tradeoffs of the various types of sunscreen actives are:

Sunscreens 141 † Polar oils tend to make the product feel greasy and oily, especially at high concentrations. † Oil soluble crystalline solids require high levels of oily solvents/emollients to dissolve them and keep them from crystallizing in the product over time, and hence make the product feel greasy and oily. † Water soluble salts tend to reduce the capability of most aqueous polymeric thickeners. This, in turn, leads to the use of much higher polymer levels to achieve a target product thickness, and these high polymer levels make the product feel sticky and heavy on the skin. † Insoluble powders/particulates can make the product feel dry and draggy, and often can lead to an undesirable white appearance on the skin. Additionally, even beyond the specific aesthetic effects above, there is a furthergeneral effect that comes from putting significant levels of sunscreen actives into aproduct—higher “coated” feel on the skin. Specifically, the single largest component ofmost non-sunscreen lotions and creams is a volatile carrier, typically water. Thus, when alayer of non-sunscreen lotion or cream is applied to the skin, most of the productevaporates, leaving behind a thin layer of non-volatile material consisting of moisturizers,emollients, thickeners, preservatives, and similar materials. By adding UV filters to aformula to achieve SPF 15 or SPF 30, for example, the level of volatile carrier in theproduct is significantly reduced. As a result, much more of the applied product is leftbehind on the skin, and the skin feels “coated.” Thus, even if the greasy, draggy, or stickyeffects of the sunscreen actives are reduced by other technologies, the skin will still be leftwith an unpleasant coated feeling given the high level of non-volatile materials left behindfrom the sunscreen product. To compensate for this, many consumers apply product at alower dose or less frequently, which will likely reduce the efficacy (50,51). As stated, all of these factors—cost, skin compatibility, and aesthetics/skin feel—will influence patient compliance, either directly, viz amount of product applied andfrequency of application/reapplication, or indirectly in decisions related to repurchasingthe product. Thus, by developing more efficient sunscreens, manufacturers can minimizethe amount of sunscreen actives needed to achieve a given efficacy target, and hencedeliver lower cost, less irritating, and better-feeling sunscreen products. Sunscreenproducts consumers will use more regularly will provide a significantly greater degreeof protection.SELF-TANNING PRODUCTSThe health and beauty of a “tan” has been ingrained in a generation of westerners (52).Unfortunately, this fashion image is diametrically opposed to the message being promotedby healthcare professions, namely to avoid sunlight or other artificial UV light sources,e.g., tanning salons, which is primarily responsible for the beautiful tan. Attempts havebeen made to provide “color” or artificial tans without intentional exposure to solar orsolar-simulated UV. The most successful of these self-tanning products are the ones whichcontaining dihydroxyacetone (DHA). These self-tanning products impart color to the skinwhich is temporary and may be a safer approach toward achieving a “tan” (53).FunctionAs stated, the function of self-tanning products is to temporarily impart color to the skin.Darkening of the skin occurs in response to solar or solar-simulated UV exposure which is

142 Nash and Tannerthe body’s natural response to UV exposure. Melanogenesis is a very complex process thatis still not fully understood (54,55). It is the image of beauty and health to sport a “tan,”and whereas the public health message to avoid intentional solar exposure has had somesmall impact, there has been an increase in the use of tanning parlors (56,57). Importantly,there are individuals who will engage in risky behavior regardless of the costs/conse-quences. As such, the use of sunless tanning products may provide an important alternativefor some. An artificial “tan” resulting from the application of a DHA-containing product doesprovide some limited, short-lived protection against UV (58–60). More recently, it hasbeen reported that topical application of DHA to hairless mice will delay UV-inducedphotocarcinogenesis (61). These protective benefits are promising as sunless tanning gainsin popularity.IngredientsMost, if not all, commercial sunless tanning products utilize DHA to deliver a tannedappearance to the skin. Dihydroxyacetone is a three-carbon sugar that reacts none-nzymatically with amino acids in the outer layers of skin to produce brown/tan coloredpolymers (62). This color-forming reaction, i.e., the Maillard Reaction, is not immediate,and hence visible tanning is not noticeable until a few hours after application. Further, thetanned color produced by DHA is substantive, lasting several days before it graduallyfades away as the outer layers of skin cells slough away. This is in contrast with commonbronzing products that provide immediate color to the skin through the use of dyes andcolored pigments that can be easily washed off. In addition to DHA, several sunlesstanning products also contain erythrulose (63), another sugar capable of reacting with skinproteins to generate a more even and longer lasting sunless tan.ProductsThe goal of a sunless tanning product is to deliver DHA to the skin in a way that providesan even, natural looking tan color (64). To achieve this, there are three importantconsiderations. First, the formulation must ensure that the DHA itself remains stable;otherwise, the product will develop an unpleasant brown color and burnt caramel off-odorin the package, and the sunless tan provided by the product will be compromised. Stabilityis achieved, for example, by a combination of an optimal product pH and avoidingmaterials in the formula that react with DHA, such as amine functional materials andcertain pigments. Second, the product needs to spread the DHA very uniformly on the skin to providean even, streak-free tanned color. To achieve good spreading, a number of new productforms beyond traditional sunless tanning lotions have been introduced, including sunlesstanning sprays, foams (mousses), and wipes. Finally, the sunless tanning product needs toabsorb into the skin and dry quickly, to make it easier and more convenient to achieve agood tan. Getting dressed or going to bed while a sunless tanning product has not fullyabsorbed into the skin can lead to uneven color as well as stained fabrics. Thus, creatingfaster absorbing/drying sunless tanning formulas, like the sprays and foams mentionedabove, ensures best results. Importantly, while all of this sunless tanning product technology has yieldedsignificantly improved sunless tanning products over the early sunless tanning products of20-plus years ago, the reality is that achieving a good, even sunless tan still depends a greatdeal on factors other than the product. For example, proper skin preparation via cleansing

Sunscreens 143and exfoliation is critical to achieving an even, lasting sunless tan. Also the reactionbetween DHA and the skin takes several hours. Avoiding sweating, swimming, orshowering for several hours after product application is also important to ensure bestresults. Finally, since DHA tends to more intensely color skin that has thicker, morecompact outer layers, it is important to wash the hands after applying product to avoid darkbrown stained palms.FORMULATION CHALLENGESGiven the potential cost, compatibility, and skin feel benefits of increased sunscreenefficiency, there have been a number of technologies developed in the past 10-plus years toimprove sunscreen products. For example, the use of film formers, better wetting/spreadingemollients, and shear-thinning rheology modifiers allow sunscreen products to spread moreevenly and form a uniform film on the skin. A more uniform film leads to increased UVefficacy/efficiency by effectively reducing and/or eliminating “holes” in the product film.The use of combinations of UV filters in both the water and oil phases of emulsions provideincreased efficacy/efficiency by ensuring that there are no unprotected areas in the productfilm. Another example is the identification/development of photostable sunscreen activecombinations which allows lower concentrations of UV filters to be used to achieve a UVefficacy target. For systems that are not photostable, much higher concentrations of UVfilters are needed to compensate for the loss of UV efficacy that occurs during productexposure to UV on the skin. Finally, the development of newer, more efficient and morephotostable UV filters allows formulators to achieve a target UV efficacy with lesssunscreen active. Reducing the concentration of UV filters may improve the productaesthetics with the potential for increasing compliance.Improving Sunscreen Product AestheticsBased on the above discussion, the first and simplest strategy for modern sunscreenformulation must be to use a lower concentration and number of UV filters to achieve thetarget UV efficacy level or, in other words, identify the most efficient sunscreen systems.Beyond this, there are other approaches that are often utilized to manage the trade-offs ofthe various sunscreen actives. These include: † The use of cosmetic powders to reduce the greasiness of the oily UV filters or solvents. These powders can absorb oily materials and give the product a drier skin feel. † Adding oil-soluble film-forming polymers to thicken the oily sunscreen actives and solvents/emollients, thus reducing slick/oily/greasy feel on the skin. Such polymers are also important as they increase the efficiency/efficacy of the sunscreen product by improving uniform skin coverage or film. † Incorporating silicone emollients to reduce the draggy, dry skin feel of zinc oxide and titanium dioxide sunscreen actives. † Utilizing alternative product forms to minimize product skin feel negatives, such as using rub-free sprays. It is these types of technologies, driving efficiency and promoting aesthetics, whichhave given birth to the new generation of sunscreens, allowing even products with SPFgreater than 15 to be formulated as recreational as well as daily use products such as

144 Nash and Tannermoisturizers. Importantly, these optimized sunscreen products can have excellentaesthetics that improve compliance and afford greater protection.REGULATORY ISSUESIn the U.S., sunscreen products are regulated by the Food and Drug Administration (FDA).Specifically, sunscreens are considered OTC drug products, required to abide by themonograph regulating such products. The OTC Drug Monographs establish conditions forsafe and effective self-treatments. These are regulatory standards for marketing of non-prescription drug products not covered by New Drug Applications (NDAs). Productsmarketed in accordance with the monograph do not require FDA approval. An abbreviatedchronology of the Sunscreen Monograph is presented in Table 3. That sunscreens are considered drugs in the U.S. sets it apart form other regions ofthe world. The FDA considers cosmetics as “. articles intended to be rubbed, poured,sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or anypart thereof for cleansing, beautifying, promoting attractiveness, or altering theappearance.” In 1978, the FDA recognized that products intended to be used forprevention of sunburn or any other similar condition should be regarded as drugs. As such,in the Advanced Notice of Public Rule Making (ANPRM) it states that “[sunscreens]reduce by varying amounts the solar radiation absorbed by the skin and thereby affect thephysiological response and extent of the erythemal reaction (redness) produced .” and assuch fit the definition of a drug: “articles (other than food) intended to affect the structureor any function of the body of man or other animals.” Since the publication of the ANPRM in 1978 up to the publication of the Final Rulein 1999 (19) and beyond for a total of 27-plus years, the Sunscreen Monograph has beendiscussed and commented on by interested parties including industry, academicians,practicing dermatologists and various trade associations (65). There has beenextraordinary criticism of the agency ranging from being too slow to completelyunresponsive. Perhaps the critics are right. However, it should be noted that there arediverse opinions on many key aspects of sunscreens including product testing andlabeling, the knowledge that consumers don’t apply enough product to achieve the labeledSPF, the absence of any meaningful and relevant acute endpoint for UVA protection, theneed for sunscreens with unlimited SPF, i.e., beyond 100-plus, and what exactly suchproducts are protecting against. This is compounded by the fact that there are sharpdisagreements regarding how best to measure and label sunscreen products (see Sept. 2000submissions to the FDA Sunscreen Docket 78N-0038). As such, it may not be surprisingthat the monograph has not been completed. Beyond the monograph, there are other regulatory processes that can be followed inorder to market a sunscreen product in the U.S. Options for marketing an OTC drugproduct besides the monograph include NDAs and the Abbreviated NDA (ANDA).An NDA is the same process that prescription drugs follow including the comprehensivesafety and clinical testing. Approval is generally for a specific product including the 10–20or so ingredients used to formulate a topically applied product. As such this approach istime consuming and costly and does not allow for minor reformulations of the product formarketing or other reasons. There are few sunscreen products which follow this processgiven the high cost in time and resources and the inflexible nature of this process. Currently, there are several suppliers attempting to have specific UV filters added tothe list of approved ingredients (Table 2). The Time and Extent Application (TEA) isbeing used. The purpose of TEA is to request that applicable conditions be considered for

Sunscreens 145Table 3 Abridged Chronology of FDA Sunscreen Monograph Date Dec 1972Federal register (FR) notification Aug 1978Pursuant to the notice published in the FR requesting the submission of data and information on OTC topical sunscreen drugs Dec 1978 March 1980Advisory review panel reviewed ingredients, claims, labeling, dosage, Sept 1987 and warnings May 1988 May 1993Advanced notice of proposed rule making (ANPRM)Establish conditions for the safety, effectiveness, and labeling of the April 1994 June 1994 OTC sunscreen drug products Aug 1996ANPRM—Extension of comment period (FR) to Dec 15, 1978 Sept 1996Docket officially closed Dec 26, 1978 Oct 1998Administrative record reopened May 1999FR announcement of public meeting held on Jan 26, 1988FR extended comment period for test procedures and related claims June 2000Tentative final monograph (TFM) Dec 2001Reflects tentative adoption of the ANPRM on the basis of the comments June 2002 received and agency’s independent evaluationFR announced public meeting to discuss UVA claims and testingFR amend TFM and reopen comment periodFR announced a public meeting to discuss the photochemistry and photobiology of sunscreensFR amendment to TFM to include avobenzoneInterim marketing was allow according to FR, April 1997FR amendment to TFM to include zinc oxideFinal rule—sunscreen products monographCompletes the TFM except for certain testing issues such as UVA testing and labeling, which will be addressed later. UVA labeling may continue in accord with the TFM and its amendmentsFR extended effective date to Dec 2002 and reopened administrative record for public comment until Sept 2000FR suspended final rule indefinitely until comprehensive monograph developedFR technical amendment updates to incorporate USP names for four active ingredients, effective Sept 2002inclusion in the monograph. This is a two-step process: first is the submission followed bydemonstration of general safety and effectiveness. The demonstration of general safetyand effectiveness has, to date, been the limiting factor for TEAs. Whereas the debate regarding sunscreens being cosmetics or drugs and the criticismof the Sunscreen Monograph and FDA will continue, it again is worthwhile pointing outthat in the U.S. such a process works by necessity if nothing else.SAFE SUN STRATEGYSkin cancers and photoaging/chronic skin damage are recognized as consequences of solarUV exposure by government agencies and numerous professional organizations. Thesegroups recommend strategies to reduce solar UV exposure (Table 4). Chief among therecommendations of any safe sun strategy is the use of sunscreen products.

146 Nash and TannerAmerican Academy of Dermatology (http://www.aad.org/)The American Academy of Dermatology’s Guidelines/Outcomes Committee hasdeveloped “Guidelines of Care for Photoaging/Photodamage.” In these guidelines thecommittee states, “No credible scientific evidence contradicts the relation of sun exposureto the development of skin cancer and the undesirable results of photoaging andphotodamage.” The committee contends that a significant portion of the approximately$14 billion spent on cosmetics in the U.S. in 1996 was specifically spent to conceal theeffects of photoaging and photodamage. An additional significant amount of money isspent on surgical and medical procedures. The committee believes that early recognitionand treatment of photodamaged and photoaged skin will lead to a decrease in the incidenceof premalignant and malignant skin lesions. † Photodamage and photoaging are at least partially reversible with photoprotec- tion, and the use of sunscreens that protect against solar UV is encouraged.American Cancer Society (http://www.cancer.org)In its efforts to educate the American public about the importance of prevention and earlydetection of nonmelanoma and melanoma skin cancers, the American Cancer Societydiscusses on its Web site the damage that UV can cause to skin and eyes, including theeffects of photoaging. The short-term results of unprotected exposure to UV rays are sunburn and tanning.The long-term effect of such damage is more serious. UV exposure that is intense enoughto cause sunburn clearly increases the risk of developing skin cancers. And UV exposurecan increase skin cancer risk even without causing sunburn. Long-term exposure can alsocause premature changes in skin including: † Aging † Wrinkles † Loss of elasticity † Dark patches (lentigos, that are sometimes called “age spots” or “liver spots” † Actinic keratoses.Skin Cancer Foundation (http://www.skincancer.org/)The Skin Cancer Foundation recently updated its brochure, “Simple Steps to Sun Safety,”which states: † Your skin is an excellent record keeper. Every moment in the sun adds up, accumulating like money in the bank. The payoff, however, is damage to the skinTable 4 Safe Sun Guideline PracticesMinimize exposure to solar UV radiation, especially between the hours of 10:00 am and 3:00 pm DSTWear protective clothing (e.g., wide-brimmed hats, sunglasses, long-sleeved shirts, and pants)Always use sun protection while outdoors, including when near snow, water, sand, and at high elevationsAvoid artificial tanning devices, such as tanning booths and sunlampsUse the UV index when planning outdoor activitiesApply sunscreens with an SPF greater than or equal to 15 daily

Sunscreens 147and possibly skin cancer. . Sunlight also causes wrinkling, blotching, drying,and leathering of the skin, making you look old before your time. The bestdefense, now, and for the future, is to limit time in the sun and protect yourselfwhenever you go outdoors.American Society for Photobiology and European Societyfor Photobiology (http://www.pol-us.net/)The American Society for Photobiology (ASP) is also “concerned with the interaction oflight and living things” including the harmful effects of UV on humans. In its publicationthe Light and Life brochure, published “to inform government officials, students, and thegeneral public about the science of photobiology,” the ASP states: † Harmful effects of light. Sunlight is implicated in several skin diseases, including premature aging of the skin and skin cancer. Skin sensitivity to sunlight is controlled by the genetic ability of an individual to produce melanin, the pigment that helps protect the skin from light-induced injury. † Photoprotection. Both topical and systemic sunscreen agents prevent the acute and chronic effects of sunlight. They enable people to work outdoors and enjoy outdoor activities with reduced risk of sun-induced injury. The damage that absorbed light creates in the skin, such as the changes recognized as aging of the skin, is preventable by using new types of water- and sweat- resistant sunscreens.Centers for Disease Control and Prevention (http://www.cdc.gov/)The Centers for Disease Control and Prevention (CDC) has educational programs andrecommendations that are targeted to apply “disease prevention and control, environmentalhealth, and health promotion and education activities designed to improve the health of thepeople of the United States.” On its Web site “Choose Your Cover,” it specifically states: † .excessive and unprotected exposure to the sun can result in premature aging and undesirable changes in skin texture. Such exposure has been associated with various types of skin cancer, including melanoma, one of the most serious and deadly forms.National Institutes of Health/Environmental Protection Agency(http://www.nih.gov/)In addition to the CDC, other government agencies including the National Institutes ofHealth (NIH) and the Environmental Protection Agency (EPA) have reiterated concernabout the effect of UVA on the skin. The “MEDLINEplus Health Information” service ofthe U.S. National Library of Medicine and the National Institutes of Health states that † .[s]unscreens help to prevent sunburn and reduce the harmful effects of the sun such as premature skin aging and skin cancer. The EPA has related materials on its Web site to promote greater public awarenessof the impact of UV exposure: † Exposure to UV radiation from the sun can seriously harm human health. Mild exposure can lead to sunburn. More extended exposure to the sun may result in premature aging and discoloration of the skin and, ultimately, skin cancer. These

148 Nash and Tanner health effects have only been made more acute by the destruction of the ozone layer which protects the earth from the sun’s UV radiation. . The EPA and other agencies also promote awareness of the dangers of sun exposure and the safety precautions such as minimizing exposure and using sunscreen.CONCLUSIONSGiven the potential health benefits of sunscreens, it is perhaps not surprising that they havebeen referred to as the “ultimate cosmetic” (66). It is clear that exposure to solar UVdamages human skin. This can be in the form of acute over-exposure resulting in sunburnor more subtle subclinical damage. In either case, repeated exposure to solar UV manifestsas photoaging and skin cancers after many years. The molecular mechanisms of skincancers and photoaging have been studied using human and animal models. Moreimportant, use of sunscreens protects against short-term markers of UV-induced skindamage and the molecular events believed to be responsible for skin cancers andphotoaging. That is, based on experimental investigations, sunscreens or UV filters reducedmolecular, biochemical, and clinical events associated with skin cancer and photoaging. An international meeting with experts from around the world concluded thatsunscreens were probably of benefit in reducing squamous cell carcinoma but there wasnot enough evidence supportive of protection against basal cell or melanoma skin cancers(67,68). Prospective clinical studies in areas of high incidence such as Australia (69,70)and Texas (71) clearly show the benefits of regular application of sunscreens.Demonstration of such effects in these relatively short duration studies, i.e., less thanfive years, are if nothing else encouraging. The formulation of sunscreen products should be focused on improving compliancerather than increasing the Protection Factor of products. It is easy for sunscreenmanufacturers to get caught up in the SPF horsepower race since consumers may purchaseproduct based on the SPF number and physicians may recommend/prescribe productsthinking that sunscreens are not applied at the proper dose and, as such, a higher SPF willcompensate for this underdosing. However, as with any preventive therapy, compliance isthe key and making products which are applied at the proper dose and reapplied should bethe goal of manufacturers. Also, sunscreen products need to protect against the breadth of solar UV and notsimply short wavelengths. Presently, consumers purchase products which infer protectionagainst harmful rays of the sun, i.e., SPF. As discussed, this does not ensure any protectionagainst long wavelength UVA-I. Arguably, sunscreen manufacturers should only marketproducts which protect against the breadth of solar UV. In the U.S., the FDA could ensureall products sold meet or exceed a single criteria to achieve a “broad spectrum” label suchas recommended by the AAD (40) thereby ensuring consumers are fully protected by thesunscreen products purchased. The public health message endorsed by numerous governmental and academicgroups is that of a “safe sun strategy,” which includes the daily use of a sunscreen at leastSPF 15. It will be important to maintain this basic message and expand it to includesunscreen products that provide “broad spectrum” protection. This could be achieved byregulatory adoption of, and in vitro substrate spectrophotometric measure of UVA efficacyand a simple pass/fail label. As such, consumers could choose products which protectagainst the solar UV spectrum.

Sunscreens 149REFERENCES 1. Goldsmith L, Koh HK, Bewerse B, et al. Proceedings from the national conference to develop a national skin cancer agenda. American Academy of Dermatology and Centers for Disease Control and Prevention, April 8–10, 1995. J Am Acad Dermatol 1996; 34:822–823. 2. Robinson JK, Amonette R, Wyatt SW, Bewerse BA, Bergfeld WF, Farris PK. Executive summary of the national “sun safety: protecting our future” conference: American Academy of Dermatology and Centers for Disease Control and Prevention. New York, May 1 and 2, 1997. J Am Acad Dermatol 1998; 38:774–780. 3. Lim HW, Cooper K. The health impact of solar radiation and prevention strategies: report of the environment council, American Academy of Dermatology. J Am Acad Dermatol 1999; 41:81–99. 4. Ichihashi M, Ueda M, Budiyanto A, et al. UV-induced skin damage. Toxicology 2003; 189:21–39. 5. Young AR. Cumulative effects of ultraviolet radiation on the skin: cancer and photoaging. Semin Dermatol 1990; 9:25–31. 6. Armstrong BK, Kricker A, English DR. Sun exposure and skin cancer. Australas J Dermatol 1997; 38:S1–S6. 7. McDonald CJ. American Cancer Society perspective on the American College of Preventive Medicine’s policy statements on skin cancer prevention and screening. CA Cancer J Clin 1998; 48:229–231. 8. Williams M, Ouhtit A. Towards a better understanding of the molecular mechanisms involved in sunlight-induced melanoma. J Biomed Biotechnol 2005; 2005:57–61. 9. Hadshiew IM, Eller MS, Gilchrest BA. Skin aging and photoaging: the role of DNA damage and repair. Am J Contact Dermat 2000; 11:19–25.10. Gilchrest BA. A review of skin ageing and its medical therapy. Br J Dermatol 1996; 135:867–875.11. Yaar M, Gilchrest BA. Skin aging: postulated mechanisms and consequent changes in structure and function. Clin Geriatr Med 2001; 17:617–630.12. Matsumura Y, Ananthaswamy HN. Toxic effects of ultraviolet radiation on the skin. Toxicol Appl Pharmacol 2004; 195:298–308.13. Wulf HC, Sandby-Moller J, Kobayasi T, Gniadecki R. Skin aging and natural photoprotection. Micron 2004; 35:185–191.14. Hussein MR. Ultraviolet radiation and skin cancer: molecular mechanisms. J Cutan Pathol 2005; 32:191–205.15. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004; 80:1678S–1688S.16. Grant-Petersson J, Dietrich AJ, Sox CH, Winchell CW, Stevens MM. Promoting sun protection in elementary schools and child care settings: the SunSafe Project. J Sch Health 1999; 69:100–106.17. Geller AC, Cantor M, Miller DR, et al. The Environmental Protection Agency’s National SunWise School Program: sun protection education in U.S. schools (1999–2000). J Am Acad Dermatol 2002; 46:683–689.18. Meves A, Repacholi MH, Rehfuess EA. Promoting safe and effective sun protection strategies. J Am Acad Dermatol 2003; 49:1203–1204.19. Food and Drug Administration, HHS. Sunscreen drug products for over-the-counter human use; final monograph. Final rule. Fed Regist 1999; 64:27666–27693.20. Naylor MF. Erythema, skin cancer risk, and sunscreens. Arch Dermatol 1997; 133:373–375.21. Young AR, Walker SL. Sunscreens: photoprotection of non-erythema endpoints relevant to skin cancer. Photodermatol Photoimmunol Photomed 1999; 15:221–225.22. Young AR, Sheehan JM, Chadwick CA, Potten CS. Protection by ultraviolet A and B sunscreens against in situ dipyrimidine photolesions in human epidermis is comparable to protection against sunburn. J Invest Dermatol 2000; 115:37–41.23. De Gruijl FR. Biological action spectra. Radiat Prot Dosimetry 2000; 91:57–63.

150 Nash and Tanner24. Agin PP, Desrochers DL, Sayre RM. The relationship of immediate pigment darkening to minimal erythemal dose, skin type, and eye color. Photodermatology 1985; 2:288–294.25. Kawada A, Noda T, Hiruma M, Ishibashi A, Arai S. The relationship of sun protection factor to minimal erythema dose, Japanese skin type, and skin color. J Dermatol 1993; 20:514–516.26. Agin PP, Edmonds SH. Testing high SPF sunscreens: a demonstration of the accuracy and reproducibility of the results of testing high SPF formulations by two methods and at different testing sites. Photodermatol Photoimmunol Photomed 2002; 18:169–174.27. Diffey B. Observed and predicted minimal erythema doses: a comparative study. Photochem Photobiol 1994; 60:380–382.28. Kligman LH, Akin FJ, Kligman AM. The contributions of UVA and UVB to connective tissue damage in hairless mice. J Invest Dermatol 1985; 84:272–276.29. Pearse AD, Gaskell SA, Marks R. Epidermal changes in human skin following irradiation with either UVB or UVA. J Invest Dermatol 1987; 88:83–87.30. Lavker RM, Gerberick GF, Veres D, Irwin CJ, Kaidbey KH. Cumulative effects from repeated exposures to suberythemal doses of UVB and UVA in human skin. J Am Acad Dermatol 1995; 32:53–62.31. Moyal D, Chardon A, Kollias N. Determination of UVA protection factors using the persistent pigment darkening (PPD) as the end point. (Part 1). Calibration of the method. Photodermatol Photoimmunol Photomed 2000; 16:245–249.32. Cole C, VanFossen R. Measurement of sunscreen UVA protection: an unsensitized human model. J Am Acad Dermatol 1992; 26:178–184.33. Cole C. Sunscreen protection in the ultraviolet A region: how to measure the effectiveness. Photodermatol Photoimmunol Photomed 2001; 17:2–10.34. Roelandts R, Sohrabvand N, Garmyn M. Evaluating the UVA protection of sunscreens. J Am Acad Dermatol 1989; 21:56–62.35. Diffey BL. A method for broad spectrum classification of sunscreens. Int J Cosmet Sci 1994; 16:47–52.36. Diffey BL, Robson J. A new substrate to measure sunscreen protection factors throughout the ultraviolet spectrum. J Soc Cosmet Chemists 1989; 40:127–133.37. Diffey BL, Tanner PR, Matts PJ, Nash JF. In vitro assessment of the broad-spectrum ultraviolet protection of sunscreen products. J Am Acad Dermatol 2000; 43:1024–1035.38. Wendel V, Klette E, Wittern KP, Gers-Barlag H. The influence of pre-irradiation on the predictability of in vivo UVA protection with a new in vitro method. Photodermatol Photoimmunol Photomed 2003; 19:93–97.39. Nash JF. Human safety and efficacy of ultraviolet filters and sunscreen products. Dermatol Clin 2006; 24:35–51.40. Lim HW, Naylor M, Honigsmann H, et al. American Academy of Dermatology Consensus Conference on UVA protection of sunscreens: summary and recommendations. Washington, DC, Feb 4, 2000. J Am Acad Dermatol 2001; 44:505–508.41. Nash JF, Tanner P, Grosick T, Zimnawoda M. Sunscreen market analysis: the evolution and use of UVA-1 actives. J Am Acad Dermatol 2004; 50:34.42. Rastogi SC. UV filters in sunscreen products—a survey. Contact Dermat 2002; 46:348–351.43. Gasparro FP, Mitchnick M, Nash JF. A review of sunscreen safety and efficacy. Photochem Photobiol 1998; 68:243–256.44. Nohynek GJ, Schaefer H. Benefit and risk of organic ultraviolet filters. Regul Toxicol Pharmacol 2001; 33:285–299.45. Moloney FJ, Collins S, Murphy GM. Sunscreens: safety, efficacy and appropriate use. Am J Clin Dermatol 2002; 3:185–191.46. Tanner PR. Sunscreen product formulation. Dermatol Clin 2006; 24:53–62.47. Comarow A. Should you pay $75 to block the sun? For most of us, a regular t-shirt is enough US News World Rep 1999; 127:59.48. Nichols K, Desai N, Lebwohl MG. Effective sunscreen ingredients and cutaneous irritation in patients with rosacea. Cutis 1998; 61:344–346.

Sunscreens 15149. Journe F, Marguery MC, Rakotondrazafy J, El Sayed F, Bazex J. Sunscreen sensitization: a 5-year study. Acta Derm Venereol 1999; 79:211–213.50. Stenberg C, Larko O. Sunscreen application and its importance for the sun protection factor. Arch Dermatol 1985; 121:1400–1402.51. Neale R, Williams G, Green A. Application patterns among participants randomized to daily sunscreen use in a skin cancer prevention trial. Arch Dermatol 2002; 138:1319–1325.52. Levy SB. Cosmetics that imitate a tan. Dermatol Ther 2001; 14:215–219.53. Draelos ZD. Self-tanning lotions: are they a healthy way to achieve a tan? Am J Clin Dermatol 2002; 3:317–318.54. Hadshiew IM, Eller MS, Gasparro FP, Gilchrest BA. Stimulation of melanogenesis by DNA oligonucleotides: effect of size, sequence and 500 phosphorylation. J Dermatol Sci 2001; 25:127–138.55. Agar N, Young AR. Melanogenesis: a photoprotective response to DNA damage? Mutat Res Fundam Mol Mech Mutagen 2005; 571:121–132.56. Lazovich D, Forster J. Indoor tanning by adolescents: prevalence, practices and policies. Eur J Cancer 2005; 41:20–27.57. Cokkinides VE, Weinstock MA, O’Connell MC, Thun MJ. Use of indoor tanning sunlamps by U.S. youth, ages 11-18 years, and by their parent or guardian caregivers: prevalence and correlates. Pediatrics 2002; 109:1124–1130.58. Fusaro RM, Johnson JA. Protection against long ultraviolet and/or visible light with topical dihydroxyacetone. Implications for the mechanism of action of the sunscreen combination, dihydroxyacetone/naphthoquinone. Dermatol 1975; 150:346–351.59. Johnson JA. Dihydroxyacetone for protection against long wavelength UVA radiation and blue light. Br J Dermatol 1992; 126:94.60. Faurschou A, Janjua NR, Wulf HC. Sun protection effect of dihydroxyacetone. Arch Dermatol 2004; 140:886–887.61. Petersen AB, Na R, Wulf HC. Sunless skin tanning with dihydroxyacetone delays broad- spectrum ultraviolet photocarcinogenesis in hairless mice. Mutat Res Genet Toxicol Environ Mutagen 2003; 542:129–138.62. Nguyen BC, Kochevar IE. Factors influencing sunless tanning with dihydroxyacetone. Br J Dermatol 2003; 149:332–340.63. Jermann R, Toumiat M, Imfeld D. Development of an in vitro efficacy test for self-tanning formulations. Int J Cosmet Sci 2002; 24:35–42.64. Muizzuddin N, Marenus KD, Maes DH. Tonality of suntan vs sunless tanning with dihydroxyacetone. Skin Res Technol 2000; 6:199–204.65. Draelos ZD. A dermatologist’s perspective on the final sunscreen monograph. J Am Acad Dermatol 2001; 44:109–110.66. Wolf R, Matz H, Orion E, Lipozencic J. Sunscreens—the ultimate cosmetic. Acta Dermatovenerol Croat 2003; 11:158–162.67. Vainio H, Bianchini F. Cancer-preventive effects of sunscreens are uncertain. Scand J Work Environ Health 2000; 26:529–531.68. International Agency for Research on Cancer, World Health Organization. Vainio H, Bianchini F, eds. IARC, Lyon France. Sunscreens. IARC handbooks of cancer prevention 2000; volume 5.69. Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med 1993; 329:1147–1151.70. Green A, Williams G, Neale R, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet 1999; 354:723–729.71. Naylor MF, Boyd A, Smith DW, Cameron GS, Hubbard D, Neldner KH. High sun protection factor sunscreens in the suppression of actinic neoplasia. Arch Dermatol 1995; 131:170–175.

10Photoprotection and the Preventionof PhotocarcinogenesisNathalie Nguyen and Darrell S. RigelDepartment of Dermatology, New York University School of Medicine,New York, New York, U.S.A.OVERVIEWExposure to ultraviolet (UV) energy leads to two significant types of skin problems—increased risk for the development of skin cancer and accelerated photoaging changes. Atcurrent rates, one in five Americans will develop a skin cancer of some sort during theirlifetime, with over 1,000,000 new cases appearing this year alone in the U.S. Theincidence of malignant melanoma is increasing faster than any other cancer in the UnitedStates. In 1935, the lifetime risk for an American developing invasive melanoma was onein 1500. In 2005, this risk was one in 62 for invasive melanomas and one in 34 if in situmelanomas are included. In addition, according to the World Health Organization,melanoma is increasing faster than any other malignancy worldwide. The economicmagnitude of this public health problem is illustrated by the fact that costs associated withthe treatment of skin cancers are over 500 million dollars annually in the U.S. alone (1).Therefore, the development and implementation of effective mechanisms that protect theskin from cancer-causing UV rays is critical. Photoprotection is therefore focused on protecting the skin from the damage thatoccurs as a result of UV exposure. The approach to photoprotection focuses on a reductionin the overall exposure to sunlight, not to just a single component of it. To put theimportance of photoprotection and skin cancer into perspective and to better understandthe key associated issues, one needs to appreciate: † The relationship of skin cancer and UV exposure † Why recent changes have made this issue even more important, † Current available agents and approaches, † How effective these approaches are and can be, † What can be done in the future to improve photoprotection effectiveness, and, † What clinical recommendations can be made to patients to lower their future risks for photoaging and skin cancer. Increasing awareness of the damaging effects of sunlight has led to an increasedneed for adequate photoprotection. Primary prevention to reduce the incidence of skin 153

154 Nguyen and Rigelcancer therefore includes a regimen consisting of effective sunscreen, protective clothing,and behavior modification.RELATIONSHIP OF UV EXPOSURE TO SKIN CANCER DEVELOPMENTThe skin is the most exposed organ to environmental UV and to the associated sequellae (2).Exposure to UV radiation on the skin results in clearly demonstrable mutagenic effects. Thep53 suppressor gene, which is frequently mutated in skin cancers, is believed to be an earlytarget of UV radiation-induced neoplasm (3). Although there is no direct way that the activewavelengths for the development of skin cancer in humans can be determined, there isample indirect evidence demonstrating probable ranges. In terms of SCC in albino hairlessmice, the action spectrum has been determined to have a strong peak at 293 nm withsecondary peaks at 354 and 380 (4). The primary wavelength influencing melanoma riskappears to be in the Ultraviolet B (UVB) (290–320 nm) range. However, studies in fish andopossums have also shown an increase in melanoma development when exposed to UVAwavelengths (5,6). Fair skinned individuals who are more sensitive to the effects of exposureat these wavelengths are at higher risk for the development of skin cancer (7). In addition,skin cancer rates are also elevated in persons with increased artificial UV exposure throughtanning salons (8). The amount of average annual UV radiation correlates with the incidence of skincancer (9). There is a direct correlation with BCC and SCC incidence and latitude (10).Scotto et al. (11) demonstrated a strong inverse correlation between latitude and incidenceof BCC and SCC for both men and women. In terms of melanoma, the relationship is not as clear-cut. Incidence rates formelanoma correlate in a lesser way with latitude as that for NMSC but other factors mayalso be involved (12). Melanoma mortality rates in the U.S. and Canada have also beenshown to directly correlate with ambient UV exposure (13). The correlation of melanomaincidence to UV radiation exposure is greater when ambient UVA (320–400 nm) radiationis also included (14). High-altitude regions tend to have a higher melanoma rate that maybe related to the higher UV fluences noted at these sites (15). Melanoma risk has also beennoted to be directly related to annual UV flux. Fears et al. (16) demonstrated that whenlifetime residential history was coupled with levels of midrange UV radiation (UVB flux)to provide a measure of individual exposure to sunlight a 10% increase in annual UVB fluxwas associated with a 19% increased risk of melanoma. Even in women who coulddevelop a deep tan, a 10% increase in hours spent outdoors was associated with 5.8%increase in melanoma incidence. The association between melanoma risk and averageannual UVB flux was strong and consistent for men and women. However, some of thestudies examining a latitudinal gradient for melanoma risk have been somewhatinconclusive (17). Although worldwide studies have only shown a weak correlation, theassociation of melanoma mortality in 1950–1967 with estimates of annual erythemal solarUVB dose across the U.S. and Canada demonstrated a stronger relationship (18). The anatomic areas that skin cancer develops on appear to be somewhat related tothe average amount of UV exposure to those sites (19). The density of skin cancer ishighest on the sites that are virtually constantly exposed to UV, namely, the head and neck.Skin cancer rates are low in rarely UV-exposed areas such as the scalp in women and thebuttocks in both sexes (20). Melanoma tends to be found more frequently in women on thelegs where more average UV exposure may occur than in men (21). The timing and periodicity of the UV exposure appears to be important in its effecton subsequent skin cancer risk. In terms of NMSC, the long-term chronic UV exposure

Prevention of Photocarcinogenesis 155appears to increase the chance of developing this cancer. Acute intermittent UV exposureelevates subsequent melanoma risk (22). Migration studies have demonstrated sunexposure early in life appears to have a greater influence on subsequent skin cancer riskthan does that at a later age. Persons born in the high-UV insolation environment ofAustralia have a increased risk for developing skin cancer compared to those born inNorthern Europe who migrated at age 10 or older (23). Several additional studies fromother countries have also found that risk of developing melanoma was less in those whomigrated to the country 10 or more years after birth than were those who were born there(24,25). However, a recent study has now demonstrated that excessive UV exposure laterin life may be equally important to that acquired earlier. Pfahlberg et al. (26) found a verysimilar upward gradient of melanoma risk in exposure categories related to the frequencyof sunburns comparing UV exposure occurring before and after age 15. More than fivesunburns doubled the melanoma risk, irrespective of their timing in life. This study did notprovide supporting evidence for the existence of a critical age interval but rather suggestedthat the hazardous impact of UV exposure seems to persist lifelong.SPECTRAL DIFFERENCES RELATED TO UVPHOTOCARCINOGENESISMost of the cutaneous damage resulting from radiation exposure occurs from the UV band.The shortest of the UV rays, UVC (100–280 nm), fail to penetrate the earth’s ozone layerand thus exert little damage. UVB (290–320 nm) is responsible for most of the cutaneouschanges induced by exposure to the sun. Known biochemical changes induced by UVBinclude alterations in DNA, RNA, and protein synthesis, induction of cyclobutylpyrimidine dimers, and production of various cytokines (27,28). In the past, UVA was believed to play less of a role in the pathogenesis of skincancer and sun damage. The longer wavelengths of UVA (320–400 nm) allow deeperpenetration into the skin. UVA induces an immediate pigment-darkening reaction and newmelanin pigment formation (29). Earlier sun protection focused primarily on eliminatingUVB exposure to the skin. UVA is now known to contribute to skin cancers by inductingDNA mutations directly as well as by augmenting damage incurred by UVB (30). Humanskin exposed to UVA has altered expression of the p53 tumor suppressor protein (31).These mutations can be reduced by using UVA sunscreens, demonstrating that there is lessp53 accumulation with better UVA protection (32).PHOTOCARCINOGENESIS-DECREASINGPHOTOPROTECTION MODALITIESProtection from exposure to UV radiation leads to decreased risk for developing skincancer. The use of multiple modalities leads to overlapping and more comprehensivespectral coverage. Therefore, optimal photoprotection includes regularly using sunscreen,wearing protective clothing, and avoiding UV exposure where possible. Recommen-dations for photoprotection which include all three of these approaches should be mosteffective in reducing skin cancer risk.

156 Nguyen and RigelSUNSCREENSSunscreens work primarily through two mechanisms: (i) scattering and reflection of UVenergy, and (ii) absorption of UV energy. Many current sunscreens contain ingredientsthat work through both mechanisms in terms of UV protection. The most important assay for determining the effectiveness of a sunscreen is the sunprotection factor (SPF). The SPF measures a sunscreen’s ability to prevent development oferythema upon exposure to UV radiation, primarily UVB. The SPF value is defined as theratio of the UV energy required to produce minimal erythema on protected skin to thatrequired to produce the same erythema on unprotected skin in the same individual. Forexample, an individual using a sunscreen SPF 4 will take four times as long to developcutaneous erythema when exposed to UVB radiation, as compared to when that individualhas no protection. The Food and Drug Administration (FDA), which oversees themarketing and distribution of sunscreen products in the United States, mandates that asunscreen agent must provide at least an SPF value of 2. Most commercially availablesunscreen products have SPF values that exceed the minimum protection. Despite attempts by the FDA to educate consumers and promote appropriatebranding by manufacturers, sunscreen labeling has its limitations. The complicated names,as well as the variations in names for any given agent, may be overwhelming for theaverage consumer. The photostability of sunscreens is not quantified or labeled, and variesaccording to the chemical agent. The SPF value primarily measures a sunscreen’s abilityto protect against UVB radiation and does not adequately address the effects of UVA. Inaddition, SPF readings may also vary for a given agent depending on the light source (33). Nonetheless, concerted efforts to educate consumers have been the goal of the FDA.Confusing terminology such as “sunblock” and “all-day protection” is prohibited. Theterm “waterproof” should be replaced with “water resistant.” The FDA discourages thebranding of a sunscreen product as having an SPF of greater than 30. Although valuesgreater than 30 offer increased protection, the risks of providing consumers with a false ofsecurity encouraged the labeling to restrict labeling to 30-plus. For sunscreen productsmaking the claim of “water resistant,” the label SPF is the SPF value determined after fortyminutes of water immersion, as determined by FDA guidelines.TYPES OF SUNSCREENS AND MECHANISMS OF ACTIONSunscreen use began in the early 20th century. Salicylates were the first agents used insunscreen preparations, with the first reported sunscreen containing benzyl salicylateand benzyl cinnamate (34). In the 1940s, p-Aminobenzoic acid (PABA) was patented andincorporated into sunscreen formulations (35). Since its debut, various formulationsand derivates of PABA have been introduced into the sunscreen market. Today, theFDA approves the use of 16 chemicals as defined sunscreen agents (Table 1). Since no single agent effectively provides adequate protection from both UVA andUVB radiation, nearly all commercially available sunscreen products contain agents fromboth groups. Two or more sunscreen active ingredients may be combined with each otherin a single product when used in the concentrations approved by the FDA for each agent.Each individual active ingredient must contribute a minimum SPF of at least 2 to thefinished product, with the finished product having a minimum SPF of not less thanthe number of sunscreen active ingredients used in the combination multiplied by two.Sunscreen agents are classified based on their method of protection. Chemical sunscreens

Prevention of Photocarcinogenesis 157Table 1 FDA-Approved Active Ingredients for Sunscreens UV absorbanceIngredient UVB UVAAminobenzoic acid UVBAvobenzone UVA, UVBCinoxate UVBDioxybenzone UVAHomosalate UVBMethyl anthranilate UVBOctocrylene UVBOctyl methoxycinnamate UVA, UVBOctyl salicylate UVBOxybenzone UVBPadimate O UVA, UVBPhenylbenzimidazole sulfonic acid InorganicSulisobenzone UVBTitanium dioxide InorganicTrolamine salicylateZinc oxideSource: From Ref. 36.absorb UV radiation while physical blockers act as particulate matters that reflect andscatter incident light.CHEMICAL SUNSCREENSChemical sunscreen agents protect the skin by absorbing UV energy and transforming itinto heat energy. These compounds absorb UV radiation and convert the energy intolonger wave radiation. The sunscreen chemical is excited to a higher energy state from itsground state. As the excited molecule returns to the ground state, energy is emitted that islower in magnitude than the energy initially absorbed. This energy is emitted in the formof longer wavelengths, typically mild heat radiation. These synthetically derived compounds can be broadly categorized into two groups:UVB (290–320 nm) and UVA (320–400 nm) absorbing chemicals. Sunscreen chemicalsare generally aromatic compounds conjugated with a carbonyl group (37). Chemicalsunscreens can be classified based on their chemical properties, and each class has its owncharacteristic absorption spectra (Table 2). PABA was a widely used sunscreen in the 1950s and 1960s. Several of the propertiespertaining to the limitations of PABA can be attributed to its chemical structure: aminoand carboxylic acid groups in a para-orientation on a benzene nucleus. The highly polarnature of PABA made this agent extremely water soluble, but the increased hydrogenbonding between molecules also promoted a crystalline physical state (39). This led tosome difficulty in manufacturing a solvent that ensured continuous dissolution of PABA.The amine and carboxyl groups also made the PABA molecule sensitive to pH changes,and therefore somewhat labile in its effectiveness as a UV chemical absorbing agent.The molecule’s lack of stability also led to changes in the color of the product whenexposed to air. Glycerol PABA was subsequently developed to protect the carboxylic acid groupfrom pH changes and therefore was slightly more stable than the original PABAformulation. Other preparations attempted to protect both the carboxyl and the amine

158 Nguyen and RigelTable 2 Sunscreen Agents and Their UV Protective Wavelengths Maximal effect of protection (nm)Sunscreen Range of protection (nm) 283 311PABA and PABA esters 260–313 309 PABA 290–315 297 Padimate O 290–315 Padimate A 260–313 311 Glycerol aminobenzoate 290 280–310Cinnamates 270–328 306 Octyl methoxycinnamate 307 Cinoxate 290–315 298 260–310 303Salicylates 269–320 303 Homosalicylate 287–323 Octyl salicylate 296–383 290,325 Triethanolamine salicylate 284,327 270–350 286–324Octocrylene 206–380Etocrylene 250–380 336Benzophenones 200–380 358 Oxybenzone 310–400 345 Dioxybenzone 310–400 328 Sulisobenzone 300–400MenthylanthranilateDibenzoylmethanes Tert-butylmethoxydibenzoylmethane (Parsol) 4-isopropyldibenzoylmethane (Eusolex) Trometrizole trisiloxane, terephthalylidene dicamphor sulfonic acid (Mexoryl XL)Source: Adapted from Ref. 38.group. Padimate O (N, N-dimethyl PABA octyl ester), addressed many of the originalstructure’s limitations and became a widely used sunscreen agent. Both the amino and thecarboxyl groups are protected, making Padimate O less sensitive to pH changes. This newchemical structure also resulted in decreased intermolecular hydrogen bonding, resultingin a sunscreen agent that is a liquid instead of a crystalline solid. The original PABA fell out of favor largely because of staining and allergic contactreactions. There is a much higher presence of contact and photocontact allergy to PABAthan to other sunscreening agents (40). The PABA derivates also were reported to inducecontact sensitization. Sensitization to PABA showed strong reactions to benzocaine,suggesting that reports of glycerol PABA allergy may in fact have been due to impuritiesin glyceryl PABA preparations (41). Other PABA derivates such as Padimate A, and to alesser extent, Padimate O, have also been reported to cause sensitization or photocontactsensitization. Padimate A was also found to cause phototoxicity and is no longer used inthe United States (42). Salicylates were the first UV chemical absorbers used in commercially availablesunscreen preparations. In contrast to the para-distribution of the carboxyl and aminegroups, the salicylates are ortho-distributed (the carboxyl and amine groups are onneighboring carbon atoms on the benzene ring). This spatial arrangement allows hydrogenbonding within the molecule itself, leading to a UV absorbance of about 300 nm (43). Thisintramolecular hydrogen bonding results in increased molecule stability, less interaction

Prevention of Photocarcinogenesis 159with other compounds, and good overall safety record. The salicylate group of sunscreenagents include octyl salicylate and homomenthyl salicylate. Cinnamates are effective sunscreen agents with a peak absorption wavelength ofabout 305 nm. They are chemically related to balsam of Peru, coca leaves, cinnamicaldehyde, and cinnamic oil. The chemical structure of the cinnamates, as a group, makesthe molecule insoluble to water, requiring more frequent reapplication of the preparation.Contact dermatitis to the cinnamates and cross-sensitization to structurally relatedproducts have been reported. Benzophenone derivates and anthranilates are effective at absorbing UVA radiation.Although the primary protective range for benzophenone is in the UVA range, a secondaryprotective band is also noted in the UVB range. The most commonly used benzophenoneagents are oxybenzone and dioxybenzone. Although these ingredients are much lessallergenic than PABA, they do nonetheless still carry a risk of photocontact and contactallergy. Anthranilates, such as menthylanthranilate, provide low-level, yet broad-spectrumcoverage. They are commonly added to sunscreens to augment protection. Camphor is anagent widely used in Europe, but not approved for use in the United States. They areeffective UVB-absorbing agents. Dibenzoylmenthanes are a relatively new group of sunscreen agents and areespecially effective at offering protection against UVA radiation. Tert-butylmethoxy-dibenzoylmethane (Avobenzone, Parsol 1789) is approved for use in the United States,while isopropyldebenzoylmethane (Eusolex 8020) has been widely used in Europe. Thelatter has been associated with a high incidence of contact dermatitis, and has not beenapproved in the United States. In a study of 19 patients with positive photopatch tests tosunscreens, eight showed positive reactions to butyl methoxy dibenzoylmethane (44).PHYSICAL SUNSCREENSPhysical sunscreens are particles that scatter and reflect UV energy back into theenvironment. In sufficient quantities, they will serve as a physical barrier to incident UVand visible light. Their popularity has grown in recent years due primarily to their lowtoxicity profile. These agents are fairly photostable and have not been shown to inducephototoxic or photoallergic reactions. They are also extremely effective in protectingagainst both UVA and UVB. The most common particulate sunscreen agents are titaniumdioxide and zinc oxide. Early formulations of physical sunscreen agents were not widely accepted because theparticulate matters had to be incorporated in high concentrations, resulting in an opaque filmon the skin in order to achieve adequate protection. This was often not cosmeticallyacceptable. Newer formulations which provide “micronized” formulations give rise to amore translucent appearance, and allow for adequate protection with improved cosmeticresults. Comparison between zinc oxide and titanium dioxide showed that zinc oxide issuperior for UVA protection in the 340–380 nm range and tends to be less pasty on theskin (45).PHOTOCARCINOGENESIS REDUCTION BY WEARING CLOTHINGClothing specifically designed to avoid sun exposure should be incorporated into acomprehensive sun-protection program. Transmission of UV radiation through fibersdepends on the radiation that is absorbed by the fiber and scattered by the fiber. Polyester

160 Nguyen and Rigelprovides more protection than cotton. The cover factor, defined as the ratio of closedspaces to open spaces in the fabric, is the most important factor in determining thephotoprotection of the fabric (46). Darker colors provide better protection than lightercolors. To enhance the ultraviolet protection factor (UPF) of clothes, UV-absorbinglaundry detergents have been shown to increase the UPF of a cotton T-shirt by 400% (47).BEHAVIOR MODIFICATIONSunscreens should be used in conjunction with daily sun-safety behavior in order toachieve maximal photoprotection. Avoidance of UV radiation to the skin is the ultimategoal. Hats, umbrellas, and protective clothing are easy ways to protect the skin. Daily useof sunscreens with frequent reapplication should be a part of the daily routine. Sunbathingand tanning salons should be strictly avoided. Sun avoidance is easy to advocate, but in reality, difficult to practice. Sunscreen isthe most common sun-protection behavior practiced, yet only about 40% of Britishcolleges students admitted to daily sunscreen use (48). Within the adult age range, womenand people with sensitive skin were most likely to be using skin protection (49). However,women were also more likely than men to sunbathe deliberately and to use sun-tanningbooths. Adolescents have the lowest skin protection rates of all age groups. Less than one-third of U.S. youths, ages 11–18, practice routine sun protection on sunny days during thesummer (50). Furthermore, adolescents are increasingly using tanning salons. In a study of1274 U.S. adolescents, 12% of boys and 42% of girls had tanned indoors (51).EFFECTIVENESS OF PHOTOPROTECTIONPrimary prevention programs for skin cancer that are focused on lowering UV exposureappear to be having a positive effect in lowering skin cancer incidence (52). Persons with aprior history of BCC had fewer subsequent BCCs develop if they protected themselvesfrom UV exposure (53). Reduction in sun exposure by daily use of a sunscreen may reduce risk of SCC (54).A meta-analysis of 11 studies of melanoma risk and sunscreen usage showed only a smallprotective advantage (55). However, when evaluating only the more recent studies wherehigh-SPF sunscreens were available, there appeared to be a protective effect and otherinherent flaws associated with retrospective studies which may be responsible forprotection not being noted (Table 3) (70).PHOTOPROTECTION AND VITAMIN DSunlight is important in the generation of Vitamin D in the skin. In addition to eating foodscontaining vitamin D, an essential hormone for normal bone development, sunlightexposure also plays a critical role in supplying the human body with its necessary dose ofvitamin D (71). Sunlight converts cutaneous stores of 7-dehydrocholesterol (provitaminD3) to previtamin D3 (precholecalciferol) and then to vitamin D3 (cholecalciferol). VitaminD3 is also the form obtained though ingestion of foods. Once in the body, vitamin D3 ishydroxylated first in the liver to 25-hydroxyvitamin D (25-OHD), and then subsequentlyhydroxylated again to the active form, 1,25-dihydroxdyvitamin D [1,25-(OH)2D], by thekidneys. It should be noted that 25-OHD is a measure of body stores of Vitamin D.

Prevention of Photocarcinogenesis 161Table 3 Studies Evaluating Protective Effects of Sunscreens on MelanomaStudy Interval of sunscreen Findings use examinedKlepp 1979 (56) 1974–75 Increased MM in usersGraham 1985 (57) 1974–80 NSHerzfeld 1993 (58) 1977–79 NSBeitner 1990 (59) 1978–83 Increased MM in a subset of usersGreen 1986 (60) 1979–80 Protective for MMHolman 1986 (61) 1980–82 NSOsterlind 1988 (62) 1981–85 NSHolly 1995 (63) 1981–86 Protective for MMWesterdahl 1995 (64) 1988–90 Increased MM in usersRodenas 1996 (65) 1989–93 Protective for MMAutier 1995 (66) 1991–92 Increased MM in usersEspinosa 1999 (67) 1994–97 Protective for MMNaldi 2000 (68) 1994–98 NSWesterdahl 2000 (69) 1995–97 Increased MM in a subset of usersAbbreviation: NS, not significant. Because sunlight is considered to be the most important source of vitamin D, therehas been concern that photoprotection may, in fact, be contributing to its deficiency.Vitamin D deficiency increases the risk of bone disease, muscle weakness, and possiblycertain types of cancer (72,73). In one study, the application of a sunscreen was shown toreduce the skin’s ability to synthesize vitamin D3 (74). 25-hydroxy vitamin D levelshave also been shown to be reduced with chronic sunscreen use (75). The active form ofvitamin D, 1,25-dihydroxyvitamin D, was shown to be lower in patients using sunscreencompared to a placebo group who did not use sunscreen (76). Although values were lowerfor the sunscreen group, they still remained within the normal range. However, otherstudies have reported conflicting findings (77). Studies of individuals who consistently sustain a lifestyle involving photoprotectionhave failed to show clinical evidence of vitamin D deficiency. A study of eight xerodermapigmentosum patients showed that, although 25-OHD levels were low normal, the1,25(OH)2D levels were normal (78). The lack of seasonal variation in 25-OHD levelsshowed that the patients received the same amount sunlight (or lack thereof) throughout theyear. The evidence provided in this study is supported by epidemiologic studies of sunscreenuse, which failed to show that regular sunscreen use led to vitamin D deficiency (79). Recent media attention to the issue of vitamin D and sunlight reinforces the need forpatient education. Although sunlight exposure is important as a source of vitamin D,photoprotection does not result in vitamin D deficiency. Furthermore, the use of tanningbeds should not be used as a source of vitamin D. Patients concerned about their vitamin Dlevels should be encouraged to eat foods rich in vitamin D, such as fish liver oils, eggyolks, and milk fortified with vitamin D or take oral vitamin D supplements.PATIENT RECOMMENDATIONS AND FUTURE DIRECTIONSThere appears to be a direct relationship between UV exposure and the development ofphotocarcinogenesis. Based upon the best current information available, a regimen ofoverall photoprotection which includes protective clothing, avoiding midday sun, and

162 Nguyen and Rigelregular use of broad-spectrum high SPF sunscreen should provide significant protectionand appears to be reducing melanoma incidence rates. This is the current recommendationof the American Academy of Dermatology, Skin Cancer Foundation, and other majorinternational organizations, and it is also the recommendation that is best supported by theexisting data. There is no reason to recommend intentional sun exposure or decreasedphotoprotection to increase vitamin D levels as adequate incidental UV exposure occurs inday-to-day activities. Hopefully, we will have even more definitive answers to questionsrelated to the optimization of effectiveness of sunscreens and other forms ofphotoprotection and for reducing the risk from exposure to UV radiation as improvedphotoprotective agents, strategies, and methods are developed in the future.REFERENCES 1. Tsao H, Rogers GS, Sober AJ. An estimate of the annual direct cost of treating cutaneous melanoma. J Am Acad Dermatol 1998; 38:669–680. 2. Marrot L, Meunier JR. Skin DNA photodamage and its biological consequences. J Am Acad Dermatol 2003 submitted. 3. Ouhtit A, Nakazawa H, Armstrong BK, et al. UV Radiation specific p53 mutation frequency in normal skin as a predictor of risk of basal cell carcinoma. Natl Cancer Inst 1998; 90:523–531. 4. de Gruijl FR, Sterenborg HJCM, Forbes PD, Davies RE, Cole C, Kelfkens G. Wavelength dependence of skin cancer induction by ultraviolet irradiation of albino hairless mice. Cancer Res 1993; 52:1–8. 5. Setlow RB, Grist E, Thompson K, Woodhead AD. Wavelengths effective in induction of malignant melanoma. Proc Natl Acad Sci USA 1993; 90:6666–6670. 6. Ley RD. Dose response for ultraviolet radiation A-induced focal melanocytic hyperplasia and nonmelanoma skin tumors in Monodelphis domestica. Photochem Photobiol 2001; 73:20–23. 7. Loria D, Matos E. Risk factors for cutaneous melanoma: a case-control study in Argentina. Int J Dermatol 2001; 40:108–114. 8. Karagas MR, Stannard VA, Mott LA, Slattery MJ, Spencer SK, Weinstock MA. Use of tanning devices and risk of basal cell and squamous cell skin cancers. J Natl Cancer Inst 2002; 94:224–226. 9. Armstrong BK, Kricker A. Epidemiology of skin cancer. Photochem Photobiol 2001; 63:8–18.10. Muir C, Waterhouse J, Mack T, Powell J, Whelan S. Cancer Incidence in Five Continents Vol. 5, International Agency for Research on Cancer, Lyon (1987).11. Scotto J, Fears TR, Fraumeni JF. Incidence of Nonmelanoma Skin Cancer in the United States, U.S. Department of Health and Human Services, Washington, 1983.12. Kafadar K. Simultaneous smoothing and adjusting mortality rates in U.S. counties: melanoma in white females and white males. Stat Med 1999; 18:3167–3188.13. Elwood JM, Lee JAH, Walter SD, Mo T, Green AES. Relationship of melanoma and other skin cancer mortality to latitude and ultraviolet radiation in the United States and Canada. Int J Epidemiol 1974; 3:325–332.14. Moan J, Dahlback AA, Setlow AB. Epidemiological support for an hypothesis for melanoma induction indicating a role for UVA radiation. Photochem Photobiol 1999; 70:243–247.15. Rigel DS, Rigel EG, Rigel AC. Effects of altitude and latitude on ambient UVB radiation. J Am Acad Dermatol 1999; 40:114–116.16. Fears TR, Bird CC, Guerry D, IV, et al. Average midrange ultraviolet radiation flux and time outdoors predict melanoma risk. Cancer Res 2002; 62:3992–3996.17. Muir C, Waterhouse J, Mack T, Powell J, Whelan S. Cancer Incidence in Five Continents Vol. 5, International Agency for Research on Cancer, Lyon, 1987.18. Elwood JM, Lee JAH, Walter SD, Mo T, Green AES. Relationship of melanoma and other skin cancer mortality to latitude and ultraviolet radiation in the United States and Canada. Int J Epidemiol 1974; 3:325–332.

Prevention of Photocarcinogenesis 16319. Bulliard JL. Site-specific risk of cutaneous malignant melanoma and pattern of sun exposure in New Zealand. Int J Cancer 2000; 85:627–632.20. Cress RD, Holly EA, Ahn DK, LeBoit PE, Sagebiel RW. Cutaneous melanoma in women: anatomic distribution in relation to sun exposure and phenotype. Cancer Epidemiol Biomarkers Prev 1995; 4:831–836.21. Parisi AV, Kimlin MG, Lester R, Turnbull D. Lower body anatomical distribution of solar ultraviolet radiation on the human form in standing and sitting postures. J Photochem Photobiol B 2003; 69:1–6.22. Walter SD, King WD, Marrett LD. Association of cutaneous malignant melanoma with intermittent exposure to ultraviolet radiation: results of a case-control study in Ontario, Canada. Int J Epidemiol 1999; 28:418–427.23. Holman CD, Armstrong BK. Cutaneous malignant melanoma and indicators of total accumulated exposure to the sun: an analysis separating histogenetic types. J Natl Cancer Inst 73:75–82.24. Iscovich J, Howe GR. Cancer incidence patterns (1972-91) among migrants from the Soviet Union to Israel. Cancer Causes Control 1998; 9:29–36.25. Hemminki K, Li X. Cancer risks in Nordic immigrants and their offspring in Sweden. Eur J Cancer 2002; 38:2428–2434.26. Pfahlberg A, Kolmel KF, Gefeller O. Timing of excessive ultraviolet radiation and melanoma: epidemiology does not support the existence of a critical period of high susceptibility to solar ultraviolet radiation- induced melanoma. Br J Dermatol 2001; 144:471–475.27. Hruza LL, Pentland AP. Mechanisms of UV-induced inflammation. J Invest Dermatol 1993; 100:35S.28. Tyrrel RM. Activation of mammalian gene expression by the UV component of sunlight— from models to reality. Bioessays 1996; 18:139.29. Irwin C, Barnes A, Veres D, Kaibey K. An ultraviolet radiation action spectrum for immediate pigment darkening. Photochem Photobiol 1993; 57:504–507.30. Sterenborg H, Van der Leun JC. Tumorigenesis by a long wavelength UVA source. Photochem Photobiol 1990; 51:325–330.31. Burren R, Scaletta C, Frenk E, Panizzon RG, Applegate LA. Sunlight carcinogenesis: expression of p53 and pyrimidine dimers in human skin following UVA1, UVA1C2 and solar stimulating radiations. Int J Cancer 1998; 76:201–206.32. Gil EM, Kim TH. UV-induced immune suppression and sunscreen. Photochem Photoimunol Photomed 2000; 16:101–111.33. Sayre RM, Stanfield J, Bush AJ, Lott DL. Sunscreen standards tested with differently filtered solar simulators. Photodermatol Photoimmunol Photomed 2001; 17:278–284.34. Patini G. Perfluoropolyethers in sunscreens. Drug Cosmet Ind 1988; 143:42.35. Shaath NA. Evolution of modern sunscreen chemicals. In: Lowe NJ, Shaath NA, Pathak MA, eds. Sunscreens: Development, Evaluation, and Regulatory Aspects. New York: Marcel Dekker, 1997. Chapter1.36. Food and Drug Administration. Sunscreen Drug Products for Over-the-Counter Human Use. Final Monograph (21 CFR 352). HHS Final Rule. Fed Regis 1999; 64:27666–27693.37. Shaath NA. Evolution of modern sunscreen chemicals. In: Lowe NJ, Shaath NA, Pathak MA, eds. Sunscreens: Development, Evaluation, and Regulatory Aspects. New York: Marcel Dekker, 1997. Chapter15.38. Rigel DS, Friedman RJ, Dzubow L, Bystryn JC, Reintgen D, Marks R, eds. Cancer of the Skin. Philadelphia: W.B. Saunders, 2005.39. Shaath NA. Evolution of modern sunscreen chemicals. In: Lowe NJ, Shaath NA, Pathak MA, eds. Sunscreens: Development, Evaluation, and Regulatory Aspects. New York: Marcel Dekker, 1997. Chapter 15.40. Mackie BS, Mackie LE. The PABA story. Australas J Dermatol 1999; 40:51–53.41. Fisher AA. Sunscreen dermatitis due to glyceryl PABA: significance of cross-reactions to this PABA ester. Curr Contact News 1976; 18:495.

164 Nguyen and Rigel42. Kaidbey KH, Kligman AM. Phototoxicity to a sunscreen ingredient: padimate A. Arch Dermatol 1978; 114:547.43. Robbins P. The Skin Cancer Foundation Journal, New York, 1985.44. Cook N, Freeman S. Report of 19 cases of photoallergic contact dermatitis to sunscreens seen at the Skin and Cancer Foundation. Australas J Dermatol 2001; 42:257–259.45. Pinnell SR, Fairhurst D, Gillies D, Mitchnick MA, Kollias N. Microfine zinc oxide is a superior sunscreen ingredient to microfine titanium dioxide. Dermatol Surg 2000; 26:309–314.46. Pailthorpe MT. Textiles and sun protection: the current situation. Australas Textiles 1994; 14:54–66.47. Wang SQ, Kopf AW, Marx J, Bogdan A, Polsky D, Bart RS. Reduction of ultraviolet transmission through cotton T-shirt fabrics with low ultraviolet protection by various laundering methods and dyeing: clinical implications. J Am Acad Dermatol 2001; 44:767–774.48. Grunfeld EA. Influences university students’ intentions to practice safe sun exposure behaviors? J Adolesc Health 2004; 35:486–492.49. Stanton WR, Janda M, Baade PD, Anderson P. Prevention of skin cancer: a review of sun protection in Australia and internationally. Health Promot Internation 2004; 19:369–378.50. Cokkinies VE, et al. Sun exposure and sun-protection behaviors and attitudes among U.S. Youths, 11 to 18 years of age. Prevent Med 2001; 33:141–151.51. Lazovich D, Forster J, Sorensen G, et al. Associated with use or intention to use indoor tanning among adolescents. Arch Pediatr Adolesc Med 2004; 158:918–924.52. Bulliard JL, Cox B, Semenciw R. Trends by anatomic site in the incidence of cutaneous malignant melanoma in Canada, 1969-93. Cancer Causes Control 1999; 10:407–416.53. Robinson JK, Rademaker AW. Relative importance of prior basal cell carcinomas. Continuing sun exposure, and circulating lymphocytes-T on the development of basal cell carcinoma. J Invest Dermatol 1992; 99:227–231.54. Vainio H, Miller AB, Bianchini F. An international evaluation of the cancer-preventive potential of sunscreens. Int J Cancer 2000; 88:838–842.55. Huncharek M, Kupelnick B. Use of topical sunscreens and the risk of malignant melanoma: a meta-analysis of 9067 patients from 11 case-control studies. Am J Public Health 2002; 92:1173–1177.56. Klepp O, Magnus K. Some environmental and bodily characteristics of melanoma patients. A case-control study. Int J Cancer 1979; 23:482–486.57. Graham S, Marshall J, Haughey B, et al. An inquiry into the epidemiology of melanoma. Am J Epidemiol 1985; 122:606–619.58. Herzfeld PM, Fitzgerald EF, Hwang SA, Stark A. A case-control study of malignant melanoma of the trunk among white males in upstate New York. Cancer Detect Prev 1993; 17:601–608.59. Beitner H, Norell SE, Ringborg U, Wennersten G, Mattson B. Malignant melanoma: aetiological importance of individual pigmentation and sun exposure. Br J Dermatol 1990; 122:43–51.60. Green A, Bain C, McLennan R, Siskind V. Risk factors for cutaneous melanoma in Queensland. Recent Results Cancer Res 1986; 102:76–97.61. Holman CD, Armstrong BK, Heenan PJ. Relationship of cutaneous malignant melanoma to individual sunlight-exposure habits. J Natl Cancer Inst 1986; 76:403–414.62. Osterlind A, Tucker MA, Stone BJ, Jensen OM. The Danish case-control study of cutaneous malignant melanoma. II. Importance of UV-light exposure. Int J Cancer 1988; 42:319–324.63. Holly EA, Aston DA, Cress RD, Ahn DK, Kristiansen JJ. Cutaneous melanoma in women. I. Exposure to sunlight, ability to tan, and other risk factors related to ultraviolet light. Am J Epidemiol 1995; 141:923–933.64. Westerdahl J, Olsson H, Masback A, Ingvar C, Jonsson N. Is the use of sunscreens a risk factor for malignant melanoma? Melanoma Res 1995; 5:59–65.65. Rodenas JM, Delgado-Rodriguez M, Herranz MT, Tercedor J, Serrano S. Sun exposure, pigmentary traits, and risk of cutaneous malignant melanoma: a case-control study in a Mediterranean population. Cancer Causes Control 1996; 7:275–283.

Prevention of Photocarcinogenesis 16566. Autier P, Dore JF, Schifflers E, et al. Melanoma and use of sunscreens: an Eortc case-control study in Germany. Belgium and France. The EORTC Melanoma Cooperative Group. Int J Cancer 1995; 61:749–755.67. Espinosa Arranz J, Sanchez Hernandez JJ, Bravo Fernandez P, et al. Cutaneous malignant melanoma and sun exposure in Spain. Melanoma Res 1999; 9:199–205.68. Naldi L, Lorenzo Imberti G, Parazzini F, Gallus S, La Vecchia C. Pigmentary traits, modalities of sun reaction, history of sunburns, and melanocytic nevi as risk factors for cutaneous malignant melanoma in the Italian population: results of a collaborative case-control study. Cancer 2000; 88:2703–2710.69. Westerdahl J, Ingvar C, Masback A, Olsson H. Sunscreen use and malignant melanoma. Int J Cancer 2000; 87:145–150.70. Rigel DS. The effect of sunscreen on melanoma risk. Dermatol Clin 2002; 20:601–606.71. Holicks MF. McCollum award Lecture, 1994: vitamin D—new horizons for the 21st century. Am J Clin Nutr 1994; 60:619–630.72. Holick MF. Sunlight “D”ilemna: a risk of skin cancer or bone disease and muscle weakness. Lancet 2001; 357:4–6.73. Kampman E, et al. Calcium Vitamin D, sunshine exposure, dairy products and colon cancer risk (United States). Cancer Causes Control 2000; 11:459–466.74. Matsuoka LY, et al. Sunscreens suppress vitamin D3 synthesis. J Clin Endocrinol Metab 1987; 64:1165–1168.75. Matsuoka LY, et al. Chronic sunscreen use decreases circulating concentrations of 25-hydroxyvitamin D: a preliminary study. Arch Dermatol 1988; 124:1802–1804.76. Marks R, et al. The effect of regular sunscreen use on vitamin D levels in an Australian population: results of a randomized controlled trial. Arch Dermatol 1995; 131:415–421.77. Farrerons J, Barnadas M, Lopez-Navidad A, et al. Sunscreen and risk of osteoporosis in the elderly: a two-year follow-up. Dermatology 2001; 202:27–30.78. Sollitto RB, et al. Normal vitamin “D levels can be maintained despite rigorous photoprotection: Six years” experience with xeroderma pigmentosum. J Am Acad Dermatol 1997;37.79. Whiteman DC, et al. Childhood sun exposure as a risk for melanoma: a systematic review of epidemiologic studies. Cancer Causes Control 2001; 12:69–82.

11Anti-aging Skin Care FormulationsDonald L. BissettP&G Beauty, Miami Valley Innovation Center, Cincinnati, Ohio, U.S.A.INTRODUCTIONThere are many cosmetic materials that are claimed to have anti-aging effects when usedtopically. Since there are so many of these materials and since the term anti-aging is verybroad (in terms of prevention vs. improvement and the wide array of possible benefit areassuch as wrinkling, sagging, texture, sallowness, hyperpigmentation, etc.), this relativelyshort chapter must necessarily be selective in its scope. Thus, this discussion will focus ononly a few classes of cosmetic agents which are reported to have bio-activity to providewrinkling and/or sagging improvement (i.e., repair or reversal). Particular attention will bedirected to those materials within these classes for which there are readily available orpublished clinical data to support their reported skin appearance improvement benefits.VITAMIN AFormsThere are several forms of vitamin A that are used cosmetically. The most widely utilizedones include retinol, retinyl esters (e.g., retinyl acetate, retinyl propionate, and retinylpalmitate), and retinaldehyde. Through endogenous enzymatic reactions, all of these areconverted ultimately to trans-retinoic acid (trans-RA), which is the active form of vitaminA in skin. Specifically, retinyl esters are converted to retinol via esterases. Retinol is thenconverted to retinaldehyde by retinol dehydrogenase. And finally retinaldehyde isoxidized to RA by retinaldehyde oxidase.MechanismsSince trans-RA is the active form of vitamin A in skin, the abundant published literature onthe former is applicable to this discussion. Trans-RA interacts with nuclear receptorproteins described as RA receptors and retinoid X receptors, which can form heterodimercomplexes. These complexes then interact with specific DNA sequences to affecttranscription, to either increase or decrease expression of specific proteins/enzymes (1).Using genomic methodology, we have observed that the expression of over 1200 genes is 167

168 Bissettsignificantly affected by topical retinoid treatment of photoaged human skin (unpublishedobservations). Many of these changes can be ascribed, at least on some level, as beingnormalization of the altered skin conditions that occur with aging (induced by bothchronological and environmental influences such as chronic sun exposure). Some specificchanges induced by retinoid that are likely relevant to skin anti-wrinkle benefits are thosethat result in thicker skin to diminish the appearance of fine lines and wrinkles, e.g.,increased epidermal proliferation and differentiation (increased epidermal thickness),increased production of epidermal ground substance [glycosaminoglycans (GAGs) whichbind water, increasing epidermal hydration and thickness], and increased dermalproduction of extracellular matrix components such as collagen (increase dermalthickness) (2). In addition to stimulation of events in skin such as those mentioned above, retinoidscan also have an inhibitory effect on other tissue components. For example, retinoids arereported to inhibit production of collagenase (3). And while retinoid will stimulateproduction of ground substance (GAGs) in epidermis, it will inhibit production of excessground substance in photoaged dermis (Fig. 1). While a low level of GAGs are required inthe dermis for normal collagen structure and function, excess dermal GAGs are associatedwith altered dermal collagen structure and wrinkled skin appearance in photoaged skin (4)and in the Shar Pei dog (5). Reduction in this excess is associated with reduced skinwrinkling (6,7). Since at least some of the epidermal effects of topical retinoid (e.g., epidermalthickening) (8) occur relatively rapidly (days) after initiation of treatment, some skinbenefits (e.g., diminution of fine lines) can be realized quickly. The dermal effects likelyoccur on a much longer time frame (weeks to months) such that reduction in skin problemslike wrinkles require much longer time frames (weeks to months) (2).EfficacyWhile much of the substantial literature on the improvement of skin wrinkles by topicalretinoids is focused on trans-RA, there are also data available on the vitamin A compoundswhich are used cosmetically. Since retinoids are irritating to skin, defining skin-tolerateddoses clinically is a key step in working effectively with these materials. Retinol is better% reduction in GAG 80 in fibroblast culture 70 60 50 30µM RP 30µM t-RA 40 30 20 10 0 6µM RPFigure 1 Retinoids reduce excess dermal GAGs. In cell culture, using fibroblasts from an olddonor (57 years old), there was a two- to three-fold increase in GAGs (measured as hyaluronic acid)versus from a young donor (neonatal). The treatments were effective in reducing the excess GAGlevel. Abbreviations: RP, retinyl propionate; t-RA, trans-retinoic acid.

Anti-aging Skin Care Formulations 169Expert grader cumulative 160 back irritation scores 140 120 100 RP RA ROH 80 60 40 20 0 controlFigure 2 Retinoid irritation in cumulative human back irritation testing (double-blind, vehicle-controlled, randomized study; daily patching for 20 days, under semi-occluded patch, nZ45; 0–3irritation grading). Doses and abbreviations used are: 0.09% RP (retinyl propionate), 0.086% RA(retinyl acetate), and 0.075% ROH (retinol). RP and RA were significantly less irritating than ROH,and RP was less irritating than RA.tolerated by the skin than trans-RA (2). In our testing we noted that retinyl propionate ismilder to skin than retinol and retinyl acetate (Fig. 2). Since retinoids in general tend to be fairly potent, topical doses of less than 1% aregenerally sufficient to obtain significant effects. At low doses, in double-blind, split-face,placebo-controlled facial testing (12-week duration), both retinol and retinyl propionatehave been shown to be significantly effective in reducing facial hyperpigmentation andwrinkles across the study (Fig. 3). Determination of treatment effects was based onquantitative computer image analysis and blinded expert grading of high resolutiondigital images.Expert grader average scores 0.5 0.15% ROH for improvement vs. baseline 0.45 0.30% RP 0.4 hyperpigmentation 0.35 0.3 0.25 0.2 0.15 0.1 0.05 0 wrinklingFigure 3 Reduction in wrinkles and hyperpigmentation in a 12-week clinical study (double-blind, left-right randomized, split-face, placebo vehicle-controlled study with once dailyapplication, nZ52–56 per product). Evaluation for reduction versus baseline in wrinkling andhyperpigmentation was done by three independent expert graders (0–4 grading scale) on blind-coded images after four, eight, and 12 weeks of treatment. The grader scores at each time pointwere averaged. There were significant effects for both treatments across the study. The datapresented here are averages for all three time points. The low irritation of RP permits use of higherlevels to achieve greater effects without significant negative aesthetic issues.

170 Bissett There are also clinical studies published on other retinoids. Retinyl palmitate hasvery low irritation potential and is effective if tested at a very high dose such as 2% (9).There are also several references describing the clinical efficacy of retinaldehyde, typicallyat a dose of 0.05% (10–12). However, retinaldehyde has irritation potential similar toretinol (13).Product/Formulation ChallengesThere are two primary challenges in working with retinoids. One is their tendency toinduce skin irritation (as noted above) which negatively affects skin barrier properties.While high doses will provide ever greater skin aging improvement, the associatedirritation tends to define an upper concentration limit where they can be used practically.While the skin may have some capacity to accommodate to retinoid treatment to yield lessirritation, it is not completely eliminated even with long-term use, as demonstrated byevaluation of skin barrier function (Fig. 4). Mitigation of the irritation may be managed tosome extent with appropriate formulation to meter delivery into the skin, use of retinylesters which are less irritating than retinol (as noted above), or inclusion of otheringredients (e.g., those with anti-inflammatory activity) to counter this issue. The second key issue is instability, especially to oxygen and light. Thus, to ensurestability of retinoid in the finished product, formulation and packaging must be done in anenvironment that minimizes exposure to oxygen and light. The final product packagingalso ideally needs to be opaque and oxygen impermeable, including use of a small packageorifice to reduce oxygen exposure once the container is opened. In addition, a variety ofother strategies can be employed, e.g., encapsulation of the retinoid and inclusion ofstabilizing antioxidants.VITAMIN B3FormsThere are three primary forms of vitamin B3 that have found utility in skin care products:niacinamide (aka nicotinamide), nicotinic acid, and nicotinate esters (e.g., myristoylnicotinate, benzyl nicotinate).TEWL (gram water per m2.hour) 6 p < 0.05 change in 5 p < 0.05 TEWL vs. 4 control 3 6 month 12 month 2 1 0 baselineFigure 4 Effect of topical 0.05% trans-retinoic acid on skin barrier as determined bytransepidermal water loss (TEWL). Although the skin becomes more tolerant of topical retinoicacid, even after 12 months of treatment there is still significant elevation of TEWL above baseline.

Anti-aging Skin Care Formulations 171MechanismsVitamin B3 serves as a precursor to a family of endogenous enzyme co-factors,specifically nicotinamide adenine dinucleotide (NAD), its phosphorylated derivative(NADP), and their reduced forms (NADH, NADPH), which have antioxidant properties.These co-factors are involved in many enzymatic reactions in the skin, and thus havepotential to influence many skin processes (14). This precursor role of vitamin B3 maythus be the mechanistic basis for the diversity of clinical effects observed for a materialsuch as niacinamide. While precisely how the dinucleotide co-factors might contribute toall these effects has not been elucidated, several specific actions of niacinamide have beendescribed (14–19). For example, topical niacinamide has the following effects: † Niacinamide inhibits sebum production, specifically affecting the content of triglycerides and fatty acids. This may contribute to the observed reduction in skin pore size and thus improved skin texture (a component of texture being enlarged pores). † Niacinamide increases epidermal production of skin barrier lipids (e.g., ceramides) and also skin barrier layer proteins and their precursors (keratin, involucrin, filaggrin), leading to the observed enhancement of barrier function as determined by reduced transepidermal water loss (TEWL). This improved barrier also increases skin resistance to environmental insult from damaging agents such as surfactant and solvent, leading to less irritation, inflammation, and skin redness (e.g., facial red blotchiness). Since inflammation is involved in development of skin aging problems, the barrier improvement may contribute to the anti-aging effects of topical niacinamide. The anti-inflammatory and sebum reduction effects of niacinamide likely contribute to the anti-acne effect reported for this material (20). † Niacinamide and its metabolite 1-methyl nicotinate have been reported (21,22) to have anti-inflammatory properties (e.g., inhibition of inflammatory cytokines). † Niacinamide increases production of collagen which may contribute to the observed reduction in the appearance of skin wrinkling. † Niacinamide reduces the production of excess dermal GAGs (glycosaminogly- cans). In cell culture testing, as noted above for retinyl propionate, 0.5 mM niacinamide reduced excess GAG production by 15%. † Niacinamide inhibits melanosome transfer from melanocytes to keratinocytes, leading to reduction in skin hyperpigmentation (e.g., hyperpigmented spots). † Niacinamide inhibits skin yellowing. A contributing factor to yellowing is protein oxidation (glycation; Maillard reaction), which is a spontaneous oxidative reaction between protein and sugar (23–25), resulting in cross-linked proteins (Amedori products) that are yellow-brown in color. These products accumulate in matrix components such as collagen that have long biological half-lives (26,27). Niacinamide has been separately reported (28,29) to have anti-glycation effects. Since nicotinic acid and its esters are also precursors to NAD(P), they would beexpected to provide these same benefits to skin. Nicotinic acid and many (if not all) of its esters(following in-skin hydrolysis to free nicotinic acid) also stimulate blood flow, leading toincreased skin redness or a flush response (30).EfficacyAs representative for the vitamin B3 family of compounds, there are several publishedreports on the diversity of clinical effects of topical niacinamide (14–18). These data

172 Bissett% reduction in total wrinkle length 6 p = 0.0005 5% niacinamide vs. placebo control 5 p = 0.06 4 3 8 weeks 12 weeks 2 1 0 4 weeksFigure 5 Topical 5% niacinamide reduces fine lines/wrinkling in facial skin. Subjects were femaleCaucasians (nZ50) who applied placebo control versus 5% niacinamide formulations to their faces(12-week, double-blind, split-face, left-right randomized clinical trial).were obtained from double-blind, placebo-controlled, left-right randomized studies.For example, topical niacinamide has been shown to reduce skin fine lines/wrinkling(Fig. 5). The effect increases over time and is significant after eight to 12 weeks oftreatment. Topical niacinamide also improves other aspects of aging skin, such asreduction in sebaceous lipids (oil control) and pore size, which likely contribute at least inpart to improved skin texture (Fig. 6). Additionally, niacinamide improves skin elasticproperties as demonstrated for two parameters of skin elasticity (Fig. 7). Beyond theseeffects, there is also improvement in appearance of skin color (reduction inhyperpigmented spots and reduced skin yellowing) as noted above. Fairly high doses(2–5%) of vitamin B3 have been used to achieve desired benefits. However, since there isvery high tolerance of the skin to niacinamide even with chronic usage, high doses can beused acceptably. In fact, as noted above, since topical niacinamide improves skin barrier, itactually increases the skin’s resistance to environmental insult (e.g., from surfactant) andreduces red blotchiness (Fig. 8). Some data on myristoyl-nicotinate have been presented (31) to suggest that a similarbroad array of benefits occurs with this agent when used topically (1–5% doses). Clinicaldata for topical nicotinic acid and other esters are not available.% reduction in total texture area p < 0.05 vs. placebo control 3 p < 0.05 2.5 5% niacinamide 2 1.5 8 weeks 12 weeks 1 0.5 0 4 weeksFigure 6 Topical niacinamide improves skin surface texture. Subjects were female Caucasians(nZ50) who applied placebo control versus 5% niacinamide formulations to their faces (12-week,double-blind, split-face, left-right randomized clinical trial).

Anti-aging Skin Care Formulations 173(A) p < 0.05 0.012Change in Cutometer R5 reading vs. placebo control 0.01 0.008 0.006 5% niacinamide 0.004 0.002 0 8 weeks 12 weeks 4 weeks(B) p < 0.05 0.009Change in Cutometer R7 reading vs. placebo control 0.008 0.007 0.006 0.005 5% niacinamide 0.004 0.003 0.002 0.001 0 8 weeks 12 weeks 4 weeksFigure 7 Topical 5% niacinamide improves skin elasticity. Subjects were female Caucasians(nZ50) who applied placebo control versus 5% niacinamide formulations to their faces (12-week,double-blind, split-face, left-right randomized clinical trial). (A) Effect on R5 parameter (measure ofviscoelastic properties). (B) Effect on R7 parameter (measure of elastic recovery).Product/Formulation ChallengesThe key challenge for working with niacinamide and nicotinate esters is avoiding hydrolysisto nicotinic acid. Nicotinic acid, even at low doses, can induce an intense skin reddening(flushing) response (30). While a little skin redness (increased skin “pinkness”) may be aImprovement in red blotchiness 0.35 p < 0.05 5% niacinamide vs. placebo control 0.3 8 weeks 12 weeks 0.25 0.2 0.15 0.1 0.05 0 4 weeksFigure 8 Niacinamide is well tolerated by the skin and even reduces facial skin red blotchiness.Subjects were female Caucasians (nZ50) who applied placebo control versus 5% niacinamideformulations to their faces (12-week, double-blind, split-face, left-right randomized clinical trial).

174 Bissettdesired effect, the flushing response among individuals is highly variable in terms of dose toinduce it, time to onset of the response, and duration of response. Additionally, the flushingcan also have associated issues such as burn, sting, and itch, particularly under cold and/ordry conditions. To avoid hydrolysis, formulating in the pH range of 5 to 7 is preferred. Thisflushing issue also requires that the purity of the raw material (e.g., niacinamide) be veryhigh to minimize any contaminating free acid. For the nicotinate esters, there are many commercial options. Many of themunfortunately are readily hydrolyzed to nicotinic acid on or in the skin such that flushingresponses occur rapidly (within seconds/minutes) even at very low concentrations (!1%).The longer chain esters (e.g., myristoyl-nicotinate) apparently are more resistant to thishydrolysis and thus appear to be more suitable for use topically.VITAMIN CFormsOf the many forms of this vitamin, some of the more commonly used are ascorbic acid,ascorbyl phosphate (typically as the magnesium and sodium salts), and other ascorbatederivatives (e.g., ascorbyl palmitate, ascorbyl glucoside).MechanismsVitamin C is well known as an antioxidant and has been utilized as a skin lightener (e.g.,via tyrosinase inhibition and/or its antioxidant effect). It also has been reported to haveanti-inflammatory properties since it reduces the erythema associated with post-operativelaser resurfacing (32). In addition, ascorbic acid also serves as an essential co-factor for theenzymes lysyl hydroxylase and prolyl hydroxylase, both of which are required for post-translational processing in collagen (Types I and III) biosynthesis (33–36). Thus, bystimulating these biosynthetic steps, ascorbic acid will increase the production of collagenwhich will lead to wrinkle reduction as discussed above. While the ascorbic acid derivatives may possess some properties of the free acid(e.g., antioxidant), hydrolysis of the derivatives would be required for the increasedcollagen production effect since the acid is the active co-factor. Demonstration of thehydrolysis of all these derivatives in skin has not been well documented.EfficacyThere are several published studies discussing the anti-aging benefit of ascorbic acid.The reported doses of vitamin C tested are fairly high, and the base sizes are relativelysmall (n%23). Some of the studies address ingredient oxidative stability, a particularchallenge with this form of vitamin C. In oil-in-water emulsion, loss of nearly half of theascorbic acid in a month is typical (37). To achieve stability, these authors used oxygenimpermeable aluminum tube packaging which reduced ascorbic acid loss to less than 10%.After one week of topical treatment of human skin, there was significant reduction ofUVA-induced oxidation by 3% ascorbic (41% reduction), whereas the reduction by 3%sodium ascorbyl phosphate was smaller (16%) and not significant. In a double-blind,placebo-controlled, split-face 12-week study (37), stabilized 3% ascorbic acid appliedtopically (nZ23) was found to be well tolerated by the skin and reduced facial wrinkles asdetermined by skin replica analysis (Fig. 9).

Anti-aging Skin Care Formulations 175Reduction in Rq units (replica analysis) 8 7 6 5 4 3 2 8 weeks 12 weeks 1 0 4 weeksFigure 9 Facial wrinkle reduction (skin replica analysis) by topical 3% ascorbic acid. In another double-blind, placebo-controlled, split-face 12-week study (38), 17%vitamin C (10% as ascorbic acid and 7% as tetrahexyldecyl ascorbate; nZ10) in ananhydrous gel was applied topically. Based on dermatologist grading, there was reducedfacial photoaging. From histological assessment of biopsy specimens, there wasimprovement in the collagen (increased Grenz zone). In a third study (39), topical 5%ascorbic acid (nZ20, 6 months) improved photodamaged forearm and upper chest skinbased on dermatologist scores, skin surface replicas, and biopsy specimen analysis(improvements in elastin and collagen fiber appearance). And lastly, a three-month study(40) of a stabilized ascorbic acid formulation (specific concentration and pH not specified,but likely approximately 10% ascorbic acid at low pH) revealed improvement in facial skinbased on dermatologist grading and facial image analysis. However, this formulation led toinstances of aesthetic issues for test subjects (sting, erythema, dryness) which may havecontributed to the very high drop-out rate in this study (started with nZ28, with nZ19finishing the study).Product/Formulation ChallengesThe key challenge with vitamin C compounds in general is stability (oxygen sensitivity),particularly with ascorbic acid. Not only does oxidation lead to loss of the active material,there is also rapid product yellowing (an aesthetic negative for the consumer). Variousstabilization strategies can be attempted to address the issue, such as exclusion of oxygenduring formulation, oxygen impermeable packaging, encapsulation, low pH, minimizationof water, and inclusion of other antioxidants. In spite of all those approaches, in generalascorbate stability remains a challenge, and some of these approaches (e.g., very low pH)can lead to unwanted aesthetic skin effects as noted above. For the ascorbyl phosphates (Mg and Na salts), the resulting high content of salt inproduct can dramatically impact the thickener system, requiring increased use of thickeneringredients. These ascorbate derivatives are also considerably more expensive than otherascorbate compounds. Another challenge is skin delivery. Ascorbic acid’s penetration across skin is ingeneral poor (typically less than 1% of the topical dose entering skin). For the phosphatederivates of ascorbate, skin penetration can be an even greater challenge due to the

176 Bissettnegative charges on the phosphate moiety. Thus, the use of skin penetration enhancementapproaches is desired.PEPTIDESFormsThere is a limitless array of possible peptides, based on amino acid sequence, numberof amino acid residues, and use of derivatives/isomers of these residues. A few peptideswith well-characterized sequences that have received particular focus in the cosmeticindustry are palmitoyl-lysine-threonine-threonine-lysine-serine (pal-KTTKS; Matrixylw),acetyl-glutamate-glutamate-methionine-glutamine-arginine-arginine (Ac-EEMQRR;Argirelinew), and the tripeptide copper glycine-histidine-lysine (Cu-GHK).MechanismsKTTKS is a fragment of dermal collagen and has been shown to stimulate productionof collagen and thus has been discussed in regard to wound healing (41). Incorporation oflong-chain lipophilic residues such as palmitoyl onto peptides can dramatically improvetheir delivery into skin, e.g., the observed five- to six-fold increase in delivery of palmitoylpeptides versus their underivatized versions (42). Thus, pal-KTTKS was synthesizedspecifically for topical use of this peptide. Like the underivatized peptide, the palmitatederivative (pal-KTTKS) is also active in stimulating collagen production (43–45).In addition, at extremely low levels (ppb) in culture, pal-KTTKS reduces excessdermal GAGs (Fig. 10). As discussed above, this effect may also contribute to an anti-wrinkle effect. Like KTTKS, GHK is also a fragment of dermal collagen (46). Copper is a requiredfactor for activity of lysyl oxidase, an enzyme involved in collagen synthesis (47). Thecomplex of these two (Cu-GHK) has been shown to stimulate wound healing processes% reduction in GAG 70 pal-KTTKS t-RA 60 50 0.9 10* 40 *10 ppm = 0.001% 30 20 10 0 0.03 0.06 0.09 0.3 0.6 ppmFigure 10 Pal-KTTKS reduces excess dermal GAGs. In cell culture, using fibroblasts from an olddonor (57 years old), there was a two- to three-fold increase in GAGs (measured as hyaluronic acid)versus from a young donor (neonatal). Pal-KTTKS was effective in reducing the excess GAG level inold fibroblasts. Abbreviation: t-RA, trans-retinoic acid.

Anti-aging Skin Care Formulations 177in laboratory model systems by increasing production of dermal matrix components suchas collagen and specific matrix remodeling matrix metalloproteinases (MMPs) (48–52). Ac-EEMQRR is described as a mimic of botulinum neurotoxin (Botoxw) whichfunctions by inhibiting neurotransmitter release, thus “relaxing” the muscles involved indefining facial wrinkles (53). Since the reported mechanisms of pal-KTTKS and Cu-GHK involve matrixproduction and remodeling, their appearance benefits would be expected to requirechronic treatment. In contrast, Ac-EEMQRR should have acute benefit effects based onits reported Botoxw-like mechanism.EfficacyThe peptide pal-KTTKS has been shown to be quite potent clinically, providing effectsfrom very low topical doses. This low dose for clinical activity is consistent with thevery low concentration (as low as ppb) required to obtain effects in vitro as noted above.In small-base human clinical testing (54), topical pal-KTTKS at 3 ppm was described asproviding improvement in appearance of wrinkled skin. To confirm this observation,a larger base size 12-week, double-blind, placebo-controlled, split-face, left-rightrandomized study (nZ94) was conducted (43), again testing the effect of topical 3 ppmpal-KTTKS. This topical peptide is extremely well tolerated by test subjects, i.e., it doesnot induce skin irritation responses (no redness, dryness, burn, sting, or itch responses).Based on quantitative computer image analysis, it reduced fine lines/wrinkles versus theplacebo control (Fig. 11). While the effect was small, it was significant at weeks 8 and 12.Expert graders evaluating blind-coded images also identified an improvement in fine lines/wrinkles, with directional and significant effects noted at weeks 8 and 12, respectively(Fig. 12). Consistent with the good skin tolerance of the peptide, there was no impact onskin barrier function, as assessed by TEWL (Table 1), indicating lack of irritation. In contrast to the potency of pal-KTTKS, the reported effects of other peptidesrequire much higher doses, such as 2% for Cu-GHK and as high as 10% for Ac-EEMQRR.There is also limited published information available on the clinical effects of thesepeptides. One study (55) describes increases in skin thickness, hydration, and smoothnessfrom topical use of a commercial product containing Cu-GHK (peptide dose not indicated)in an open-label study involving 40 subjects. A series of clinical studies of eight to12 weeks, duration (up to nZ71) describing skin improvements such as reducedTotal fine line/wrinkle length (mm) 175 p < 0.20 control 170 p < 0.10 3 ppm pal-KTTKS 165 p < 0.10 160 155 4 weeks 8 weeks 12 weeks 150 145 140 135 130 baselineFigure 11 Topical pal-KTTKS improves the appearance of facial skin wrinkles (quantitativecomputer image analysis). Smaller numbers indicate fewer fine lines/wrinkles.

178 Bissett p < 0.20 p < 0.10Expert grader assessment for 1 control Fine line/wrinkle improvement 0.9 3 ppm pal-KTTKS 0.8 8 weeks 12 weeks 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 4 weeksFigure 12 Topical pal-KTTKS improves the appearance of facial skin wrinkles (blinded expertgrader image analysis). Grading was on a 0–4 grading scale. Larger numbers indicate fewer finelines/wrinkles.wrinkling, apparently using topical 2% Cu-GHK, have been presented as meeting posters(56–59). For Ac-EEMQRR, a conference platform presentation (53) describes 30%reduction in wrinkle depth with 10% of this peptide used topically in a 30-day study.Product/Formulation ChallengesAn important challenge is delivery into skin since peptides are poorly penetrating,especially as the number of amino acid residues increases. An approach to that problemis addition of a lipophilic chain (e.g., palmitate), which in the case of KTTKS increasedskin penetration several-fold over the underivatized peptide. An additional challenge is the cost. As the number of amino acid residues increases,the cost of peptide can increase dramatically. The consequences are that only low levelsof peptide can be used in product (which is acceptable if the peptide is potent as in the caseof pal-KTTKS) or the finished product cost to the consumer must be very high.DIMETHYLAMINOETHANOL (DMAE)MechanismDMAE (also known as deanol) is a precursor to acetylcholine, a neurotransmitter involvedin increased muscle tone. There thus could be firming of the skin via effects on the facialTable 1 Lack of Effect of Pal-KTTKS on Skin Barrier Properties as Assessed by TransepidermalWater Loss Transepidermal water loss (g water/m2/hr)Time point Placebo formulation Pal-KTTKS formulation p valueBaseline 11.15 11.40 pO0.384 weeks 8.10 8.24 pO0.608 weeks 8.56 8.41 pO0.6012 weeks 7.89 8.15 pO0.35

Anti-aging Skin Care Formulations 179musculature. In addition, acetylcholine may affect the keratinocytes (specifically theirproliferation, adhesion, and motility) leading to “epidermal contractility,” leading toa firming/tightening effect on the skin (60). DMAE also has antioxidant properties, whichmay contribute to its anti-aging effects (61,62).EfficacySeveral studies have been discussed and overviewed (60). For example, in an open-label,one-month study with a DMAE-containing formulation (DMAE dose not specified), theskin of 50 subjects was compared at the end of the treatment period versus baseline bydermatologist grading and subject self-assessment. Significant improvements were reportedin several measures, particularly in the area of skin firming and lifting. The topical treatmentwas well tolerated by the subjects. As a further example, in a double-blind, placebo-controlled, 16-week, full-face study (nZ156), 75% of the subjects used a DMAE-containing formulation (DMAE dose not specified), and 25% of the subjects used a placeboformulation (60). Effects were determined based on dermatologist grading and imageanalysis. The statistical p value presentation indicates several facial benefits related to skinfirming (e.g., under-eye firming, cheek area firming, jaw line lifting and firming, increasedelasticity, etc.). Again, the skin tolerated the DMAE formulation well. These reportedobservations are consistent with other small-base (nZ8) clinical testing showing improvedskin firmness instrumentally from topical use of 3% DMAE in a one-day study (63). The interesting aspect of the clinical effects is that while some testing has beenweeks/months in duration, the onset of the benefit was reported to be very rapid, withinminutes of topical application (60,63). This seems consistent with the suggestedmechanism if sufficient DMAE can penetrate into skin and be converted to acetylcholinein such a short time period.Product/Formulation ChallengeDMAE, a base, has historically been used as a formula pH adjusting agent. In the un-neutralized state, its pH is approximately 10. Thus, pH adjustment to the desired valueappears to be sufficient.KINETIN (N6-FURFURYLADENINE)MechanismsKinetin is a plant hormone. While its specific mechanisms have not been elucidated, it hasbeen observed to promote growth and have anti-senescence effects in plants. It isa powerful natural antioxidant with effects in protecting DNA and protein from oxidativedamage. In human fibroblast cell culture, even very low levels (ppm) delay the onsetof changes associated with cell aging, e.g., appearance of lipofuscin, appearance ofmultinucleate cells, and microtubule disorganization (64).EfficacyIn three reported clinical tests (10–24-week duration, nZ30–98), topical 0.1% kinetin wasreported to improve several aging skin problems, such as wrinkling, poor texture, andhyperpigmentation (64). All of these studies apparently did not involve a placebo control,

180 Bissettbut rather were comparisons (dermatologist grading and self-assessment) of treatmenteffects versus baseline. The 0.1% dose is well tolerated by the skin, with no significantirritation issues described.Product/Formulation ChallengeThe limitation with kinetin is its fairly low solubility in formulation. This restricts theupper dose to approximately 0.1% for an aesthetically elegant formulation. This alsoimpacts delivery into skin, although even from this relatively low dose sufficient materialdoes enter skin to provide clinical effects.TRITERPENOIDSFormsThere are numerous plant-derived triterpenoid compounds and derivatives of them, with afew receiving attention in the cosmetic area, e.g., asiatic acid, ursolic acid, medacassicacid, oleanolic acid, betulinic acid, and boswellic acid. There are also naturally occurringsaccharide esters of these, such as asiaticoside, which is the ester of asiatic acid.MechanismsThere are many reported mechanisms for triterpenoids, for example, antioxidant, anti-inflammatory, elastase inhibition, wound healing, and promotion of collagen and ceramideproduction (65,66). Since triterpenoids share some structural similarity to steroidalcompounds such as hydrocortisone, they may also share some of the mechanisticproperties and potency of such compounds (e.g., anti-inflammatory effects).EfficacyThere is little published information to illustrate the clinical effects of triterpenoids.Topical ursolic acid in liposomes (final concentration of ursolic acid !0.002%) resulted inincreased skin ceramides in small-base forearm testing (nZ3; 11 days of treatment). Theincreased ceramides were suggested to indicate improved skin barrier (66). In a double-blind, placebo-controlled, left-right randomized forearm clinical study of 20 subjects (67),treatment with topical liposomal triterpenoid (specific content not indicated) was done forone month. Improvements in skin extensibility and firmness (instrumentally determined)were reported. While the dose of triterpenoid was not specified, it was probably low andapparently consisted of a blend of boswellic acid, asiatic acid, and possibly others since thecontent may have included extracts.Product/Formulation ChallengeThe key issue with triterpenoids is poor solubility which also results in limited skindelivery. Formulation in liposomes has been employed to improve both delivery andformula solubility, although the resulting increase in oil content of the formulationsmay negatively impact the aesthetics.

Anti-aging Skin Care Formulations 181UBIQUINONE (CO-ENZYME Q10)MechanismUbiquinone is an endogenous antioxidant present throughout the body, including the skin.The levels decrease with age. Topical ubiquinone replenishes the skin (68).EfficacyWhile much has been discussed regarding the skin care benefits of topical ubiquinone,the available data address only the antioxidant properties of this ingredient (69).Product/Formulation ChallengeUbiquinone is yellow-orange in color. Thus, only low doses (!1%) can be used in topicalcosmetic skin care products to avoid aesthetic color concerns. This low dose likely limitsthe benefit potential of this ingredient.OTHER TECHNOLOGIESHydroxy and Keto AcidsThere are many compounds within this group: alpha-hydroxy acids such as glycolic acidand lactic acid, alpha-keto acids such as pyruvic acid, and beta-hydroxy acids such assalicylic acid. Their mechanism involves accelerated exfoliation of stratum corneum,leading to a variety of skin surface texture and color appearance improvement effects.These materials are the subject of another chapter in this volume.MoisturizersTopical materials such as glycerol and hyaluronic acid will readily hydrate the skin surfaceand will diminish the appearance of fine lines simply by plumping the skin. Moisturizersare the subject of another chapter in this volume.FlavonoidsThis family of plant-derived and synthetically prepared chemicals encompasses a hugevariety of compounds. They are beginning to appear in cosmetic products and are a fertilearea for identification of materials active in improving aging skin.Plant Extract ComponentsIn addition to flavonoids, plant extracts are a rich source of diverse compounds that arebeing explored to identify skin care bioactives.DISCUSSIONIt is clear that many anti-aging ingredients that are used cosmetically do provideappearance improvement benefits to the skin, but for others data supporting their claimedeffects are not readily available for assessment. For the active ones, while the benefits

182 BissettSpot appearance reduction 0.9 0.8 0.7 0.6 0.5 RP 0.4 RP + N 0.3 0.2 0.1 0 week 8 week 4 RP = retinyl propionate; N = niacinamideFigure 13 Combining niacinamide with retinyl propionate increases the skin appearanceimprovement effect.may be small, they are significant and do meaningfully improve skin appearance withcontinued use of the materials. It is difficult to quantitatively compare the magnitude ofthe effects among the various technologies since there are many variables across studies:the specific end points measured are often different (e.g., surface replicas vs. facial imageanalysis), equipment and method sensitivities vary, formulation types vary which canimpact active delivery into skin, different body sites were used (e.g., forearm vs. face),clinical base sizes ranged from very small to large, etc. But it is reasonable to state thatthey are all less effective than a technology such as trans-RA. This simply presents anopportunity to identify more potent cosmetic materials. While the benefits of current technology may be small, the magnitude can increaseby combining materials, especially those with different mechanisms of action. Forexample, combining a vitamin B3 with a vitamin A (Fig. 13) or with a peptide (Fig. 14)leads to greater benefits than the individual materials. There is certainly opportunity tocontinue to explore this avenue. There is ample room for exploration of new materials within the current classes ofcompounds (e.g., peptides) and in newer classes of compounds (e.g., flavonoids).Wrinkle length reduction (mm) 9 vs. placebo control 8 7 3 ppm pal-KTTKS 6 + 3.5% N 5 4 3 2 1 0 3 ppm pal-KTTKSFigure 14 Combining niacinamide (N) with pal-KTTKS increases the skin appearanceimprovement effect.

Anti-aging Skin Care Formulations 183Considering the enormous diversity of compounds to be found in natural extracts, forexample, the future possibilities seem limitless for identifying new active materials andmechanisms to improve the appearance of aging skin.REFERENCES 1. Davies PJA, Basilion JP, Haake AR. Intrinsic biology of retinoids in the skin. In: Goldsmith LA, ed. In: Physiology, Biochemistry, and Molecular Biology of the Skin, Vol. 1. New York: Oxford University Press, 1997:385–409. 2. Varani J, Fisher GJ, Kang S, et al. Molecular mechanisms of intrinsic skin aging and retinoid- induced repair and reversal. J Invest Dermatol Symp Proc 1998; 3:57–60. 3. Kang S, Duell EA, Fisher GJ, et al. Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins characteristic of retinoic acid but without measurable retinoic acid levels of irritation. J Invest Dermatol 1995; 105:549–556. 4. Gonzalez S, Moran M, Kochevar IE. Chronic photodamage in skin of mast cell-deficient mice. Photochem Photobiol 1999; 70:248–253. 5. Dunstan RW, Kennis RA. Selected heritable skin diseases of domesticated animals. In: Sundberg JP, ed. Handbook of Mouse Mutations with Skin and Hair Abnormalities. Boca Raton, Florida: CRC Press, 1994:524–525. 6. Kligman AM, Baker TJ, Gordon HL. Long-term histologic follow-up of phenol face peels. Plast Reconstr Surg 1975; 75:652–659. 7. Schwartz E, Kligman LH. Topical tretinoin increases the tropoelastin and fibronectin content of photoaged hairless mouse skin. J Invest Dermatol 1995; 104:518–522. 8. Griffiths CE, Finkel LJ, Tranfaglia MG, et al. An in vivo experimental model for effects of topical retinoic acid in human skin. Br J Dermatol 1993; 129:389–394. 9. Erling T. Skin treatment with two different galenical formulations of retinyl palmitate in humans. J Appl Cosmetol 1993; 11:71–76.10. Creidi P, Humbert P. Clinical use of topical retinaldehyde on photoaged skin. Dermatol 1999; 199S:49–52.11. Diridollou S, Vienne MP, Alibert M, et al. Efficacy of topical 0.05% retinaldehyde in skin aging by ultrasound and rheological techniques. Dermatol 1999; 199S:37–41.12. Creidi P, Vienne MP, Ochonishy S, et al. Profilometric evaluation of photodamage after topical retinaldehyde and retinoic acid treatment. J Am Acad Dermatol 1998; 39:960–965.13. Fluhr JW, Vienne MP, Lauze C, et al. Tolerance profile of retinol, retinaldehyde, and retinoic acid under maximized and long-term clinical conditions. Dermatol 1999; 199S:57–60.14. Matts PJ, Oblong JE, Bissett DL. A review of the range of effects of niacinamide in human skin. Int Fed Soc Cosmet Chem Magn 2002; 5:285–289.15. Bissett DL. Topical niacinamide and barrier enhancement. Cutis 2002; 70S:8–12.16. Bissett DL, Oblong JE, Saud A, et al. Topical niacinamide provides skin aging appearance benefits while enhancing barrier function. J Clin Dermatol 2003; 32S:9–18.17. Hakozaki T, Minwalla L, Zhuang J, et al. The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. Br J Dermatol 2002; 147:22–33.18. Bissett DL, Miyamoto K, Sun P, et al. Topical niacinamide reduces yellowing, wrinkling, red blotchiness, and hyperpigmented spots in aging facial skin. Int J Cosmet Sci 2004; 26:231–238.19. Tanno O, Ota Y, Kitamura N, et al. Nicotinamide increases biosynthesis of ceramides as well as other stratum corneum lipids to improve the epidermal permeability barrier. Brit J Dermatol 2000; 143:525–531.20. Griffiths CEM. Nicotinamide 4% gel for the treatment of inflammatory acne vulgaris. J Dermatol Treat 1995; 6S:8–10.21. Ungerstedt JS, Blomback M, Soderstrom T. Nicotinamide is a potent inhibitor of proinflammatory cytokines. Clin Exp Immunol 2003; 131:48–52.

184 Bissett22. Gebicki J, Sysa-Jedrzejowska A, Adamus J, et al. 1-Methylnicotinamide: a potent anti- inflammatory agent of vitamin origin. Pol J Pharmacol 2003; 55:109–112.23. Wu JT. Advanced glycosylation end products: a new disease marker for diabetes and aging. J Clin Lab Anal 1993; 7:252–255.24. Vlassara H. Recent progress on the biologic and clinical significance of advanced glycosylation end products. J Lab Clin Med 1994; 124:19–30.25. Wolff SP, Jiang ZY, Hunt JV. Protein glycation and oxidative stress in diabetes mellitus and aging. Free Radic Biol Med 1991; 10:339–352.26. Dyer DG, Dunn JA, Thorpe SR, et al. Accumulation of maillard reaction products in skin collagen in diabetes and aging. J Clin Invest 1993; 91:2463–2469.27. Odetti P, Pronzato MA, Noberasco G, et al. Relationships between glycation and oxidation related fluorescence in rat collagen during aging. Lab Invest 1994; 70:61–67.28. Reber F, Geffarth R, Kasper M, et al. Graded sensitiveness of the various retinal neuron populations on the glyoxal-mediated formation of advanced glycation end products and ways of protection. Graefes Arch Clin Exp Ophthalmol 2003; 241:213–225.29. Thornalley PJ. Glycation in diabetic reuropathy: characteristics, consequences, causes, and therapeutic options. Int Rev Neurobiol 2002; 50:37–57.30. Andersson RG, Aberg G, Brattsand R, et al. Studies on the mechanism of flush induced by nicotinic acid. Acta Pharmacol Toxicol 1977; 41:1–10.31. Jacobson MK, Kim H, Kim M, et al. Modulating NAD-dependent DNA repair and transcription regulated pathways of skin homeostatis: evaluation in human subjects. New Orleans, LA: Poster, 60th Annual Meeting of the American Academy of Dermatology, Feb 2002:22–27.32. Alster TS, West TB. Effect of topical vitamin C on postoperative carbon dioxide laser resurfacing erythema. Dermatol Surg 1998; 24:331–334.33. Tajima S, Pinnell SR. Ascorbic acid preferentially enhances type I and III collagen gene transcription in human skin fibroblasts. J Dermatol Sci 1996; 11:250–253.34. Phillips CL, Combs SB, Pinnell SR. Effects of ascorbic acid on proliferation and collagen synthesis in relation to the donor age of human dermal fibroblasts. J Invest Dermatol 1994; 103:228–232.35. Geesin JC, Darr D, Kaufman R, et al. Ascorbic acid specifically increases type I and type III pro-collagen messenger RNA levels in human skin fibroblasts. J Invest Dermatol 1988; 90:420–424.36. Pinnell SR. Regulation of collagen biosynthesis by ascorbic acid: a review. Yale J Biol Med 1985; 58:553–559.37. Raschke T, Koop U, Dusing HJ, et al. Topical activity of ascorbic acid: from in vitro optimization to in vivo efficacy. Skin Pharmacol Physiol 2004; 17:200–206.38. Fitzpatrick RE, Rostan EF. Double-blind, half-face study comparing topical vitamin C and vehicle for rejuvenation of photodamage. Dermatol Surg 2002; 28:231–236.39. Humbert PG, Haftek M, Creidi P, et al. Topical ascorbic acid on photoaged skin: clinical, topographical and ultrastructural evaluation: double-blind study vs. placebo. Exp Dermatol 2003; 12:237–244.40. Traikovich SS. Use of topical ascorbic acid and its effects on photodamaged skin topography. Arch Otolaryngol Head Neck Surg 1999; 125:1091–1098.41. Katayama K, Armendariz-Borunda J, Raghow R, et al. A pentapeptide from type procollagen promotes extracellular matrix production. J Biol Chem 1993; 268:9941–9944.42. Foldvari M, Attah-Poku S, Hu J, et al. Palmitoyl derivatives of interferon alpha: potent for cutaneous delivery. J Pharm Sci 1998; 87:1203–1208.43. Robinson L, Fitzgerald N, Berge C, et al. Pentapeptide offers improvement in human photoaged facial skin. Ann Dermatol Venereol 2002; 129:1S405.44. Lintner K, Mas-Chamberlin C, Mondon P. Pentapeptide facilitates matrix regeneration of photoaged skin. Ann Dermatol Venereol 2002; 129:1S401.45. Lintner K. Promoting ECM production without compromising barrier. Ann Dermatol Venereol 2002; 129:1S105.46. Pickart L. Copperceuticals and the skin. Cosmet Toilet 2003; 118:24–28.

Anti-aging Skin Care Formulations 18547. Smith-Mungo LL, Kagan HM. Lysyl oxidase: properties, regulation and multiple functions in biology. Matrix Biol 1998; 16:387–398.48. Canapp SO, Farese JP, Schultz GS, et al. The effect of topical tripeptide-copper complex on healing of ischemic open wounds. Vet Surg 2003; 32:515–523.49. Simeon A, Wegrowski Y, Bontemps Y, et al. Expression of glycosaminoglycans and small proteoglycans in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L- lysine-Cu2C. J Invest Dermatol 2000; 115:962–968.50. Simeon A, Emonard H, Hornebeck W, et al. The tripeptide-copper complex glycyl-L-histidyl- L-lysine-Cu2C stimulates matrix metalloproteinase-2 expression by fibroblast cultures. Life Sci 2000; 67:2257–2265.51. Simeon A, Monier F, Emonard H, et al. Expression and activation of matrix metalloproteinases in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2C. J Invest Dermatol 1999; 112:957–964.52. Buffoni F, Pino R, Dal Pozzo A. Effect of tripeptide-copper complexes on the process of skin wound healing and on cultured fibroblasts. Arch Int Pharmacodyn Ther 1995; 330:345–360.53. Blanes-Mira C, Clemente J, Jodas G, et al. A synthetic hexapeptide (Argireline) with antiwrinkle activity. Queensland, Australia: Presentation, 37th Annual Conference of the Australian Society of Cosmetic Chemists, 2003 March:13–16.54. Mas-Chamberlin C, Lintner K, Basset L, et al. Relevance of antiwrinkle treatment of a peptide: 4 months clinical double blind study vs excipient. Ann Dermatol Venereol 2002; 129:1S456.55. Kruger N, Fiegert L, Becker D, et al. For the treatment of skin aging: trace elements in form of a complex of copper tripeptide. Cosmet Med 2003; 24:31–33.56. Appa Y, Stephens T, Barkovic S, et al. A clinical evaluation of a copper-peptide-containing liquid foundation and cream concealer designed for improving skin condition. New Orleans, LA: Poster #66, 60th Annual Meeting of the American Academy of Dermatology 2002:22–27.57. Leyden JJ, Grove G, Barkovic S, et al. The Effect of Tripeptide to Copper Ratio in Two Copper Peptide Creams On Photoaged Facial Skin. New Orleans, LA: Poster #67, 60th Annual Meeting of the American Academy of Dermatology, 2002 Feb.:22–27.58. Leyden JJ, Stephens T, Finkey MB, et al. Skin care benefits of copper peptide containing facial cream. New Orleans, LA: Poster #68, 60th Annual Meeting of the American Academy of Dermatology, 2002 Feb:22–27.59. Leyden JJ, Stephens T, Finkey MB, et al. Skin Care Benefits Of Copper Peptide Containing Eye Creams. New Orleans, LA: Poster #69, 60th Annual Meeting of the American Academy of Dermatology 2002 Feb.:22–27.60. Cole CA, Bertin C. Dimethylaminoethanol: a new skin-care ingredient for aging skin. In: Baran R, Maibach HI, eds. Textbook of Cosmetic Dermatology. 3rd ed. Abingdon, Oxon, U.K.: Taylor & Francis, 2005:95–101.61. Nagy I, Floyd RA. Electron spin resonance spectroscopic demonstration of the hydroxyl free radical scavenger properties of dimethylaminoethanol in spin trapping experiments confirming the molecular basis for the biological effects of centrophenoxine. Arch Gerontol Geriatr 1984; 3:297–310.62. Nagy I, Nagy K. On the role of corss-linking of cellular proteins in aging. Mech Ageing Dev 1980; 14:245–251.63. Uhoda I, Faska N, Robert C, et al. Split-face study on the cutaneous tensile effect of 2-dimethylaminoethanol (deanol) gel. Skin Res Technol 2002; 8:164–167.64. Levy SB. In: Baran R, Maibach HI, eds. Textbook of Cosmetic Dermatology. 3rd ed. Abingdon, Oxon, U.K.: Taylor & Francis, 2005:129–132.65. Lu L, Ying K, Wei SM, et al. Asiaticoside induction for cell-cycle progression, proliferation and collagen synthesis in human dermal fibroblasts. Int J Dermatol 2004; 43:801–807.66. Yarosh DB, Both D, Brown D. Liposomal ursolic acid (Merotaine) increases ceramides and collagen in human skin. Horm Res 2000; 54:318–321.

186 Bissett67. Martelli L, Berardesca E, Martelli M. Topical formulation of a new plant extract complex with refirming properties: clinical and non-invasive evaluation in a double-blind trial. Int J Cosmet Sci 2000; 22:201–206.68. Passi S, De Pita O, Grandinetti M, et al. The combined use of oral and topical lipophilic antioxidants increases their levels both in sebum and stratum corneum. Biofactors 2003; 18:289–297.69. Stab F, Wolber R, Blatt T, et al. Topically applied antioxidants in skin protection. Methods Enzymol 2000; 319:465–478.

12The Role of Cosmeceuticalsin DermatologyDavid H. McDanielThe Institute of Anti-Aging Research, Virginia Beach, Virginia, U.S.A.Joseph DiNardo and Joseph LewisPharma Cosmetix Research, LLC, Richmond, Virginia, U.S.A.WHAT ARE “COSMECEUTICALS”—COSMETICS VS. RX DRUGSHistory and BackgroundThe term “cosmeceuticals” was first popularized about twenty-five years ago by AlbertKligman, MD, PhD, to bridge the gap between cosmetics and drugs or pharmaceuticals.Historically, after the Food, Drug, and Cosmetic Act of 1938, the world of topical skin careproducts was divided into two groups: cosmetics and drugs. Drugs were for the treatment orprevention of diseases, and it was required that safety and efficacy be established beforesales and marketing could proceed. In contrast, cosmetics were viewed as agents to enhancethe beauty of the skin or improve the appearance of the skin, and safety and efficacy were notrequired to be demonstrated before sales and marketing of these products (1). Another organization, the Cosmetic, Toiletry, and Fragrance Association (CFTA), inthe United States was formed in 1894 and today serves as a valuable liaison amongsuppliers, manufacturers, and distributors of cosmetic products for the personal careindustry. No formal organization exists at this time specifically for the cosmeceutical realm. At a fundamental level cosmetics are products which affect the appearance of theskin, while drugs affect the structure and function of the skin. Thus the term“cosmeceutical” is intended to describe skin care products that fall in between thesecategories. Increasingly though products which are considered cosmeceuticals actually doaffect the structure or function of the skin and thus have drug-like effects but are marketedusing appearance-based claims. This has given rise to much confusion and ironically mayprovide some disincentive for manufacturers to conduct or publicize clinical testing sincethe data generated may support the drug-like effects. For example, a drug may be marketedas a product that “reduces wrinkles by stimulating collagen production,” but a cosmeticwhich could potentially have essentially the same mechanism of action and clinical effectswould be marketed as a product that “reduces the appearance of wrinkles.” While some 187

188 McDaniel et al.cosmeceuticals are “drugs in disguise” as cosmetics, if marketing claims push the edge ofthe claims envelope too hard, then the Food and Drug Administration (FDA) mayintervene with various warnings or actions; thus, the issue of “when” does a cosmeceuticalbecome a drug is likely to become more significant in the future (2,3). If one looks at sunscreens and antiperspirants, these are regulated as over-the-counter (OTC) drugs in the United States but not in Europe. One need only look at thedelays in availability in the United States of some of the new and highly effectivesunscreens to appreciate some of the archaic aspects of the 1938 legislation. Thus the term“cosmeceutical” encompasses a broad range of the ill-defined territory which lies betweencosmetics and drugs. It is a very useful concept scientifically and has been accordinglyembraced on a broad global scale. The years ahead will see a struggle to define and refinethis cosmeceutical concept. Some exemplary efforts towards this have been made in Japan,but a global uniform concept is yet to emerge (4).The Skin’s Response to Environmental Damageand Chronologic AgingThe skin is the body’s first line of defense for environmental exposure. Much of the“premature” aging (in contrast to intrinsic or chronologic aging) occurs as a direct orindirect result of the skin’s interaction with its environment. While photoaging is properlyrecognized as one of the principal causes of aging in lighter skin types, many other factorsare also significant. For example, tobacco smoke produces a host of problems and in somedarker skinned ethnic populations may be the primary cause of wrinkles rather thanultraviolet (UV) light. Ozone, air pollution, industrial, occupational, or recreationalexposures bring contact with a diverse array of potential toxins. Personal skin care habitsand excessive or improper use of products can also cause problems. Disease and drugs andtherapies for diseases may produce many challenges to the skin as well. Traditionally the sun protection factor (SPF) has been the primary focus ofprotection from the environment for UV light. Various moisturizer products have somefunction for barrier protection (5–7). However, there is a growing realization that theissues are more complex than this. As a result, discussion is growing about SPF to includea broader range of UV exposure including UVA-1 wavelengths. You will be reading moreabout immune protection factor (IPF) and also environmental protection factor (EPF) inthe years ahead as our understanding of the full spectrum of environmental insults to theskin is explored. The common pathways of much of the environmental damage to the skin aretwofold: free radical generation and DNA damage. The concept of repetitive small“injuries” to the skin resulting in cumulative long term chronic alteration of the optimalstructure and function of the skin resulting in “scars” is a good one. In this scenariowrinkles might be considered “solar scars” . or “tobacco scars” . or “environmentalinjury scars.” The latter is more comprehensive, but the former are useful teaching toolsfor educating our patients. The growing evidence that environmental damage reduces theefficiency of mitochondrial ATP production provides a unique area of future research. Theability to “re-energize” skin cells as one ages using cosmeceuticals is another very excitingarea for the future (8,9). If one considers environmental damage then the first goal of therapy is avoidance .followed by protection . then minimizing or neutralizing free radical damage . andfinally repair or restorative treatments. As clinicians we try to focus on all of these factorsand develop practical, useful, and affordable treatment plans that adapt to our patient’s

Role of Cosmeceuticals in Dermatology 189lifestyle so that compliance is maximized. One of the great challenges with the proliferationof cosmeceuticals is finding good scientific and clinical data like we are accustomed tohaving for our pharmaceutical drug therapies. Such information is often absent or studies arepoorly designed and physicians are often left sorting through marketing claims instead ofscientific data. This scenario has led to the increasingly popular practice of dispensingcosmeceuticals within the physician’s office. This provides the physician with the abilityto control and select products that are scientifically based, but it also opens the door formisuse of the privilege and trust that our patients place in us. The American Academy ofDermatology has a formal policy and guidelines for this practice which is useful to review(Fig. 1) (10). Properly used, office dispensing can be a very valuable tool for the optimal use ofcosmeceuticals (11). Dispensing “private label” products to “control” patient purchasehabits or using products which have no scientific or clinical basis established is a goodexample of practices which do not enhance the physician’s professional stature nor benefitthe consumer. Since nearly half of dermatologists currently dispense products, the need forbetter educational resources for physicians is growing and the availability of textbookssuch as this are one part of the effort to put cosmeceutical skin care on a solid scientific andacademic basis. The sales growth of cosmeceuticals is dramatically increasing relative to skin careproducts in general with special interest for the anti-aging category of products. This trendis likely to continue. The consumers have a need for reliable information, not justmarketing claims. Physicians are the traditional source of such information; however,many are poorly informed and their patients are increasingly seeking this expertise andadvice elsewhere at non-traditional and often non-medical sources. With the proliferationof products and marketing claims that are ahead of or unsupported by clinical data, it istruly an information wilderness for many products.RX vs. Cosmetics—the Response of the Skin’s Structureand Function to CosmeceuticalsThe skin plays many roles ranging from barrier function to highly complex biochemicaland photobiochemical processes. If we follow the definition above then cosmeceuticalsare inherently not simply cosmetics to beautify the appearance of the skin. American Academy of Dermatology Office Dispensing Guidelines for Prescription and Non-prescription Products * DO NOT place your own financial interests above the well-being of patients * DO NOT price products at an excessive mark-up * DO NOT create an atmosphere of coercive selling * DO NOT sell products whose claims of benefit lack validity * DO NOT represent products as \"special formulations\" not available elsewhere if this is not the case * DO clearly list all ingredients, including generic names of drugs * DO advise patients of alternative purchase options if products are available elsewhere * DO provide prescription refills that can be filled outside the office if patients so chooseFigure 1 American Academy of Dermatology Office Dispensing Guidelines for Prescription andNon-prescription Products. Source: American Academy of Dermatology, 2003.

190 McDaniel et al.Cosmeceuticals then affect either the structure or the function (or both) of the skin.Unlike drugs, cosmeceuticals typically are very safe and have few significant seriousadverse events. However, like drugs, these active agents can impact many diversefunctions of the skin and we do not fully comprehend the implications of these actions inmany cases. For example, take botanical-based actives in cosmeceuticals. These plant-derivedsubstances have the potential for contact dermatitis like reactions similar to poison ivydermatitis. Irritant reactions are also possible as are phytophotodermatoses. Typicallyproducts are selected which do not pose these concerns and also the concentrations used inthe formulations are below the threshold of reaction (12). There are also issues of bioequivalency. Most physicians recall the use of digitalis inpast for cardiac treatments—before standardized digoxin became available. An examplewith cosmeceuticals is that the polyphenol content of a particular botanical may vary frombrand to brand; even though the percentage concentration of that active seems equalamong brands, the difference in polyphenol content may make one product less efficaciousthan the other brand, which has a higher content of polyphenols (13). Another example of an issue is with one of the very popular alpha-hydroxy acid(AHA) actives, glycolic acid, where the pH and pKa values impact the clinical effects andside effects. For these products, simply comparing the percentage of glycolic acid did notprovide the physician, esthetician, or consumer with an accurate assessment of the effectson the skin. In fact, a lower percent glycolic acid product could potentially be moreirritating than a higher percentage glycolic acid product depending on the pH (14,15). An issue infrequently discussed is that of pesticide residues or other contaminantsfor botanicals. So bioequivalency and bioavailability and purity are all issues for thesetypes of active ingredients. Also, while we are thinking in the “drug” pattern, the “dose” isimportant. So the percentage of actual active ingredient also determines to some extent theeffects of cosmeceuticals compared to Rx drugs. Also, physician-dispensed products oftenhave a higher “dose” or concentration of actives than the OTC products. Other factors are synergistic reactions and stability. Many cosmeceuticalformulations have complex mixtures of actives the interactions of which are not allwell defined. Some antioxidants are not that stable and others may be unstable after theyare opened. Novel new “airless” pump delivery systems or mixing as pumped onto skinfrom applicator provide ways to combat these problems. Data on the relative potency is often lacking on active ingredients within the samecategory. Antioxidants are a good example, and this data has only recently begun to bepublished. Much of the data about the drug-like effects on the skin’s structure and functionare considered proprietary and not available for physicians or the consumer to review.Additionally many products are sold widely with minimal scientific or clinical datawhatsoever. Thus, while cosmeceuticals increasingly affect the skin’s structure andfunction like drugs, the data that is traditionally available for drug evaluation is oftenincomplete or nonexistent. The great safety of most cosmeceutical actives is one of themitigating factors in this scenario. We will see antioxidants grow dramatically in their rolewith the cosmeceutical armamentarium to protect and also in some cases repair environ-mental damage and aging in general. In summary, cosmeceuticals may have profound effects on the structure and/orfunction of the skin—or they may have little or no effect and behave like cosmetics. Acomprehensive discussion of this is beyond the scope of this section, but the use ofcosmeceuticals to improve the appearance and health of the skin is a fascinating areaof science and one which we will see explored and mapped in the years ahead.

Role of Cosmeceuticals in Dermatology 191DOMESTIC AND INTERNATIONAL REGULATORY GUIDELINESIMPACTING COSMETICSDomestic RegulationsThere have been many misunderstandings relating to the regulation of cosmetic productsand OTC drugs in the United States. For the most part, the cosmetic industry has neverbeen directly regulated by any government agency and does not require the FDA toapprove a cosmetic/cosmeceutical product prior to marketing. Additionally, in 1972 theFDA initiated a monograph process for OTC drugs which eliminated the need to have pre-market approval for certain product categories (sunscreens, antiperspirants, anti-acne, etc.)by companies prior to being sold to consumers. The process of regulation for cosmeticsand OTC drugs would appear to be better described as “self-regulated” and, therefore,impacted by various guidelines, legislation, and regulatory bodies as opposed to governedby these entities. Outlined below is a brief review of the laws that are currently in place. Amore detailed review can be obtained through other references and/or review of thevarious regulatory agency Web sites (FDA.gov, FTC.gov, EPA.gov, etc.) (16). The most important regulations to note are the Food, Drug, and Cosmetic Act of 1938and the 1960 amendment, the Fair Packaging and Trade Act of 1966 and 1973, the OTCDrug Monograph Process introduced in 1972, and the 1916 Federal Trade Commission Act.With the exception of the latter, which is governed by the FTC, the others are theresponsibility of the FDA. Additionally, there have been laws brought about by individualmembers of the government (Delaney Amendment in 1958—anti-cancer act) as well as byindividual state legislatures (California, New York, New Jersey, and Massachusetts, toname a few) which relate to areas such as the Volatile Organic Compounds (VOCs) and theSafe Drinking Water and Toxic Enforcement Act (Proposition 65). Lastly, it should be notedthat cosmetic manufacturers are allowed to use any ingredient in a product, as long as theproduct has been tested and shown to be safe for its intended use, with the exception ofhexachlorophene, mercury compounds, chlorofluorocarbon propellants, bithionol, haloge-nated salicylanilides, chloroform, vinyl chloride (aerosol products), zirconium (aerosolproducts), methylene chloride, acetylethyltetramethyltetralin, musk ambrette, 6-methyl-coumarin, nitrosamines, dioxane, and estrogen.International RegulationsNumerous countries all around the world have recently instituted some form of cosmeticregulation, other than product registration with their ministries of health, with respect toprotecting the consumers of their respective countries. The amount of information ismassive and to simply list current activities would go far beyond the scope of this chapter.However, it should be noted that Australia (http://www.nicnas.gov.au/) as well as Canada(http://www.hc-sc.gc.ca/english/media/releases/2004/cosmetic_labelling.htm) have takenvery proactive approaches to cosmetic regulation, and the Web sites noted above can beaccessed for additional information if so desired. The European Union (EU) has probablybeen the most proactive globally in attempting to regulate cosmetics. New provisions madein the seventh amendment to the EU cosmetic directives are outlined below identifyingsome of the significant changes in how cosmetic manufacturers will need to do business inthe EU as well as what information will need to be provided to consumers in order for theproduct to be sold in the various EU countries. These regulations are all in effect as of March11, 2005.

192 McDaniel et al. † A product information dossier on qualitative and quantitative composition of the product and existing data on undesirable effects must be made “easily accessible to the public by means including electronic means.” Companies can list themselves and this information in the European Cosmetic Toiletry and Perfumery Association (COLIPA) database (www.European-Cosmetics.info). Additionally, the dossier must include information on any animal testing relating to development or safety evaluation of a product or ingredient. † A Quantitative Declaration of Ingredients containing any ingredient(s) listed in the Dangerous Substances Directive (67/548/EEC) must list the concentration or concentration range of the substance(s) in question. † Information on Undesirable Effects on Human Health Resulting from Use of the Cosmetic Product. Undesirable effects are, essentially, irritant or allergic reactions that can in rare cases affect skin or eyes. It is also recommended that companies present the number of undesirable effects in context of the number of units placed in the marketplace (i.e., to date there have been zero undesirable effects per one million units placed in the EU market). † A ban on animal testing went into effect immediately for finished products and for ingredients. † Need exclusive exposure assessments for products intended for children under 3 years of age and for intimate hygiene products. † Color additives for the entire range of decorative cosmetics may be listed at the end of the ingredient list after the term “may contain” or the symbol “C/K.” † Any ingredient identified as carcinogenic, mutagenic, and/or a reproductive hazard (CMR) Category 1 and 2 must not be intentionally added to cosmetic products. Any ingredient identified as CMR Category 3 must not be intentionally added unless evaluated by SCCNFP and found acceptable for use in cosmetic products. † Products that have a durability (shelf life) over thirty months must have the a “Period After Opening” (PAO) symbolized by an open jar with the number of months which indicates how long after a product is opened it can be used without harm to the consumer (see example below under “How to Select the ‘Best’ Formulation of a Cosmeceutical.” † Problem fragrance ingredients (26 fragrances ingredients with a history for contact dermatitis) need to be labeled by INCI name in the ingredient label if they are used in the formula at 0.001% in leave-on and 0.01% in rinse-off products.CATEGORIES OF CURRENTLY POPULAR COSMECEUTICALSIN DERMATOLOGYAmino Filaggrin Acids—Filaggrin Protein/Fruit Acids 1. Science and clinical studies: Although no peer review articles were found, studies outlined by the manufacturer of the product claim that the product has been tested over the last three years and is effective in reducing the appearance of visible lines and improving tone and texture of the skin. 2. Key benefits: Amino Filaggrin Acids (AFAs) are amino acids that are naturally found in skin and are associated with increasing moisture retention in skin. They claim to be able to penetrate through the keratinized epidermis.

Role of Cosmeceuticals in Dermatology 1933. Primary adverse effects: None found. Considered to be milder than AHA or BHA preparations.4. Practical applications in dermatology: AFA in-office peels may be used on an alternating basis with AHA peels, or may be helpful in patients having problems with long term use of various peeling agents. Can be used with microdermabrasion or other minimally invasive procedures.Vitamins: C and E 1. Science and clinical studies: Numerous studies have been published on both of these ingredients relating to antioxidant function and protection against UV damage. Additionally, vitamin C has been shown to enhance collagen and elastin production. Both ingredients are essential in a formula if any antioxidant and/or anti-aging claims are to be made. The two ingredients work together to a redox manner to neutralize free radicals by converting to both a pro-oxidative and natural state. 2. Key benefits: Vitamin E is an effective antioxidant which can act synergistically with vitamin C to help fight against free radical damage associated with premature aging. 3. Primary adverse effects: Although uncommon, some contact dermatitis reactions have been reported to vitamin E over the years as well as irritant reactions caused by vitamin C due to some products low pH. 4. Practical applications in dermatology: Used alone or in combination these antioxidants have a variety of applications for anti-aging.Vitamins: K 1. Science and clinical studies: Two studies have been published whereby vitamin K has been used to minimize purpura production after pulse dye laser treatments (17). Both studies employed approximately 20 subjects, with one evaluating the effects of the ingredient alone and the other with the use of retinol BID weeks before and two weeks after laser treatment. The side of the face treated with topical vitamin K with or without retinol demonstrated significantly lower scores of bruising severity when compared with the side treated with placebo (18). 2. Key benefits: Reduces bruising and can minimize damage associated with pulse dye lasers. 3. Primary adverse effects: None noted. 4. Practical applications in dermatology: Using vitamin K, two weeks before and after pulse dye laser treatments may reduce adverse cutaneous reactions. Efficacy for bruising from other etiologies is unknown.Vitamins: B3 (Niacinamide) 1. Science and clinical studies: Niacinamide was evaluated clinically in Japanese women for the inhibition of pigmentation. Eighteen subjects with hyperpig- mentation received either a 5% Niacinamide containing product or a placebo. Additionally, 120 subjects with facial tanning were given either a 2%

194 McDaniel et al. Niacinamide cream containing a sunscreen, a sunscreen, or a vehicle. Changes in facial pigmentation were evaluated via computer analysis and visual grading of high-resolution digital images of the face. Niacinamide significantly decreased hyperpigmentation and increased skin lightness compared to vehicle alone after four weeks of use. Other studies have been reported whereby topical Niacinamide application demonstrates improvement of barrier function via decreased transepidermal water loss (TEWL) and skin appeared to be more resistant to irritation produced by topical irritants such as detergents (19,20). 2. Key benefits: Decreases hyperpigmentation and may improve barrier function and resiliency to environmental insults. 3. Primary adverse effects: Well tolerated. 4. Practical applications in dermatology: Niacinamide may be a suitable replacement for treating hyperpigmentation when results are not obtainable with hydroquinone and/or other conventional forms of treatment.Vitamins: B5 (Panthenol) 1. Science and clinical studies: Topical application of Pantothenic Acid has been shown to provide moisturizer-like benefits, improving stratum corneum hydration, reducing transepidermal water loss, and maintaining skin softness and elasticity. Activation of fibroblast proliferation, which is of relevance in wound healing, has been observed both in vitro and in vivo, and accelerated re- epithelization in wound healing has been demonstrated via transepidermal water loss. Pantothenic Acid has also been shown to have an anti-inflammatory effect reducing UV-induced erythema. In double-blind, placebo-controlled clinical trials, a Pantothenic Acid-containing cream resulted in significantly less damage to the stratum corneum barrier, compared with no pretreatment over three to four weeks. 2. Key benefits: Moisturizer-like benefits, reduction in TEWL, fibroblast activation, and anti-inflammatory potential. 3. Primary adverse effects: Topical administration of Pantothenic Acid prep- arations are generally well tolerated, with minimal risk of skin irritancy or sensitization. 4. Practical applications in dermatology: Pantothenic Acid may be beneficial in patients who have undergone skin transplantation or scar treatment, or therapy for burn injuries and different dermatoses.Enzymes: SOD 1. Science and clinical studies: Superoxide Dismutase (SOD) is the most effective internal antioxidant found in humans. Superoxide radials are reduced to hydrogen peroxides by SOD and then further reduced by catalase to water. Data from the literature indicate a protective effect of SOD in topical application against UV-induced cutaneous damage (21). When an SOD cream containing 0.6 mg/ml of bovine SOD was applied locally onto the skin and mucosal lesions caused by progressive systemic sclerosis, systemic lupus erythematosus, Behcet’s disease, herpes simplex, and burns, the lesions and symptoms were rapidly improved in many cases after its administration, even when the

Role of Cosmeceuticals in Dermatology 195 symptoms were stabilized for several weeks before the treatment (22). SOD was concluded to be effective for these conditions. In another study, topical application of free Mn-SOD or Cu, Zn-SOD showed complete healing in a burn patient who was advised to undergo skin transplantation (23). However, the later study noted that SOD dissolved in a white petrolatum vehicle rapidly lost its activity (within three months) and commented that SOD should be dissolved in the vehicle before use (24–26).2. Key benefits: Suppression of UV-induced cutaneous damage and possible reversal of free radical-mediated disease states.3. Primary adverse effects: None known.4. Practical applications in dermatology: May be effective in treating progressive systemic sclerosis, systemic lupus erythematosus, Behcet’s disease, herpes simplex, and burns.Growth Factors: EGF/TGF 1. Science and clinical studies: No peer review clinical data was found on the effects associated with epidermal growth factor (EGF/TGF). However, several in vitro studies are obtainable. A bioassay for EGF reported by Carpenter and Zendegui was described as rapid, specific, and extremely sensitive (27). The bioassay detects as little as 25 pg of EGF and was considered more sensitive than commonly used radioreceptor assays and nearly as sensitive as radioimmuno assays. The bioassay involved measurement of the proliferation of cultures of an EGF-requiring cell line and can be carried out in a quantitative manner over a 40-fold range of EGF concentrations. One in vivo study in rabbits evaluated wound healing with a placebo ointment and one containing EGF (28). Less wound contracture occurred in the EGF-treated wounds, and wound maturation occurred earlier. The healed wounds that had been treated with EGF more closely resembled the surrounding normal tissue, producing less local deformity than in the controls. A study evaluating the epidemiological and experimental evidence that dietary poly- phenolic plant-derived compounds have anticancer activity is also note worthy (29). The investigators found that green tea components induce apoptosis via a TGF-beta superfamily protein, non-steroidal anti-inflammatory drug activated gene (NAG-1) and showed that ECG is the strongest NAG-1 inducer among the tested catechins and that treatment of HCT-116 cells results in an increasing G(1) sub-population, and cleavage of poly (ADP-ribose) polymerase (PARP), consistent with apoptosis. The data generated by this study elucidate mechanisms of action for components in green tea and was hopeful in leading to the design of more effective anticancer agents and informed clinical trials (30). 2. Key benefits: May facilitate wound healing. 3. Primary adverse effects: None reported. 4. Practical applications in dermatology: May accelerate normal wound healing in patients under going evasive cosmetic procedures.Growth Factors: Kinetin (Plant Growth Factor) 1. Science and clinical studies: Kinetin is a plant-derived nucleotide (growth factor) known to delay senescence (aging) in plants. Two one-year long clinical

196 McDaniel et al. studies have been completed on Kinetin. Study results report that Kinetin can reverse the signs of photodamaged skin and improve the overall appearance of the skin, making it smoother and more even in color and visibly diminishing the appearance of fine lines and wrinkles. These studies also demonstrated that Kinetin can significantly improve the skin barrier function and help the skin to retain more moisture, making the skin softer and smoother. Additionally, Kinetin is also thought to process some antioxidant capabilities; however, this activity is not considered to be the mechanism of action for the reversal of photoaging observed in the clinical studies noted. 2. Key benefits: It demonstrates antioxidant and barrier function benefits. 3. Primary adverse effects: None reported. 4. Practical applications in dermatology: May be useful in treating photodamaged skin.Antioxidants: Alpha-Lipoic Acid 1. Science and clinical studies: Topical application of 3% Alpha-Lipoic Acid has been shown to decrease UVB-induced erythema. These observations are thought to reflect the ingredient’s ability to function as an antioxidant blocking the transcription factor of nuclear factor-kappa B (NF-kappa B) (31). Clinical testing in 33 women with photodamage indicated that 12 weeks of treatment with a cream containing 5% Lipoic Acid improved clinical characteristics related to photoaging of facial skin (32). 2. Key benefits: Antioxidant functions, inhibition of NF-kappa B and secondary oxidative products. 3. Primary adverse effects: None known. 4. Practical applications in dermatology: May be useful in treating photodamaged skin.Antioxidants: Co-Q10 (Ubiquinone) 1. Science and clinical studies: Co-Q10 plays a vital role in mitochondrial enzymes of the oxidative phosphorylation pathway and is essential for the production of the high-energy phosphate, adenosine triphosphate (ATP), upon which all cellular functions depend. Numerous in vitro studies have been reported demonstrating the antioxidant efficacy of Co-Q10. However, limited clinical studies are available reporting on the benefits of topical administration. One study was found which noted that Co-Q10 penetrates into the viable layers of the epidermis and reduces the level of oxidation measured by weak photon emission and a reduction in wrinkle depth was also shown (33). Co-Q10 also protected against UVA-mediated oxidative stress in human keratinocytes in terms of thiol depletion, activation of specific phosphotyrosine kinases, and prevention of oxidative DNA damage. 2. Key benefits: Antioxidant functions which mediate UVA oxidative stress in human keratinocytes minimizing DNA damage. 3. Primary adverse effects: None known. 4. Practical applications in dermatology: May be useful in treating photodamaged skin.

Role of Cosmeceuticals in Dermatology 197Antioxidants: Idebenone (Hydroxydecyl Ubiquinone)1. Science and clinical studies: Idebenone is a synthetic version of Co-Q10 with a molecular weight approximately 60% smaller. A multi-step in vitro process utilizing a variety of biochemical and cell-biological methods combined with in vivo studies was designed to compare the oxidative stress protective capacity of commonly used antioxidants. Summarizing and totaling the data equally weighted for each oxidative stress study, the overall oxidative protection capacity score of 95, 80, 68, 55, 52, and 41 was obtained for idebenone, DL-a- tocopherol, kinetin, ubiquinone, L-ascorbic acid, and DL-a-lipoic acid, respectively. The higher the score the better the overall oxidative stress protection capacity of the antioxidant. This multi-step protocol was thought to serve as a standard when investigating and comparing new putative antioxidants for topical use (34). In a non-vehicle control study, 0.5%, and 1.0% idebenone commercial formulations were evaluated in a clinical trial. Forty-one female subjects, age 30–65, with moderate photodamaged skin completed the study. After six weeks of BID use, the 1.0% idebenone formula produced a 26% reduction in skin roughness/dryness, a 37% increase in skin hydration, a 29% reduction in fine lines/wrinkles, and a 33% improvement in overall global assessment of photodamaged skin. The 0.5% idebenone formulation demon- strated a 23% reduction in skin roughness/dryness, a 37% increase in skin hydration, a 27% reduction in fine lines/wrinkles, and a 30% improvement in overall global assessment of photodamaged skin. Additionally, punch biopsies were taken from random select subjects, baseline at and after six weeks, and stained for certain antibodies Interleukin [(IL)-6, IL-1b, Matrixmetalloprotei- nase (MMP)-1, Collagen I] using immunofluorescence microscopy. The immunofluorescence staining revealed a decrease in IL-1b, IL-6, and MMP-1 and an increase in Collagen I for both concentrations (35).2. Key benefits: Antioxidant protection against multiple free radical pathways, modulation, and regulation of inflammatory markers, and treatment of photodamaged skin.3. Primary adverse effects: None known.4. Practical applications in dermatology: May be useful in treating photodamaged skin.Cell Signaling: Amino Peptides 1. Science and clinical studies: Amino peptides are chemically linked to Palmitic Acid to enhance solubility allowing the peptide to become non-polar to cross lipids bilayers. Palmitoyl Pentapeptide-3, tested in a six-month clinical study, demonstrated improvement in the visual appearance of wrinkles by possibly stimulating fibroblast to rebuild the extra-cellular matrix and induce collagen synthesis. Palmitoyl Tetrapeptide-3 is said to control the secretion of cytokine (IL-6), delaying the effects of premature aging. Recent studies have shown that Palmitoyl Tetrapeptide-3 can make a substantial difference in the appearance of stretch marks. In one study, 93% of subjects showed a marked improvement in the length and depth of stretch marks and wrinkles. In addition, there was a substantial improvement in the skin smoothness and tone. Similarly, Acetyl Hexapeptide-3 is thought to reduce wrinkles by disrupting the nerve signals sent

198 McDaniel et al. to tense muscle beneath the dermis—functionally relaxing them and smoothing the overlying skin. 2. Key benefits: Collagen and glycosaminoglycan stimulation, inhibition of cytokines, disruption of nerve signaling. 3. Primary adverse effects: None known. 4. Practical applications in dermatology: May be useful in treating photodamaged skin.Cell Signaling: Copper Peptides 1. Science and clinical studies: Benefits of copper peptides for tissue regeneration were discovered in the 1970s. Copper peptides have been shown to be effective in healing wounds and skin lesions as well as some gastrointestinal conditions (36). A double-blind, placebo-controlled study demonstrated that topical application of a copper peptide cream accelerated the rate of skin healing and reduced irritation after both irritant and allergic contact dermatitis. Although the primary area of studying copper peptides relates to wound healing, there has been some research implying that the complex has anti-inflammatory and antioxidant functions. 2. Key benefits: Cell signaling, wound healing, may have anti-inflammatory and antioxidant activity. 3. Primary adverse effects: None known, well tolerated. 4. Practical applications in dermatology: Acceleration of wound healing and may serve as an alternative to patients who are cannot tolerate retinoids.Cell Signaling: DHEA 1. Science and clinical studies: DHAE and the sulfated conjugate (DHAE-S) are abundantly produced human adrenal steroids which become minimized with age. These materials relate to skin aging through the regulation of and degradation of extra cellular protein. DHEA has been shown to increase procollagen synthesis and inhibit collagen degradation by inhibiting metallo- proteinase (MMP-1) and increase tissue inhibition of MMP (TIMP-1) in dermal fibroblasts. Inhibition of cellular damage caused by UV exposure is thought to be due to inhibition of AP-1 activity. DHAE was also found to induce growth factor-beta 1 and connective tissue growth factor mRNA in cultured fibroblast. In a four-week study, a 5% DHAE mixture was applied to buttock skin three times a week to volunteers and produced a significant increase in the expression of procollagen alpha 1 mRNA and protein in both young and old skin and significant reduced basal expression of MMP-1 mRNA and protein, but increased TIMP-1 protein in aged skin. 2. Key benefits: Increase collagen synthesis, decrease MMP-1, and increase TIMP-1 to enhance collagen production and minimize collagen breakdown. 3. Primary adverse effects: None known. 4. Practical applications in dermatology: May be useful in treating photodamaged skin.

Role of Cosmeceuticals in Dermatology 199Cell Signaling: DMAE1. Science and clinical studies: DMAE is considered a tertiary amine and a precursor of choline. At concentration of 1% to 5% when applied to facial skin, DMAE have been shown to produce and increase tone in about 20 to 30 minutes. Half-and full-face studies applied over 16 weeks to one year have been shown to produce periorbital tightening as well as tightening in the molar and mandible regions. These results appear to reverse when product application is stopped after eight weeks (36).2. Key benefits: Enhances muscle tonality and can act as a penetration enhancer.3. Primary adverse effects: Low toxicity and no side effects.4. Practical applications in dermatology: Non-surgical treatment to correct loss facial anatomic positions.HOW TO SELECT THE “BEST” FORMULATION OF A COSMECEUTICALStabilityMost companies do not state if a product is stable or how long it will last either opened orunopened, with the exception of OTC products, which are expiration dated if they do notlast more than three years. However, international cosmetic and/or cosmeceuticalcompanies marketing in the EU are required to put an expiration date on products ifthey do not last for at least 30 months. Most recently, the EU has instituted in law thatcompanies must now include an icon of an open jar with the number of months that theproduct is good for after it has been opened (Fig. 2). The latter is the best way for theconsumer and skin care professionals to determine how stable a product may be. Althoughthis regulation has become effective as of March 2005, it will eventually appear ondomestic products manufactured by international marketing companies. With theexception of waiting for this system to come into practice in the U.S., the only otherway to determine the stability of a product not expiration dated would be to call themanufacturer directly and ask. 36M on or near the open jar icon (below) would represent the number of months thata product is stable (in this case, 36 months or three years) after it has been opened.This number and icon must be present on both the product container as well as the box(if applicable) that it is sold in. At this time there is no standard for testing or minimalFigure 2 Example of period after opening (PAO) icon.

200 McDaniel et al.requirements that a product most be stable for in order to be marketed; however, it isexpected that guidelines will follow shortly.EfficacyWith the age of computers and Internet access, the best and easiest way to evaluate theefficacy of a product is to run a simple Internet search using an engine similar to Google(http://www.google.com). More advance searches may be conducted using various data-bases like PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?DBZpubmed). Thelatter will be more specific; however, remember that not all manufacturers publish data inpeer-reviewed scientific journals. Short of running your own database searches, the onlyother way to obtain this information is to call manufacturers directly and request copies ofany data they have on file.Science vs. Science FictionAlthough it would be great to be able to find all the information you want in a straight-forward peer-reviewed journal search, it is highly unlikely. The basic information that isobtained from an on-line database like Google will have a great deal of marketing hypewith little to no science. However, it may not be a bad place to at least start to learn somebasic information prior to contacting a manufacturer for additional information.ValueWith the cost of cosmeceuticals escalating to as much as $500 per ounce, it is extremelydifficult to determine how to advise patients. First and foremost are questions of efficiencyand safety. Is the product effective at all? Is it effective for each of the claims? Is therewell-controlled statistically significant claimed data to substantiate these claims? Howeffective is the product relative to other effective products (OTC or Rx)? What is therelative cost to the patient compared to other available and effective products? Would youpurchase this product using your own money for use on your own family?THE FUTURE OF COSMECEUTICALSOur knowledge of the cellular signaling pathways is growing by leaps and bounds due toadvances in gene microarray analysis and other genomics and proteinomic discoveries.These are being rapidly translated into practical applications for skin care. The ability tounderstand the molecular biology associated with the development and maintenance of theskin’s structure and function is vital to the future of scientifically sound skin care. As we learn more about how the skin interacts with the environment around it andhow it responds to injuries, we will see significant advances in therapies. There are vastnumbers of botanical products available to evaluate which produce many uniquemolecules. Some of these are part of the plant’s defenses against their environment andhave applications for our skin as well. The ability to synthetically manufacture some ofthese complex compounds has expanded greatly in recent years, and the future is bright forour ability to not only copy but also to create new analogs and derivatives of suchcompounds. The impact of free radicals/ROS on the skin and how to neutralize or control this atan early stage as ROS are initially generated will lead to more “preventive/defensive”

Role of Cosmeceuticals in Dermatology 201products and, with proper public education, hopefully a more proactive approach to skincare. This is the true “anti-aging”—much of current therapies are still focused on “agereversal” or repair rather than preventive therapies. The cascade of cellular events anddamage triggered by free radicals and the negative impact of chronic upregulation/activa-tion of degrading enzymes and chronic inflammation in the skin contribute greatly to“premature” aging. The years ahead will see more emphasis on “beauty maintenance” or“skin fitness for life” as products and actives and delivery systems become morescientifically sound. The large pharmaceutical companies may begin to play a more significant role incosmeceutical development as the ability to use cosmeceuticals for drug-like effectsallows them to utilize their resources to develop effective new skin care products withoutsome of the regulatory burdens and costs associated with drugs. The time delay from newdiscoveries to actual products available for consumer use can potentially be dramaticallyreduced by this pathway. Single Nucleotide Polymorphism (SNP) testing via a mouth swab may well play arole in determining long-term skin care plans/needs for people in the near future as thistesting becomes more available. Correlations of testing results with actual clinical needsbased on solid science and clinical studies will be a challenge since this database will needto be developed. However, the ability to look at one’s “variation” from the “normal”population in SNP could provide very useful insights into skin care. Major breakthroughs in photoaging and repair of DNA damage and telomere repairappear to be imminent. Genetic engineering is still a struggling infant but can become agiant in skin care in the future. Hormonal regulation and immune function issues with theskin will be more important in the future. Much of what we were taught was “intrinsicaging” and thus not alterable by medicine and science will soon be able to be manipulatedat some level—only time and some core genetic issues will be immutable. Treatments thatwere unthinkable a few decades ago will become a reality, and cosmeceuticals or theirderivatives may well play a role in this area of medicine. The use of low intensity light tophotomodulate skin cells and/or to activate or interact with topical cosmeceutical agentsmay also enter the market place. Marketing claims will likely continue to push the edge of the envelope. It is unclearif or when (and at what point) the FDA may intervene in this arena, but this too bearswatching closely. The science needed to support the claims is sadly absent in many cases,but there are also some stellar examples of great science and clinical studies forcosmeceuticals and this trend is growing. Hopefully we will see some new standards set inthis industry for science and data that will allow us to discern what benefits are real andwhich products deliver them. However, in the short term it is likely that the currentconfusion in the marketplace will continue or perhaps worsen so education will be the key.Dermatology residency programs need to increase their training related to cosmeceuticalsso that dermatologists are not left behind and maintain their tradition of being the true“skin care experts” and the best resource for consumers who need guidance in planningtheir skin care regimen. Dermatology needs to take a strong leadership position incosmeceutical research and development as well. Hopefully the near future will see more science and less “science fiction” in researchand marketing claims for cosmeceuticals. The issue of hype versus hope versus reality is avery real one for contemporary advertising. The ability to harness the power of naturalproducts and their derivatives for treating skin diseases and for anti-aging purposes isabout to undergo giant leaps forward as genomic research gives us new understanding ofthe structure and function of the skin—and also provides much more accurate ways to

202 McDaniel et al.screen for active compounds and produce optimal formulations. Cosmeceuticals are thewave of the future in science-based skin care.REFERENCES 1. Kligman AM. Cosmeceuticals as a third category. Cosmet Toilet 1998; 113:33. 2. Vermeer BJ, Gilchrest BA. Cosmeceuticals. A proposal for rational definition, evaluation and regulation. Arch Dermatol 1996; 132:337. 3. Millikan LE. Cosmetology, cosmetics, cosmeceuticals: defense and regulations. Clin Dermatol 2001; 19:371–374. 4. Draelos Zoe Diana. Cosmeceuticals. China: Elsevier Saunders, 2005. 5. Forester T. Cosmetic lipids and the skin barrier. New York: Marcel Dekker, 2002. 6. Leyden JJ, Rawlings AV. Skin moisturization. New York: Marcel Dekker, 2002. 7. Loden M, Maibach HI. Dry skin and moisturizers: chemistry and function. Boca Raton, Florida: CRC Press, 2000. 8. Gilchrest, Barbara A. Photodamage. Massachusetts: Blackwell Science Inc, 1995. 9. Leveque Jean-Luc, Agache Pierre G. Aging skin. New York: Marcel Dekker Inc, 1993.10. American Academy of Dermatology 1999 Position Statement of Dispensing. American Academcy of Dermatology: Schaumberg, Illinois September 26, 2999.11. Farris PK. Office dispensing: a responsible approach. Semi Cutan Med Surg 2000; 19:195–200.12. Draelos Zoe Diana. Botanical antioxidants. Cosmet Dermatol 2003; 16:46–48.13. Gilchrest Barbara A. Signaling pathway requirements for induction of senescence by telomere homolog oligonucleotides. Exp Cell Res 2004; 301:189–200.14. Johnson AW, Nole G, Rozen M, DiNardo JC. Skin tolerance of alpha-hydroxy acids, systematic study of lactic and glycolic acids. Cosmet Dermatol 1997; 10:38–45.15. DiNardo JC. Studies show cumulative irritation potential based on pH. Cosmet Dermatol 1996:12–13. May Supplement—New Advances in AHAs and Skin Rejuvenation Techniques.16. DiNardo JC. “Regulations effecting cosmetic and over-the-counter drug products”. In: Gad SC, ed. Regulatory Toxicology. 2nd ed. New York: Taylor and Francis London/New York, 2001:167–191.17. Lou WW, Quintana AT, Geronemus RG, Grossman MC. Effects of topical vitamin K and retinol on laser-induced purpura on nonlesional skin. Dermatol Surg 1999; 25:942–944.18. Shah NS, Lazarus MC, Bugdodel R, et al. The effects of topical vitamin K on bruising after laser treatment. J Am Acad Dermatol 2004; 50:241–244.19. Bissett D. Topical niacinamide and barrier enhancement. Cutis 2003; 70:8–12.20. Hakozaki T, Minwalla L, Zhuang J, et al. The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. Br J Dermatol 2002; 147:202–231.21. Filipe P, Emerit I, Vassy J, et al. Epidermal localization and protective effects of topically applied superoxide dismutase. Exp Dermatol 1997; 6:116–121.22. Mizushima Y, Hoshi K, Yanagawa A, Takano K. Topical application of superoxide dismutase cream. Drugs Exp Clin Res 1991; 17:127–131.23. Niwa Y. Lipid peroxides and superoxide dismutase (SOD) induction in skin inflammatory disease, and treatment with SOD preparations. Dermatological 1989; 179:101–106.24. Biro K, Thaci D, Ochsendorf FR, Kaufmann R, Boehncke WH. Efficacy of dexpanthenol in skin protection against irritation: a double blind, placebo-controlled study. Contact Dermat 2003; 49:80–84.25. Gehring W, Gloor M. Effect of topically applied dexpanthenol on epidermal barrier function and stratum corneum hydration. Results of a human in vivo study. Arzneimittelforschung 2000; 50:659–663.26. Ebner F, Heller A, Rippke F, Tausch I. Topical use of dexpanthenol in skin disorders. Am J Clin Dermatol 2002; 3:427–433.

Role of Cosmeceuticals in Dermatology 20327. Carpenter G, Zendegui J. A biological assay for epidermal growth factor/urogastrone and related polypeptides. Anal Biochem 1986; 153:279–282.28. Franklin JD, Lynch JB. Effects of topical applications of epidermal growth factor on wounds healing. Experimental study on rabbits ears. Plast Reconstr Surg 1979; 64:766–770.29. Baek SJ, Kim JS, Jackson FR, Eling TE, McEntee MF, Lee SH. Epicatechin gallate-induced expression of NAG-1 is associated with growth inhibition and apoptosis in colon cancer cells. Carcinogenesis 2004; 25:2425–2432.30. Todd I, Clothier RH, Huggins ML, et al. Electrical stimulation of transforming growth factor- beta 1 secretion by human dermal fibroblasts and the U937 human monocytic cell line. Altern Lab Anim 2001; 29:693–701.31. Taborda V, Baumann L. What to tell your patients about alpha lipoic acid. Skin Aging 1999; November.32. Beitner H. Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% alpha lipoic acid related to photoaging of facial skin. Br J Dermatol 2003; 149:841–849.33. Hoppe U, Bergemann J, Diembeck W, et al. CoenyzmeQ10, a cutaneous antioxidant and energizer. Biofactors 1999; 9:371–378.34. McDaniel DH, Neudecker BA, DiNardo JC, Lewis JA, II, Maibach HI. Idebenone: a new antioxidant- Part I relative assessment of oxidative stress protection capacity compared to commonly known antioxidants. J Cosmet Dermatol 2005; 4:10–17.35. McDaniel DH, Neudecker BA, DiNardo JC, Lewis JA, Maibach HI. Clinical efficacy assessment in photodamaged skin of 0.5% and 1.0% idebenone. Journal of Cosmetic Dermatology 2005; 4:167–173.36. Perricone N. The latest anti-aging therapies. Skin Aging 2001; December.

13Skin Lightening AgentsWen-Yuan ZhuDepartment of Dermatology, The First Affiliated Hospital, Nanjing Medical University,Nanjing, P.R. ChinaRu-Zhi ZhangDepartment of Dermatology, The Affiliated Hospital, BangBu Medical College,BangBu, P.R. ChinaThe ideal depigmentating compound should have a potent, rapid, and selective bleachingeffect on hyperactivated melanocytes, carry no short- or long-term side effects, and leadto a permanent removal of undesired pigment. Depigmentation can be achieved byregulating (i) the transcription and activity of tyrosinase, tyrosinase related protein-1(TRP-1), tyrosinase related protein-2 (TRP-2), and/or peroxidase, (ii) the uptake anddistribution of melanosomes in recipient keratinocytes, and (iii) melanin and melanosomedegradation and turnover of “pigmented keratinocytes” (1).TYROSINASE INHIBITIONTyrosinase is a copper enzyme, which catalyses both the hydroxylation of monophenolsto o-diphenols and the oxidation of o-diquinones to o-quinones. Most whitening agentsact specifically to reduce the function of this enzyme by means of the following mechanisms(2): (i) interference with its transcription and/or glycosylation, (ii) inhibition by differentmodalities, (iii) reduction of by-products, and (iv) post-transcriptional control.HydroquinoneHydroquinone (HQ), which is a hydroxyphenolic chemical, has been the gold standard fortreatment of hyperpigmentation for over 50 years. Its therapeutic efficacy alone or inassociation with other compounds (3) seems to exert mainly in melanocytes with activetyrosinase activity. HQ may interfere with pigmentation even through: (i) the covalentbinding to histidine or interaction with coppers at the active site of tyrosinase, (ii) theinhibition of DNA and RNA synthesis, (iii) the alteration of melanosome formation andmelanization extent, and (iv) selectively damaging melanosomes and melanocytes. 205

206 Zhu and Zhang The effectiveness of HQ is related directly to the concentration of the preparation.Concentrations of HQ vary from 2% (over the counter) to as high as 10% that are prescribedextemporaneously for resistant cases. It was known that the higher concentrations ofHQ were more effective, but the irritating and toxin for melanocytes sign were obvious.There was a reduction in the effectiveness of HQ preparation due to oxidation so thatstabilizing agents like sodium bisulphate and ascorbic acid were used as antioxidants. Themost suitable vehicle for the formulation is a hydroalcoholic solution (equal parts ofpropylene glycol and absolute ethanol) or an hydrophilic ointment, or a gel containing 10%alpha-hydroxy acids (AHAs), taking into consideration the desired 3% to 5% HQconcentration in ethanol and propylene glycol 1:1 (or in a cream base or an AHA 10% gel). The skin lightening effect of HQ can be enhanced by adding various topical agentssuch as tretinoin and corticosteroids. The following combination has been proposed byKligman and Willis (5): HQ 5%, tretinoin 0.1%, dexamethasone 0.1%, in ethanol andpropylene glycol 1:1 or in hydrophilic ointment. In this formula, tretinoin stimulates the cellturnover promoting the rapid loss of pigment via epidermopoieses, and acts as a mild irritantfacilitating the epidermal penetration of HQ and as an antioxidant preventing the oxidationof HQ. Corticosteroids can eliminate the irritation caused by HQ and/or tretinoin (6). Depigmentation of HQ preparation begins within three weeks after twice-dailyapplication and it is used for a maximum of five to seven weeks. The formulation withoutantioxidants should never be more than 30 days old. A slight modification of the Kligmanand Willis formula is the following: HQ 4%, tretinoin 0.05%, fluocinolone acetonide0.01% (or hydrocortisone 1%), in ethanol and propylene glycol 1:1 or in hydrophilicointment. In this formulation the concentration of tretinoin is lowered to 0.05%, and theaim is to minimize the irritation caused by tretinoin and eliminates local steroid sideeffects (7). The improvement rate of melasma was ranging from 40% to 87.5% in two tofour months. The side effects of HQ include allergic contact dermatitis, irritant contact dermatitis(more probable with the higher concentrations), and post-inflammatory hyperpigmentationand nail discoloration. Irritation, stinging, and/or burning were observed transiently duringthe first day of application and disappeared with use of the medication after a few days.Kojic AcidKojic acid (5-hydroxy-2-hydroxymethyl-4H-pyrane-4-one, KA) (8), a naturally occurringhydrophilic fungal derivative evolved from certain species of Acetobacter, Asperigillusand Penicillium, is used in the treatment of hyperpigmentation disorders (9). Its molecularformula is C6H6O4,5, and its molecular weight is 142.1. It also eliminates free radicals,strengthens the activity of cells and keeps the food fresh. The depigmetation action of kojic acid is attributed to the chelating ability (10), evenif an interference with different steps of melanin synthesis (11) and inhibition of nuclearfactor-kappa B (NF-kappa B) activation in keratinocytes, contrasting with thehyperpigmentation associated with inflammatory response (12). It is a kind of specializedinhibitor for melanin for preventing the tyrosinase activity through synthesizing withcopper ion in the cells after it enters skin cells. KA and its derivative have better inhibitoryeffect on tyrosinase than any other skin whitening agents. At present it is assigned intovarious kinds of cosmetics for curing freckles, age spots, pigmentation, and acne. It hasbeen used alone in concentration 2–4% and it has also been combined with HQ 2% in anAHA gel base (13). KA dipalmitate is a modified kojic acid derivative, which not only overcomes theinstability to light, heat, and metallic ion, but also keeps the inhibitory tyrosinase activity

Skin Lightening Agents 207and prevents the forming of melanin. As fat-soluble skin whitening agent, it is more easilyabsorbed by skin. Kojic acid has the potential for causing contact dermatitis and erythema(14). The heterozygous p53-deficient CBA mice were fed a diet containing 0%, 1.5%, and3% KA for 26 weeks. KA induced diffuse hypertrophy and hyperplasia of the thyroidfollicular epithelial cells and tumorigenic potential in the liver (15).Azelaic AcidAzelaic acid (AZA) is a naturally occurring 9-carbon dicarboxylic acid compoundisolated from cultures of Pityrosporum Ovale. It inhibits tyrosinase activity in vitro (KiZ2.73!10K3M) and may also interfere with DNA synthesis and mitochondria activity inhyperactive and abnormal melanocytes. AZA has been used to treat melasma and post-inflammatory hyperpigmentation and to arrest the progression of the lentigo maligna tomelanoma. This specificity may be attributed to its selective effects on abnormalmelanocytes (16). AZA produced ultra structural damage to normal melanocytes (17). AZA cream has been reported to be of benefit in the treatment of melasma. Thecream is applied twice daily and most patients report a mild but transient irritation anddryness of the skin at the beginning of the treatment. In the treatment of melasma, a24-week study in South America found that a 20% concentration of AZA was equivalentto 2% HQ (18). In the Philippines, a study found that 20% AZA was better than 2% HQ.Three hundred and twenty nine patients with melasma were treated with 20% AZA and4% HQ. Fifty six percent of the AZA group had good or excellent results while 73% HQhad a similar result (19). Topical potent steroids and 20% AZA cream combines the beneficial effects of bothbesides perhaps increasing the compliance of the patients (20). AZA with tretinoin causedmore skin lightening after three months than AZA alone, and a higher proportion ofexcellent responders at the end of treatment (16). The combination of AZA 20% cream andglycolic acid 15% or 20% lotion was as effective as HQ 4% cream in the treatment ofhyperpigmentation in darker skinned patients, with only a slightly higher rate of mild localirritation (21). Particular advantages of AZA therapy include its favorable safety and side effectprofile. It is non-teratogenic, is not associated with systemic adverse events orphotodynamic reactions, exhibits excellent local tolerability, and does not induce resistancein Propionibacterium acnes (22). Adverse effects from the AZA included irritant contactdermatitis that was usually mild and transient, but occasionally was pronounced.Paper Mulberry ExtractMulberry (Morus alba L.) leaves containing many nutritional components are the bestfood for silkworms. The extracts from mulberry leaves have a potent antihyperglycemicactivity in diabetic mice. Many phenolic compounds have been identified from the rootbark of mulberry tree. Morus alba L. also contains rutin, isoquercitrin, and astragalin. Theroot bark of Morus alba has been shown to have a skin whitening effect. Lee et al. (23) investigated the in vitro effects of an 85% methanol extract of driedMorus alba leaves on melanin biosynthesis. These extracts inhibited the tyrosinaseactivity that converts dopa to dopachrome in the biosynthetic process of melanin.Mulberroside F (moracin M-6, 30-di-O-beta-D-glucopyranoside), which was obtainedafter the bioactivity-guided fractionation of the extracts, showed inhibitory effects ontyrosinase activity and on the melanin formation of melan-a cells. But its activity waslow and weaker than that of KA.

208 Zhu and ZhangAloesinAloesin, a natural hydroxymethylchromone derivative isolated from aloe vera, acts by twodifferent mechanisms of action on tyrosinase activity, e.g., aloesin inhibits the formationof DOPA quinone by competitive inhibition at the DOPA oxidation site, reduction ofcopper ions at the hydroxylase site, and consequently tyrosine hydroxylation by non-competitive inhibition (24). In comparison with other depigmenting agents, aloesin showsno cytotoxicity in cell-based assays, no skin irritation in preliminary human studies andany genotoxicity or mutagenicity in the Ames assay. Cultured cells used in tyrosinaseactivity assays show no morphologic abnormalities when treated with aloesin, and humanmelanocytes appear normal with multiple dendrites (24). Thus aloesin is a potent inhibitor of human tyrosinase. However, because of thehydrophilic nature of the compound and moderately high molecular weight, penetration ofhuman skin was poor. Jones et al. (24) demonstrated aloesin dissolved in ethanolpenetrates the skin slowly with approximately 1.59% of a finite dose penetrating the skinover a 32-hour period. At non-cytotoxic concentration aloesin probably acting as acompetitive inhibitor on DOPA oxidation and as a non-competitive on tyrosinehydroxylase activity. Aloesin treatment showed pigmentation suppression in a dose-dependent manner; thus, aloesin might be used as an agent that inhibits melanin formationinduced by UV radiation (25). In vivo, aloesin and arbutin co-treatment inhibits UV-induced melanogenesis in a synergistic manner. The mixture of aloesin and arbutin showed a significant inhibition on tyrosinaseactivity of human melanocytes and reduced significantly melanin content, and had littleinfluence on melanocytes viability (26).ArbutinArbutin was first discovered in Arctostapylos uva-ursi (L.) Spreng and then in the leaves ofVaccinicum vitis-idaca L., Pyrus pyrifolia (Burm.f.) Kakai. and Saxifraga stolonifera (L.)Meerb. It is a naturally occurring HQ beta-D-gluconopyranoside, which causesdepigmentation at non-cytotoxic concentrations. In both normal human melanocytesand melanoma, arbutin induces a decrease of tyrosinase activity without affectingmessenger RNA (mRNA) expression, inhibits the 5,6-dihydroxyindole-2-carboxylic acid(DHICA) polymerase activity (pmel 17/silver protein) (27), and exerts an inhibitory effecton melanosome maturation. It was found to inhibit the oxidation of l-tyrosine catalyzed bymushroom tyrosinase (28). The kinetics and mechanism for inhibition of tyrosinaseconfirms the reversibility of arbutin as a competitive inhibitor of this enzyme (29). Arbutinwas much less cytotoxic than HQ to cultured human melanocytes. A clinical trial performed with Japanese women with melasma found a 3% arbutin-containing skin lotion, milky lotion and cream, applied twice daily for three months, to beeffective in reducing melasma intensity and lesion size (good-to-excellent clinicalresponse in 71.4% of patients) (30). Higher concentrations are more efficacious than lowerconcentrations, but they may also result in a paradoxical hyperpigmentation.Licorice ExtractThe licorice extract includes liquiritin, isoliquertin (a chalcone) that occurs as a glycosideand during drying is partly converted into liquiritin, liquiritigenin, isoliquiritigenin, andother compounds. Liquiritin causes depigmentation by two mechanism: (i) via melanindispersibility by means of the pyran ring of the color dispersing flavonoidal nucleus of

Skin Lightening Agents 209liquiritin, and (ii) via amelanodermic and epidermal stain removing property. Acute andchronic toxicity studies have been carried out with no adverse effects. Glabrene andisoliquiritigenin (20, 40, 4-trihydroxychalcone) in the licorice extract can inhibit bothmono- and diphenolase tyrosinase activities. The IC50 values for glabrene andisoliquiritigenin were 3.5 and 8.1 mM, respectively, when tyrosine was used as substrate.The effects of glabrene and isoliquiritigenin on tyrosinase activity were dose-dependentand correlated to their ability to inhibit melanin formation in melanocytes (31). Liquiritin cream is a new bleaching agent. Amer et al. (32) described that topicalliquiritin cream applied at 1 g/day for four weeks is therapeutically effective in melasma.Good to excellent results with complete disappearance of melasma were observed in 18(90%) out of 20 patients. Yasuaki (33) described the formulation of a liquiritin creamcontaining 20% liquorice. The cream was applied at 1 g/day to patients with melasma forone to four months and showed good efficacy. Side effects were minimal with mildirritation, which disappeared with continuation of treatment.Ellagic Acid (Copper Chelation)A polyphenol widely distributed in plants, is capable of preventing pigmentation causedby sunburn (34). Ellagic acid inhibits tyrosinase non-competitively in a dose-dependentmanner, through its capacity to chelate copper, even if other mechanisms, such as ascavenger effect have been suggested. Interestingly, in brownish guinea pigs (34),ellagic acid induced a reversible inhibition of melanin synthesis only in UV-activatedmelanocytes (34).PRODUCT REDUCTION AND REACTIVE OXYGEN SPECIESCompounds with redox properties can have depigmenting effects by interacting witho-quinones, thus avoiding the oxidative polymerization of melanin intermediates, or withcopper at the active site. Therefore, that melanin cannot be formed by the action oftyrosinase until all ascorbic acid is oxidized.Ascorbic AcidAscorbic acid (AsA) interferes with the different steps of melanization, by interactingwith copper ions at the tyrosinase active site and reducing dopaquinone and DHICAoxidation. Melanin can be changed from jet black to light tan by the reduction of oxidizedmelanin (35). AsA is an effective reducing agent, which, at high concentrations, can momentarilyretard the melanin-biosynthesis pathway, but never eliminate it. On the contrary, theresultant accumulation of diphenol produces an indirect activation on this pathway whenthe reductant is completely depleted (36). However, AsA is highly instable, being quicklyoxidized and decomposed in aqueous solution and, because of its prevalent hydrophilicnature, has a low degree of penetration into the skin. Vitamin C iontophoresis may be aneffective treatment modality for melasma (37). Sixteen women with idiopathic melasma were instructed to use, at night, 5%ascorbic acid cream on one side of the face and 4% HQ cream on the other side, for16 weeks. The improvement was observed on the HQ side with 93% good and excellentresults, compared with 62.5% on the ascorbic acid side. Side effects were present in 68.7%with HQ versus 6.2% with ascorbic acid (38).

210 Zhu and Zhang The numbers of DOPA-positive melanocytes of guinea pigs treated with VC, VE,and cystine were significantly decreased compared with those in VC group. In B16melanoma cells, simultaneous treatment of VC, VE, and N-acetyl-cysteine was the mosteffective to decrease the melanin contents and to inhibit tyrosinase activity (39). A multi-clinical, double-blind study on therapeutic effect of combinationpreparation of vitamins E and C was undertaken in comparison with single preparationof vitamin E and vitamin C in the treatment of chloasma or pigmented contact dermatitis(PCD). Objective data revealed significantly better results with combination treatment inchloasma than vitamin C alone and, in PCD, than vitamin E or C alone. The total serumlipoperoxide level and its ratio to total serum lipids tended to decline in the combinationgroup and decreased significantly in vitamin E group. The sebum lipoperoxide leveldecreased significantly only in the combination group (40).Magnesium-L-Ascorbyl-2-Phosphate (VC-PMG)AsA is quickly oxidized and decomposed in aqueous solution and thus is not generallyuseful as a depigmenting agent. To resolve that problem, Magnesium-L-ascorbyl-2-phosphate (VC-PMG) was synthesized. VC-PMG is stable in water, especially in neutralor alkaline solution containing boric acid or its salt. VC-PMG is hydrolyzed byphosphatases of liver or skin to AsA and thus exhibits vitamin C-reducing activity (41).VC-PMG significantly suppressed melanin formation on purified tyrosinase or culturedcells and inhibited melanin formation without cell growth suppression on cultured humanmelanoma cells. Inhibition of melanogenesis was stronger when the activity ofmelanogenic enzymes was relatively high. VC-PMG is absorbed percutaneously, stays in the skin, and inhibits tyrosinaseactivity of melanocytes. The addition of 1% to 3% 1,1-methyleneglycol-bis increases theabsorption of VC-PMG. In situ experiments demonstrated that 10% VC-PMG cream wasabsorbed into the epidermis and that 1.6% remained 48 hours after application. When the10% VC-PMGcream was topically applied to the patients, the lightening effect wassignificant in 19 of 34 patients with chloasma or senile freckles and in three of 25 patientswith normal skin (42).Thioctic Acid (Alpha-Lipoic Acid)A disulfide derivative of octanoic acid, it exhibits several biologic effects, which includethe quenching of ROS, metal chelation, interaction, and the regeneration of otherantioxidants, redox regulation of protein thiol groups, and effects on gene expression andapoptosis (43). Thioctic acid has been reported to prevent UV-induced photo-oxidativedamage, mainly through the down-modulation of NF-kappa B activation and to inhibittyrosinase activity probably by chelating the copper ions (44). Dihydrolipoic acid, lipoid acid, and resveratrol reduced microphthalmia-associatedtranscription factor and tyrosinase promoter activities. Dark skinned Yucatan swinetreated with these agents showed visible skin lightening, which was confirmedhistological, whereas ultraviolet B-induced tanning of light skinned swine was inhibitedusing these agents (45).Alpha-Tocopherol (a-Toc)Alpha-Tocopherol (alpha-Toc) and its derivatives inhibit tyrosinase in vitro andmelanogenesis in epidermal melanocytes. The antioxidant properties of alpha-Toc,

Skin Lightening Agents 211which interferes with lipid peroxidation of melanocyte membranes and increases theintracellular glutathione content, could explain its depigmenting effect. Alpha-Toc has amore effective and long-lasting antioxidant response. Topical application of alpha-Tocand AsA, in vivo, decreases the tanning response inhibiting the UV-inducedmelanogenesis and proliferation of melanocytes. An alternative compound is alpha-To-copherol ferulate (alpha-Toc-F), a derivative of alpha-Toc linked by an ester bond toferulic acid, an antioxidant, which provides stabilization to alpha-Toc, similar to AsA.Alpha-Toc inhibited melanogenesis in cultured normal human melanocytes, although itdid not influence melanin synthesis in enzyme solution prepared as cell homogenates. Inaddition, alpha-Toc stimulated intracellular glutathione (GSH) synthesis (46). Thirty m/ml of alpha-TF dissolved in 150 mg/ml of lecithin inhibited melanizationsignificantly without inhibiting cell growth. No significant effect on DOPA chrometautomerase (DT) activity was observed (47).INHIBITION OF MELANOSOME TRANSFERThe activation of protease-activated receptor-2 (PAR-2), a seven trans-membraneG-protein coupled receptor, which is expressed in keratinocytes and not in melanocytes,was found to activate keratinocyte phagocytosis, enhancing the melanosome transfer (48).Inhibition of PAR-2 cleavage by serine protease inhibitor, such as RWJ-50353,completely avoids the UVB-induced pigmentation of epidermal analogs (49,50).NiacinamideNiacinamide or nicotinamide is a biologically active form of niacin (vitamin B3) involvedin over 200 enzyme reactions in the form of nicotinamide adenine dinucleotide andnicotinamide adenine dinucleotide phosphate. Hakozaki et al. (51) suggested that niacinamide has no effect on tyrosinase activity,melanin synthesis, or cell number in melanocyte monoculture system, and no effect on theproliferation of keratinocytes. The research results showed that niacinamide down-regulated the amount of melanosomes transferred from melanocytes to surroundingkeratinocytes in a coculture system by approximately 35–68%. Daily use of a niacinamide moisturizer was effective in reducing hyperpigmentationand in increasing lightness of basal skin color compared with control moisturizer. Theefficacy of topical niacinamide for decreasing facial hyperpigmentation and lighteningskin color in vehicle-controlled protocols was evaluated (51).RWJ-50353RWJ-50353, a serine protease inhibitor that reduced melanosome uptake in culture, isshown to have a dose-dependent depigmenting activity in vivo with no irritation or otherside effects. Treatment with increasing concentrations of RWJ-50353 did not affecttyrosinase mRNA levels. Interestingly, this treatment led to decreased levels of TRP-1 andincreased levels of TRP-2 mRNAs (49). The downregulation of TRP-1 by RWJ-50353should lead to reduced tyrosinase activity and reduced pigment production. RWJ-50353 inhibits melanosome transfer from melanocytes to keratinocytes byits inhibitory effect on the keratinocyte PAR-2 signaling pathway. RWJ-50353-treatedkeratinocytes are unable to actively take or receive melanosomes from the presentingdendrites. Electron microscopy studies illustrated an accumulation of immature

212 Zhu and Zhangmelanosomes inside melanocytes and abnormal dendrite dynamics in RWJ-50353-treatedepidermal equivalents. In vivo RWJ-50353 (up to 10mM, twice-daily treatment to swine skin) could notcompletely inhibit melanogenesis or pigment transfer, and the transferred melanosomesare of poor quality (50). Treatment of dark skinned Yucatan swine for eight weeks withRWJ-50353 induced visible skin lightening. Histological analysis of treated sites ateight weeks shown only minimally stained melanin granules dispersed in the basal layerof epidermis (50).Soybean Trypsin InhibitorSoybean trypsin inhibitor (STI) inhibited PAR-2 cleavage, and completely inhibited theUVB-induced pigmentation of the epidermal equivalents containing melanocytes (50).Treatment with STI resulted in significant depigmentation, and reduced pigmentdeposition within the swine epidermis and prevented UVB-induced pigmentationin vivo. STI reduced keratinocyte ingestion of microspheres or E.coli particles (48).STI-treated cells showed reduced number and shorter length podia. STI-treated melanocytes within epidermal increased the number of less maturemelanosome and dendrites with mature melanosomes. UV-induced tanning of Yucatanswine was prevented with topical treatments of STI-containing compositions (52).SKIN TURNOVER ACCELERATIONThe capacity of several compounds to disperse melanin pigment and/or accelerateepidermal turnover can result in skin lightening. Chemical substances used as exfoliates,such AHAs, free fatty acids, and retinoic acid, stimulate cell renewal facilitating theremoval of melanized keratinocyte, leading to melanin granules loss (53). Topicalapplication has been shown to reduce the visibility of age spots without reducing their sizeor number (54), and can be useful in the treatment of melasma (55). Unsaturated fatty acid, such as oleic acid, linoleicacid, or alpha-linolenic acid,suppress pigmentation, in vitro, whereas saturated fatty acids, such as palmitic acid,increase the rate of melanogenesis (56).Alpha Hydroxy AcidsThe benefits of AHAs have long been recognized. Sour milk [contains lactic acid (LA)]and sugarcane juice [contains glycolic acid (GA)] were applied to the face. In lowconcentrations, AHAs decreased corneocyte cohesion, leading to sloughing of dead cellsand stimulation of new cell growth in the basal layer. In higher concentrations, they causeepidermilysis. AHAs have been reported to be effective in treating pigmentary lesionssuch as melasma, solar lentigines, and post-inflammatory hyperpigmentation. Themechanism of this effect might be due to epidermal remodeling and accelerateddesquamation, which would result in quick pigment dispersion. GA and LA might work onpigmentary lesions not only by accelerating the turnover of the epidermis but also bydirectly inhibiting melanin formation by inhibiting tyrosinase in melanocytes (57). GA orLA (at doses of 300 or 500 mg/ml) inhibited melanin formation in similar dose-dependentmanner, without affecting cell growth. The bioavailability of AHAs increases as the pHdecreases (desirable pH 2.8–4.8), and they are the only peels that are time-dependent andcan be neutralized easily.

Skin Lightening Agents 213 A cream containing 4% HQ, 10% buffered GA, vitamins C and E, and sunscreen issafe and effective in the treatment of melasma (58). The addition of kojic acid to a gelcontaining 10% GA and 2% HQ further improves melasma (59). Javaheri et al. (55)concluded that a prepeel program of daily application of topical sunscreen (SPF-15) and10% GA lotion at night for two weeks, followed by 50% GA facial peel with a duration oftwo, four and five minutes once every month for three consecutive months proved to be aneffective treatment modality for melasma in Indian patients. The beneficial resultsachieved can be maintained with topical application of 10% GA and 2% HQ. There arehardly any side effects.Linoleic AcidLinoleic acid in vivo showed the greatest lightening effect in UVB-induced pigmentation,without toxic effects on melanocytes (53). Several protease inhibitors caused theaccumulation of an approximately 60 kDa tyrosinase doublet promoted the translationof the enzyme to melanosomes (60). The evidence suggests that tyrosinase in selectivelytargeted by fatty acids, which seem to act on the degradation of the enzyme during thephysiologic proteasome-dependent mechanism (61). Linoleic acid accelerates the processwhereas palmitic acid works in an antagonistic manner mimicking protease inhibitors (61). In vitro experiments using cultured murine melanoma cells showed that melaninproduction was inhibited most effectively by alpha-linolenin acid, followed by linoleicacid and then by oleic acid. Furthermore, the turnover of the stratum corneum, which playsan important role in the removal of melanin pigment from the epidermis, was acceleratedby linoleic acid and by alpha-linolenic acid (62). Topical application of linoleic acid isconsidered to be effective in the treatment of melasma patients (63).TRADITIONAL CHINESE MEDICINETraditional Chinese herbs are a very popular mode for the treatment of hyperpigmentationdisorders. Two hundred nineteen kinds of herbs have been screened; among them 19 kindshave been shown to inhibit tyrosinase in vitro (64). The inhibitory effects of tyrosinaseactivity of Atractylodes macrocephala, Bombyx mori, Ligusticum sinense, Bletilla striata,Typhonium giganteum, Astragalus complanatus, Serissa erissoides, and Diospyros kakiwere either superior or similar to that of arbutin (64).Cinnamic AcidCinnamic acid, a naturally occurring aromatic fatty acid of low toxicity, has a longhistory of human exposure. The cinnamic acid induces cytostasis and a reversal ofmalignant properties of human tumor cells in vitro. The cinnamic acid was found toinduce cell differentiation as evidenced by morphological changes and increased melaninproduction in melanoma cells (65). Cinnamic acid does not influence the fungal growthbut decreases the yield of the pigment from the mycelium (66).SophorcarpidineTyrosinase activity can be greatly inhibited by cinnamic acid, aloin, and sophorcarpidine,of which sophorcarpidine functions as an uncompetitive inhibitor, compared to aloin andcinnamic acid, which are mixed-type inhibitors (67). Tan et al. (67) demonstrated that

214 Zhu and Zhangsophorcarpidine, aloin, and cinnamic acid can not only bind to the enzyme, but also to theenzyme-substrate complex as well, leading to the inactivation of tyrosinase. Chemical structures of some depigmenting agents. Most of the compounds aremodulators of melanogenic enzyme activity, their structures show chemical analogy withL-tyrosinase the natural substrate of tyrosinase. 1. Structure of hydroquinone HO OH2. Structure of kojic acidHO O OH O3. Structure of ellagic acid O O OHHO OH O O4. Structure of aloesin CH2COCH2HO O CH2 O5. Structure of arbutinHO O O OH HO OH OH6. Structures of liquiritin and liquirigeninHO O OR OLiquiritin, RZGlucosyl liquirigenin, RZH.

Skin Lightening Agents 215REFERENCES 1. Briganti S, Gamera E, Picardo M. Chemical and instrumental approaches to treatment hyperpigmentation. Pigment Cell Res 2003; 16:101–110. 2. Kasraee B. Peroxidase-mediated mechanisms are involved in the melanocytotoxic and melanogenesis-inhibiting effects of chemical agents. Dermatology 2002; 205:329–339. 3. Bolognia JL, Sodi SA, Osber MP, et al. Enhancement of the depigmenting effect of hydroquinone by cystamine and buthionine sulfoximine. Br J Dermatol 1995; 133:349–357. 4. Penney KB, Smith CJ, Allen JC. Depigmenting action of hydroquinone depends on disruption of fundamental cell processes. J Invest Dermatol 1984; 82:308–310. 5. Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol 1975; 111:40–48. 6. Guevara IL, Pandya AG. Melasma: treated with hydroquinone, tretinoin, and a fluorinated steroid. Int J Dermatol 2001; 40:212–215. 7. Taylor SC, Torok H, Jones T, et al. Efficacy and safety of a new triple-combination agent for the treatment of facial melasma. Cutis 2003; 72:67–72. 8. Ahmad VU, Ullah F, Hussain J, et al. Tyrosinase inhibitors from Rhododendron collettianum and their structure-activity relationship (SAR) studies. Chem Pharm Bull 2004; 52:1458–1461. 9. Serra-Baldrich E, Tribo MJ, Camarasa JG. Allergic contact dermatitis from kojic acid. Contact Dermat 1998; 39:86–87.10. Battaini G, Monzani E, Casella L, et al. Inhibition of the catacholase activity of biomimetic dinuclear copper complexes by kojic acid. J Biol Inorg Chem 2000; 5:262–268.11. Kahn V. Effect of kojic acid on the oxidation of DL-DOPA, norepinephrine, and dopamine by mushroom tyrosinase. Pigment Cell Res 1995; 8:234–240.12. Moon KY, Ahn KS, Lee J, et al. Kojic acid, a potential inhibitor of NF-kappa B activation intransfectant human HaCat and SCC13 cells. Arch Pram Res 2001; 24:307–311.13. Lim JT. Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid. Dermatol Surg 1999; 25:282–284.14. Nakagawa M, Kawai K, Kawai K. Contact allergy to kojic acid in skin care products. Contact Dermat 1995; 32:9–13.15. Takizawa T, Mitsumori K, Tamura T, et al. Hepatocellular tumor induction in heterozygous p53-deficient CBA mice by a 26-week dietary administration of kojic acid. Toxicol Sci 2003; 73:287–293.16. Breathnach AS. Melanin hyperpigmentation of skin: melasma, topical treatment with azelaic acid, and other therapies. Cutis 1996; 57:36–45.17. Nazzaro-Porro M. Azelaic acid. J Am Acad Dermatol 1987; 17:1033–1041.18. Balina LM, Graupe K. The treatment of melasma. 20% azelaic acid versus 4% hydroquinone cream. Int J Dermatol 1991; 30:893–895.19. Verallo-Rowell VM, Verallo V, Graupe K, et al. Double-blind comparison of azelaic acid and hydroquinone in the treatment of melasma. Acta Derm Venereol Suppl (Stockh) 1989; 143:58–61.20. Sarkar R, Bhalla M, Kanwar AJ. A comparative study of 20% azelaic acid cream monotherapy versus a sequential therapy in the treatment of melasma in dark-skinned patients. Dermatology 2002; 205:249–254.21. Kakita LS, Lowe NJ. Azelaic acid and glycolic acid combination therapy for facial hyperpigmentation in darker-skinned patients: a clinical comparison with hydroquinone. Clin Ther 1998; 20:960–970.22. Graupe K, Cunliffe WJ, Gollnick HP, et al. Efficacy and safety of topical azelaic acid (20 percent cream): an overview of results from European clinical trials and experimental reports. Cutis 1996; 57:20–35.23. Lee SH, Choi SY, Kim H, et al. Mulberroside F isolated from the leaves of Morus alba inhibits melanin biosynthesis. Biol Pharm Bull 2002; 25:1045–1048.24. Jones K, Hughes J, Hong M, et al. Modulaton of melanogenesis by aloesin: a competitive inhibitor of tyrosinase. Pigment Cell Res 2002; 15:335–340.

216 Zhu and Zhang25. Choi S, Lee SK, Kim JE, et al. Aloesin inhibits hyperpigmentation induced by UV radiation. Clin Exp Dermatol 2002; 27:513–515.26. Yang ZQ, Wang ZH, Tu JB, et al. The effects of aloesin and arbutin on cultured melanocytes in a synergetic method. Zhonghua Zheng Xing Wai Ke Za Zhi 2004; 20:369–371.27. Chakraborty AK, Funasaka Y, Komoto M, et al. Effect of arbutin on melanogenic proteins in human melanocytes. Pigment Cell Res 1998; 11:206–212.28. Hori I, Nihei K, Kubo I. Structural criteria for depigmenting mechanism of arbutin. Phytother Res 2004; 18:475–479.29. Maeda K, Fukuda M. Arbutin: mechanism of its depigmenting action in human melanocyte culture. J Pharmacol Exp Ther 1996; 276:765–769.30. Kimura K, Shimada H, Nomura S, et al. Studies on the qualifying of crude drugs in Japanese Pharmacopoeia. Determination of arbutin. Yakugaku Zasshi 1970; 90:394–397.31. Nerya O, Vaya J, Musa R, et al. Glabrene and isoliquiritigenin as tyrosinase inhibitors from licorice roots. J Agric Food Chem 2003; 51:1201–1207.32. Amer M, Metwalli M. Topical liquiritin improves melasma. Intern J Dermatol 2000; 39:299–301.33. Yasuaki O. Liquiritin for the removal of stains from the skin. Chem Abstr 1992; 117:476.34. Shimogaki H, Tanaka Y, Tamai H, et al. In vitro and in vivo evaluation of ellagic acid on melanogenesis inhibition. Int J Cosmet Sci 2000; 22:291–303.35. lemer AB, Fitzpatrick TB. Biochemistry of melanin formation. Physiol Rev 1950; 30:91–126.36. Ros JR, Rodriguez-Lopez JN, Garcia-Canovas F. Effect of L-ascorbic acid on the monophenolase activity of tyrosinase. Biochem J 1993; 295:309–312.37. Huh CH, Seo KI, Park JY, et al. A randomized, double blind, placebo-controlled trial of vitamin C iontophoresis in melasma. Dermatology 2003; 206:316–320.38. Espinal-Perez LE, Moncada B, Castanedo-Cazares JP. A double blind randomized trial of 5% ascorbic acid vs. 4% hydroquinone in melasma. Int J Dermatol 2004; 43:604–607.39. Fujiwara Y, Sahashi Y, Aritro M, et al. Effect of simultaneous administration of vitamin C, L-cysteine and vitamin E on the melanogenesis. Biofactors 2004; 21:415–418.40. Hayakawa R, Ueda H, Nozaki T, et al. Effects of combination treatment with vitamins E and C on chloasma and pigmented contact dermatitis. A double blind controlled clinical trial. Acta Vitaminol Enzymol 1981; 3:31–38.41. Mima H, Nomura H, Imai Y, et al. Chemistry and application of ascorbic acid phosphate. Vitamins (Japanese) 1970; 41:387–398.42. Kameyama K, Sakai C, Kondoh S, et al. Inhibitory effect of magnesium L-ascorbyl-2- phosphate (VC-PMG) on melanogenesis in vitro and in vivo. J Am Acad Dermatol 1996; 34:29–33.43. Packer L, Witt H, Tritscheler H. Lipoic acid as a biological antioxidant. Free Radic Biol Med 1995; 19:227–250.44. Saliou C, Kitazawa M, McLaughlin L, et al. Antioxidants modulate acute solar ultraviolet radiation-induced NF-Kappa-B activation in a human keratinocyte cell line. Free Radic Biol Med 1999; 26:174–183.45. Lin CB, Babiarz L, Liebel F, et al. Modulation of microphthalmia-associated transcription factor gene expression alters skin pigmentation. J Invest Dermatol 2002; 119:1330–1340.46. Yamamura T, Onishi J, Nishiyama T. Antimelanogenic activity of hydrocoumarins in cultured normal human melanocytes by stimulating intracellular glutathione synthesis. Arch Dermatol Res 2002; 294:349–354.47. Funasaka Y, Komoto M, Ichihashi M. Depigmenting effect of alpha-tocopheryl ferulate on normal human melanocytes. Pigment Cell Res 2000; 13:170–174.48. Sharlow ER, Paine CS, Babiarz L, et al. The protease-activated receptor-2 upregulates keratinocyte phagocytosis. J Cell Sci 2000; 113:3093–3101.49. Seiberg M, Paine C, Sharlow E, et al. The protease-activates receptor-2 regulates pigmentation via keratinocyte-melanocyte interactions. Exp Cell Res 2000; 254:25–32.50. Seiberg M, Paine C, Sharlow E, et al. Inhibition of melanosome transfer results in skin lightening. J Invest Dermatol 2000; 115:162–167.

Skin Lightening Agents 21751. Hakozaki T, Minwalla L, Zhuang J, et al. The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. Br J Dermatol 2002; 147:20–31.52. Paine C, Sharlow E, Liebel F, et al. An alternative approach to depigmentation by soybean extracts via inhibition of the PAR-2 pathway. J Invest Dermatol 2001; 116:587–595.53. Ando H, Ryu A, Hashimoto A, et al. Linoleic acid and alpha-linolenic acid lightens ultraviolet-induced hyperpigmentation of the skin. Arch Dermatol Res 1998; 290:375–381.54. Smith W. The effects of topical L—lactin acid and ascorbic acid on skin whitening. J Cosmet Sci 1999; 21:33–44.55. Javaheri SM, Handa S, Kaur I, et al. Safety and efficacy of glycolic acid facial peel in Indian women with melasma. Int J Dermatol 2001; 40:354–357.56. Ando H, Watabe H, Valencia JC, et al. Fatty acids regulate pigmentation via proteasomal degradation of tyrosinase: a new aspect of ubiquitin-proteasome function. J Biol Chem 2004; 279:15427–15433.57. Usuki A, Ohashi A, Sato H, et al. The inhibitory effect of glycolic acid and lactic acid on melanin synthesis in melanoma cells. Exp Dermatol 2003; 12:43–50.58. Guevara IL, Pandya AG. Safety and efficacy of 4% hydroquinone combined with 10% glycolic acid, antioxidants, and sunscreen in the treatment of melasma. Int J Dermatol 2003; 42:966–972.59. Lim JT. Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid. Dermatol Surg 1999; 25:282–284.60. Halaban R, Cheng E, Zhang Y, et al. Aberrant retention of tyrosinase in the endoplasmic reticulum mediates accelerated degradation of the enzyme and contributes to the dedifferentiated phenotype of amelanotic melanoma cells. Proc Natl Acad Sci USA 1997; 94:6210–6215.61. Ando H, Funasaka Y, Oka M, et al. Possible involvement of proteolytic degradation of tyrosinase in the regulatory effect of fatty acids on melanogenesis. J Lipid Res 1999; 40:1312–1316.62. Ando H, Itoh A, Mishima Y, et al. Correlation between the number of melanosomes, tyrosinase mRNA levels, and tyrosinase activity in cultured murine melanoma cells in response to various melanogenesis regulatory agents. J Cell Physiol 1995; 163:608–614.63. Lee MH, Kim HJ, Ha DJ, et al. Therapeutic effect of topical application of linoleic acid and lincomycin in combination with betamethasone valerate in melasma patients. J Korean Med Sci 2002; 17:518–523.64. Lei TC, Zhu WY, Xia MY, et al. Extracts from 82 kinds of traditional Chinese Herbs are inhibitors to the tyrosinase. Tradit Chin Herbs 1999; 30:336–339.65. Liu L, Hudgins WR, Shack S, et al. Cinnamic acid: a natural product with potential use in cancer intervention. Int J Cancer 1995; 62:345–350.66. Malama AA, Smirnova LA. Effect of cyclic compounds on pigment formation in Aspergillus niger cultures. Prikl Biokhim Mikrobiol 1975; 11:57–62.67. Tan C, Zhu WY, Lu Y. Aloin, cinnamic acid and sophorcarpidine are potent inhibitors of tyrosinase. Chin Med J 2002; 115:1859–1862.

14Medical and Surgical Approachesto Skin LighteningMarta I. RendonDermatology and Aesthetic Center and University of Miami, Miami, and Florida AtlanticUniversity, Boca Raton, Florida, U.S.A.Jorge I. GaviriaMedical Hair Research Group, Inc. and Clinical Research, Skin Care Research, Inc.,Boca Raton, Florida, U.S.A.INTRODUCTIONWhen approaching a patient with a pigmentary disorder, four issues must be taken intoconsideration: the patient’s skin type and ethnic background, type of disorder, history ofreaction to prior surgical treatments, and post-inflammatory hyperpigmentation (PIH).This information is necessary to determine the most appropriate treatment option.Hyperpigmentation is caused by a wide variety of conditions, diseases, and entities,most of which are acquired. Pigmentary disorders have a tremendous impact onpatients’ self-esteem and social interactions; therefore, improving patients’ quality oflife is essential. Treatments for these disorders can be difficult and lengthy, often resulting in a highdegree of patient dissatisfaction and causing some patients to seek care from anotherdermatologist. Therefore, educating patients to have realistic expectations is an importantaspect of the therapeutic process. This chapter will discuss the factors essential to choosingthe optimal therapeutic approach, and includes a discussion of first-line therapies, whenbotanicals should be incorporated, and at what point surgical or other procedures shouldbe used. The treatment of pigmentary disorders is one of the greatest challenges indermatology (Table 1). The therapeutic armamentarium has been reduced due to the lackof efficacy of most depigmenting agents available on the market. Relapses, as well as lackof permanent remissions, are the norm rather than the exception. Hyperpigmentation is caused by a wide variety of factors (Tables 1 and 2). Themechanisms inducing hyperpigmentation have not been completely elucidated.Pigmentation is a complex metabolic process that includes tyrosinase activity,melanosome formation, and a cascade of intermediate metabolites that result in theformation of melanin. A rational therapeutic approach should be medications or 219

220 Rendon and GaviriaTable 1 Causes of HyperpigmentationAcanthosis nigricansAddison’s diseaseArgyriaBecker’s nevusCafe´ au lait maculesDrug-induced hyperpigmentation (Table 2)Dyschromatosis symetrica hereditariaDyschromia of photoagingEphelidesErythema dyschromicum persistansErythromelanosis follicularisExogenous ochronosisFamilial periorbital hyperpigmentionHemochromatosisHyperthyroidismLentiginesLinea fuscaLiver diseaseMcCun-Albright syndromeMelasmaNeviNevus de otaPhotoallergic reactionPituitary tumorsPoikiloderma of civattePost-inflammatory hyperpigmentationPolycistic ovarian syndromePregnancySclerodermaRiehl’s melanosisSolar lentiginesSun exposureTinea versicolorCauses of acquired hyperpigmentationSkin diseases and conditionsErythromelanosis follicularisLinea fuscaMelasmaPoikiloderma of civattePostinflammatory hyperpigmentationRiehl’s melanosisExogenous causes of acquired hyperpigmentationCosmeticsDrugs (Table 2)Photosensitizing agents (e.g., berloque dermatitis due to bergamot oil, furocoumarins)Ultraviolet exposure (e.g., melasma, solar lentigines, ephelides)Ultraviolet tanning bedscompounds acting at different levels of the melanogenesis cascade to produce betteraesthetic and clinical results. Treatment of hyperpigmentation induced by medications should be individualized.In some cases, discontinuation of the drug is impossible, and treatment must be delayed

Medical and Surgical Approaches to Skin Lightening 221Table 2 Drugs Known to Induce HyperpigmentationAmiodaroneAmitriptylineArsenicBismuthBleomycinBusulfanClofazimineCyclophosphamideDaunorubicinDibromomannitolDoxorubicinGoldMercuryMinocyclineNitrogen mustardPhenothiazinesPhenytoinSilverSulfonamidesTetracyclinesZodovudineuntil that medication is no longer in use. In other cases, progressive discontinuation of themedication is the answer. Use of an alternative medication can solve the pigmentationphenomenon in other patients (1). No standard therapeutic guidelines exist for treating the most commonhyperpigmentation disorders, including lentigines, melasma, pigmentation of aging, andPIH. Due to variations in therapeutic regimes, the different population groups studied, andthe limited number of comprehensive studies performed to date, comparison of results isvery difficult. This chapter is an overview of topical depigmenting agents and a discussionof physical and combination therapies currently available to treat hyperpigmentation (2).TOPICAL DEPIGMENTING AGENTSSee Tables 3, 4, and 5.PHENOLIC DEPIGMENTING AGENTSHydroquinoneHydroquinone, a phenolic compound, is considered the gold standard depigmenting agent.Multiple studies have shown its efficacy in the treatment of many different types ofhyperpigmented lesions (3).Monomethyl of HydroquinoneMonomethyl of hydroquinone, also known as 4-hydroxyanisole, mequinol, 4-methoxyphenol,hydroquinone monomethyl ether, and p-hydroxyanisole, is a substance widely used in France

222 Rendon and GaviriaTable 3 Cosmeceutical Skin Lightening AgentsAloesinAlpha-lipoic acidArbutin and bearberryAscorbic acidAzelaic acidEmblicaGlycolic acidHelix aspersa mu¨llerHydroquinoneIdebenoneKojic acidLicorice extract—glabridinLinoleic acidLiquiritinMelatoninNiacinamide-niacinOleic acidPaper mulberryRetinoidsSoy extractTyrostatUnsaturated fatty acids, oleic acid, linoleic acid, and alpha-linolenic acidVitamin Cfor melasma and PIH, and throughout the European Union as an alternative to hydroquinone.It was recently approved in the United States for the treatment of lentigines. Reported sideeffects include contact dermatitis, hypomelanosis at distant sites, leukoderma, and PIH. In arecent study of mequinol in the treatment of solar lentigines, two women diagnosed withsolare lentigines were successfully treated with a combined regimen of mequinol 2% andtretinoin 0.01% (4).Table 4 Prescription Skin Lightening AgentsHydroquinoneMequinolRetinoid monotherapy, tretinoin (all-trans-retinoic acid), tazaroteneAzelic acidCombination productsHydroquinone, retinoic acid and steroidsHydroquinone, retinolHydroquinone, retinol and vitaminsOther depigmenting agents4-N-butylresorcinol4-IsopropylcatecholKojic acidMonomethyl of hydroquinoneN-acetyl-4-S-cystalminylphenolPolipodium leucotomos

Table 5 Therapeutic Approaches to Hyperpigmentation Medical and Surgical Approaches to Skin LighteningMild Moderate Severe Sunscreen Sunscreens SunscreensHydroquinone 4%, Tretinoin Azelaic acid Hydroquinone 3%–4% Hydroquinone 3%–4% Hydroquinone 4% Tretinoin 0.05% and 0.05% and Fluocinolone Glycolic acid Hydroquinone 4% Tretinoin 0.05% and Fluoci- Kojic acid Fluocinolone aceto- acetonide 0.01% nide 0.01% Hydroquinone Kojic acid Hydroquino- nolone acetonide 0.01%Retinol / Tretinoin 2%–4% ne/Retinol Kojic acid Hydroquinone/RetinolMaintenance: Retinol / Tretinoin HydroquinoneCG.A. Retinol / TretinoinTretinoin Chemical Peels Hydroquinone C MicrodermabrasionAzelaic acidKojic acid RetinolCosmeceuticals 223

224 Rendon and Gaviria4-Isopropylcatechol4-isopropylcatechol has been known as a potent depigmenting agent for more than35 years. Like other phenolic compounds, it is a tyrosinase inhibitor. In a study done in theearly 1970s, most of the melasma patients treated showed skin irritation, and atopicdermatitis. Yet two-thirds also showed significant improvement (5). Due to its specificmechanism of action targeting melanocytes, it has promise for use in melanoma andmelasma patients (6–8).N-Acetyl-4-S-Cystalminylphenol (NA-CAP)N-acetyl-4-S-cystalminylphenol (NA-CAP) is one of the four known synthesized phenolicthioether amines that are tyrosine-amine derivative analogues. Their toxicity is tyrosinasedependent and targets only melanocytes. This makes NA-CAP, a promising anti-melanoma and anti-melasma medication (9). In vitro and in vivo studies of NA-CAP havedemonstrated its selective melanocytotoxic and antimelanoma effects (10,11), particularlyin the selective disintegration of melanocytes in black hair and skin. NA-CAP is morestable than catechols, and its toxicity appears after oxidation by tyrosinase. A small studyshowed its efficacy in melasma patients (12). Due to the fact that it is less irritating thanhydroquinone, this phenolic thioether known for 20 years is a promising stable moleculefor use in melasma patients.4-N-Butylresorcinol4-N-butylresorcinol has been approved in Japan, where it is used to treat melasma. Thiscompound decreases PIH following laser therapy in melasma patients.AloesinAloesin a low-molecular-weight ingredient of latex exudates and glycoproteins from aloevera gel. Aloesin is a hydroxychromone that inhibits tyrosinase at non-toxicconcentrations. In vivo, aloesin inhibits UV-induced melanogenesis (13,14).NON-PHENOLIC AGENTSAzelaic AcidAzelaic acid is a 9-carbon dicarboxylic acid used in melasma and PIH. Azelaic acid isoften better tolerated in individuals sensitive to hydroquinone. Although its lighteningeffects are mild, several large studies done with a diverse ethnic background populationhave compared its efficacy to that of hydroquinone. This has led to the conclusion thatalthough skin irritation is greater, the efficacy of azelaic acid is similar to that ofhydroquinone (15–18).Kojic AcidKojic acid is a fungal metabolic product used for the treatment of hyperpigmentation.Kojic acid has been used as an agent to treat melasma (19). When combined withhydroquinone, kojic acid improves the melasma outcome treatment (20). Studiescomparing the product to hydroquinone shows kojic acid has the same efficacy (21).

Medical and Surgical Approaches to Skin Lightening 225Ascorbic AcidAscorbic acid. The stable ester of ascorbic acid (ascorbyl) is used in treatinghyperpigmentation. It acts on the melanogenesis cascade, interacting with copper ionsto reduce dopaquinone and block dihydrochinindol-2-carboxyl acid oxidation (22). Whenobjective measures were used in a double-blind, randomized trial study to determineefficacy, ascorbic acid (Mg L-ascorbyl-2 phosphate) in a 10% cream base had an efficacysimilar to that of hydroquinone in melasma patients (23). Subjective measurementsfavored hydroquinone. However, these data are limited, and larger studies should be doneto verify its efficacy.RetinoidRetinoid monotherapy is conducted with tretinoin (all-trans-retinoic acid), which isformed from the oxidation of the aldehyde group of retinene to a carboxyl group. Tretinoinreduces epidermal pigment in a variety of pigmentary disorders (lentigines, melasma,pigmentation of aging, and PIH) in dark skinned people (24). Results are encouraging, butimprovement can take from several months to one year (25).TazaroteneTazarotene, an acetylenic topical retinoid, produces good results in pigmentedaging spots. Moderate to marked depigmenting effect occurs when used as a gel in aconcentration of 0.1%.TOPICAL COSMECEUTICALSTopical skin lightening cosmeceuticals are becoming more popular. They have been usedalone and in combination therapy. In medical practice they are sometimes used asmaintenance agents, and very seldom used in patients who are unable to tolerate variousprescription medications or in place of other properties such as antioxidants, anti-agingproducts, or moisturizers. Commonly used depigmenting agents include arbutin, ascorbic acid, bearberryextract, idebenone, indomethacin, licorice extract, melawhite, mercury, and mulberryplant extract (Table 3). No controlled studies investigating the efficacy and safety of thesecompounds have been conducted, and although insufficient data exist to conclude theirefficacy, successful results have been published (26).Thioactic AcidThioactic acid (alpha-lipoic acid) is a disulfide derivative of octanoic acid that inhibitstyrosinase activity and prevents UV-induced photodamage. Clinical data proving itsefficacy are minimal (27).Unsaturated Fatty AcidsUnsaturated fatty acids [oleic acid (C18:1), linoleic acid (C18:2), and alpha-linolenic acid(C18:3)], suppress pigmentation in vitro. A clinical study done with Korean women usingtopical linoleic acid showed significant improvement in melasma (28).

226 Rendon and GaviriaIdebenoneIdebenone, a potent antioxidant, is a benzoquinone that has shown depigmentingproperties in pilot studies of patients with melasma and facial hyperpigmentation.Idebenone has been recently introduced to the U.S. market as Prevage.Licorice ExtractsLicorice extracts (Glycyrrhiza Glabra and Glycyrrhiza Uralensis), marketed as liquiritin,contains flavanoids and a glycoside called glycyrrhizin, and have shown utility in treatingmelasma (29).BOTANICALSIn the early 20th century, cosmetics and skin care treatments were made at home fromfruits, herbs, and vegetables. A century later, manufacturers and consumers are returningto the notion that natural is healthier, and the holistic approach to skin care is in demand. A47.3% increase in the demand for alternative remedies occurred between 1990 and 1997,and an estimated 60% of doctors recommend alternative therapies; 47% use alternativetherapies themselves (30). The search for alternatives to hydroquinone led to the discovery of a wide variety ofnatural depigmenting agents that are now available commercially and are found incosmetics and in various skin lightening agents sold over the counter. In addition to their lightening effects, these products can have antiseptic,antioxidant, and moisturizing properties. In many cases, synthetic ingredients are addedto enhance results. However, there is a rising tide of patients demanding that allcomponents of skin care products and cosmetics be natural, including preservatives. Thechallenge is to find naturally derived preservatives that interact with advancedformulations for today’s skin care demands. Manufacturers are using all-naturalpreservatives, such as essential oils, herbs, and fruit extracts that when processed canbe 75 to 100 times more potent that their original source. The research and development departments of cosmeceutical skin companiescontinually search for new avenues in the treatment of skin pigmentation, new ingredients,and alternate delivery systems. The use of botanicals should be considered in patients with hypersensitivity tomultiple prescription products, patients with contraindications to the use of laser or pulselight therapies, and patients seeking alternative therapies without invasive procedures.PHYSICAL THERAPIESThis section will focus on physical therapies and lasers, concentrating on the mostcommon hyperpigmenting disorders seen in our daily dermatology practice: lentigines,melasma, pigmentation of aging, and PIH. We will also discuss the use of combinationtherapies in managing these disorders. Most authors believe that physical therapies have a place in the treatment ofpigmentary disorders. This is also our personal experience. Medium and deep chemicalpeels with trichloroacetic acid, dermabrasion, and laser therapy may be used in thetreatment of hyperpigmentation. However, their success and clinical efficacy are limited.

Medical and Surgical Approaches to Skin Lightening 227Medium-depth peels and dermabrasion are rarely used when treating types IV-VI skinphototypes, as these approaches often result in hypopigmentation or hyperpigmentation inthis population (31).CHEMICAL PEELSChemical peels with glycolic acid, trichloroacetic acid, Jessner’s solution, kojic acid,salicylic acid, and tretinoin are used in the treatment of melasma. Peels are usually done asadjunctive therapy or when faster results are desired. Glycolic acid peels in concentrationsranging from 10% to 70% can produce excellent results in dark skinned patients, as well asin Asians and Latinos. In one study involving 25 non-pregnant women with melasma whowere treated with 50% glycolic acid once a month for three consecutive months, a 91%improvement was seen (32). Serial glycolic acid peels have been shown to provide additional benefit when addedto triple-combination therapy (5% hydroquinone, 0.05% tretinoin, and 1% hydrocortisoneacetate) in epidermal melasma. In a study done in 40 dark skinned Indian patients, 20 weregiven triple combination therapy plus serial glycolic acid peels and 20 received tripletherapy alone. Both groups showed statistically significant improvement from baseline.However, there was a trend toward more rapid and greater improvement in the groupreceiving serial peels (33,34). Further success has been achieved through the combinationof glycolic acid peels and hydroquinone with kojic acid (20). In dark skinned patients, 1% tretinoin peels have shown similar efficacy andtolerance to 70% glycolic acid peels. In a study of Asian women, clinical, and histologicalimprovement was achieved with twice-weekly topical 1% tretinoin peels for two-and-a-half weeks. Minimal skin reactions were noted (35). The combination of glycolic acid peels with hydroquinone has proven no moreeffective than hydroquinone alone. However, the combination subjectively improvesmelasma. In one study, 10 Asian women were treated with a 10% glycolic acid and 2%hydroquinone combination product applied to the entire face twice daily. The patients alsoreceived a 20–70% glycolic acid peel every three weeks to one side of the face (eight peelstotal). All participants were evaluated by an independent dermatologist. Munsell colorchart and photographs showed improvement in pigmentation and fine wrinkling on bothsides of face. The side receiving glycolic acid peel showed slightly better improvement,but it did not reach statistical significance (25). Another study of combination therapy involving hydroquinone and glycolic acidpeels produced no difference in 21 Latin women with epidermal and mixed melasma. Inthis split-faced study lasting eight weeks, patients applied 4% hydroquinone to the entireface twice daily and 20%–30% glycolic acid peels hemifacially every two weeks (fourpeels total). Objective evaluation showed that both treatments significantly reduced skinpigmentation, although no significant difference between the combination therapy andhydroquinone alone were seen (37). Superficial peels have been shown to hasten the effect of topical treatments. Sixteenwomen with Fitzpatrick skin types II-VI received pre-treatment peels with 0.05% tretinoinfor one to two weeks. They were then given three peels one month apart in which half theface was treated with 70% glycolic acid and half with Jessner’s solution. Post-treatmentwas done with 4% hydroquinone and 0.05% tretinoin. Objective evaluation showedaverage lightening on both sides of the face (38). Similar improvement was seen in asimilar study where topical tretinoin alone was used for 10 months (24).

228 Rendon and Gaviria Topical therapies can also enhance the results of resurfacing techniques. Heviashowed that 0.1% tretinoin accelerates healing after 35% trichloroacetic acid peels in asplit-face, placebo-controlled study of 16 male patients. In this cohort, 75% of tretinoin-pretreated hemifaces were completely healed at day 7, as compared with 31% of theplacebo-treated hemifaces (39). Alpha-hydroxy acid peels have been shown to increase efficacy when combinedwith topical treatments containing bleaching agents on patients with melasma. They havealso shown efficacy in patients with pigmentation due to photodamage. Alpha-hydroxyacid peels have proven safe and effective on all skin phototypes (40).MICRODERMABRASIONAluminum oxide crystal microdermabrasion was developed in 1995 (41). This processproduces superficial epidermal abrasion, and has been used primarily for facial scarringand photodamage. No clinical studies have been done in melasma or any otherhyperpigmentation disorder. Although data are lacking in this regard, the effect ofmicrodermabrasion on accelerating the epidermal barrier function makes it a valuableadjuvant therapy (42). Microdermabrasion is a “feel-good” procedure that can be used to complementtopical regimens. We usually alternate the procedure with a series of glycolic acid peels,since their mechanisms of action are different.DERMABRASIONDermabrasion is rarely used in pigmentary disorders. One Asian study involving 410patients with recalcitrant melasma treated with dermabrasion reported 97% clearing.Erythema and PIH was seen following dermabrasion, and partial recurrence ofpigmentation can occur following initial clearance of melasma (43). No clinical trials of combination therapy with dermabrasion and other physicaltherapies or topical depigmenting agents for melasma or PIH have been performed.LASERSCO2 and ErbiumCO2 and erbium resurfacing lasers are commonly used in the treatment of photoaging andacne scarring. They are seldom used for treating pigmentary disorders. Although nogeneral consensus exists on the value of CO2 laser treatment for hyperpigmentationdisorders, some authors have reported its use in recalcitrant melasma.The Combination of CO2 and Q-Switched Alexandrite LasersThe combination of CO2 and Q-switched alexandrite lasers has produced better resultsthan the Q-switched alexandrite laser alone. In a study done in Thailand, six women weretreated on one side of the face with combined ultrapulse CO2 laser and Q-switchedalexandrite laser, and on the other side with the Q-switched alexandrite laser alone. Thecombination of lasers produced a superior and significant reduction in pigmentation, ascompared with the single laser (45,46). However, an increase in undesirable side effects,

Medical and Surgical Approaches to Skin Lightening 229including PIH, was also seen. Some authors believe that treatment with hydroquinone andretinoic acid prevents PIH after treatment with CO2 laser (47,48).Pigment-Specific Lasers (Pulse-Dye Pigment, Q-Switched AlexandriteCO2, Q-Switched Ruby, and Q-Switched Nd-Yag)Pigment-specific lasers (pulse-dye pigment, Q-switched alexandrite CO2, Q-switchedruby, and Q-switched Nd-Yag) are generally recommended only for recalcitrant melasmafollowing the failure of all other therapies. On the other hand, these lasers are the treatmentof choice for isolated pigmented lesions, such as lentigos (49).Q-Switched Ruby LasersQ-switched ruby lasers have been successfully used treating specific pigmented lesionssuch as benign melanosis, labial melanotic macules, mucocutaneous melanosis associatedwith Peutz-Jeghers syndrome, and phacomatosis pigmentovascularis. Efforts to treatmelasma and solar lentigines with the Q-switched ruby laser have not been successful(50–54).Q-Switched Alexandrite LasersQ-switched alexandrite lasers combined with chemical peels have been used to successfullytreat acquired bilateral nevus of Ota, freckles, PIH, and recalcitrant dermal melasma inKorean patients with Fitzpatrick skin types IV–VI. The combination is effective and safe(55). Statistically significant results were achieved in a study group of Koreans withFitzpatrick skin types II–IV and solar lentigines using an alexandrite laser for hair removal(56). When used in combination with CO2 laser, the results in the treatment of refractorymelasma were superior to the use of the alexandrite laser alone (45).Q-Switched Nd-YagQ-switched Nd-Yag lasers have proven useful for treating deep-pigmented lesions, such asnevi of Ota and tattoos in dark skinned persons, with a reduction in the risk of epidermalinjury (57). Freckles and lentigines in Fitzpatrick prototypes IV or prototypes IV-IV canalso be successfully treated with the Q-Switched Nd-Yag laser. Minimum adversereactions and good cosmetic results can be expected (58). Tattoos also can be effectively treated and removed with several Q-switched lasers,resulting in minimal scarring (59). In our clinical practice, a thorough and detailed medical history is performed on eachpatient seeking treatment for a pigmentary disorder before using any kind of laser. This isdone to identify high-risk patients, such as dark skinned patients with Fitzpatrick IV–VI,since post-laser repigmentation and PIH are common occurrences (Table 6).Erbium:YAG LasersErbium:YAG lasers have been shown to improve melasma, but the nearly universalappearance of PIH necessitates prophylactic skin preparation with tretinoin, hydro-quinone, and desonide nightly for two to four weeks prior to laser treatment (60).

230 Rendon and GaviriaIntense Pulsed Light (IPL)Intense pulsed light (IPL) has been successfully used in refractory melasma in Asians, andhas been found to be more useful than pigment-specific lasers in severe cases of melasma.It is also an excellent laser for treating lentigenes associated with photoaging (61). In astudy of 33 Asian women with refractory dermal or refractory mixed melasma, thecombination of IPL with 4% hydroquinone for one month was more effective thanhydroquinone alone. Objective measurements were used to evaluate the skin lighteningeffect. A 39.8% improvement in relative melanin index was seen in the combinationtreatment group, versus 11.6% in the hydroquinone group at week 16 (p!0.05). Fourtreatments were done at one-month intervals. Two patients in the IPL group experiencedPIH. Partial transient repigmentation was noted 24 weeks after the last treatment session intwo patients (62). IPL has also proven effective in the treatment of freckles in Asianpatients (61) and in disfiguring lentigines associated with Peutz-Jeghers syndrome (63,64). Intense pulse light can be safely used in dark skinned people with dermalhyperpigmentation.Pigment Dye LasersPigment dye lasers have been used with success in cafe´-au-lait macules, ephelides,lentigines, and orange, red, and yellow tattoos. However, they are no longer recommendeddue to serious secondary reactions reported, including skin discoloration and purpura (66).When topical 0.05% retinaldehyde is used with the 1540 nm erbium:glass laser, the effectsof the increasing dermal thickness is potentiated. In one study, half the subjects applied0.05% retinaldehyde daily after laser treatment and for up to three months after the fifthtreatment, and half applied it daily for seven months. Dermal thickness increased in allpatients, with a larger increase seen in the retinaldehyde group. A statistically significantincrease in forehead dermal thickness was noted in the retinaldehyde group (67). Although laser treatment has been used in pigmentary disorders in dark skinnedpatients, their cautious use is warranted. Prospective studies with larger populations ofFitzpatrick phototypes IV–VI are needed to determined their safety and efficacy (68).OUR THERAPEUTIC APPROACHAs the pigmentary system yields its secrets, and pathogenic disease mechanisms are moreintensely investigated and studied, therapeutic options for pigmentary disorders expand. Once a pigmentary disorder has been diagnosed, the first step is to educate thepatient about the condition. This is particularly important if the condition has a chronicnature that will require long-term follow-up, such as melasma.Table 6 Clinical Parameters to Be Considered Before Using Lasers in the Hyperpigmented PatientEthnicityMedical and surgical historyHistory of hypertrophic scarring and keloid formationHistory of post-inflammatory hyperpigmentationSkin type (Fitzpatrick phototype)Use of isotretinoin Results of previous cosmetic procedures

Medical and Surgical Approaches to Skin Lightening 231 Sun protection must be the primary preventive measure for all patients. In order fortherapy to be successful, counseling patients on sun safety is crucial. A broad-spectrumsunscreen with sun protection factor (SPF) 30 and physical blockers containing titaniumdioxide or zinc oxide are preferred. Sunscreens block the stimulatory effect of the sun onmelanocytes, as well as the transfer of existing melanosomes to keratynocytes. In general, therapy for pigmentary disorders must be disease-specific and designedfor the individual patient. Due to the complexity of the pigmentary system and the manypathogenic mechanisms involved in most acquired pigmentary disorders, it is only logicalto assume that attacking the pigmentary cascade at different levels with differentcompounds would be the most reasonable approach. First-line treatment for conditions such as melasma and PIH is topical therapy with adual- or triple-combination product. Triple combinations contain hydroquinone witha retinoid and a mild corticosteroid; dual combination products contain hydroquinone and aretinoid. In the presence of sensitivity to any of these ingredients, alternative bleachingagents such as kojic acid, azelaic acid, or a cosmeceutical herbal compound canbe considered. Physical therapies are also introduced early in the treatment program. Thesetherapies might include chemical peels, dermabrasion, microdermabrasion, laser, orpulsed light (Table 5). While there is insufficient evidence to conclude that these therapiesare indispensable, we feel they are synergistic and help with maintenance control. Theirhelp with the prevention of PIH is an added benefit. The most commonly used physical therapies are salicylic acid peels, glycolic acidpeels, and Jessner’s solution. These are primarily superficial peels. Our success rate withthese mild procedures used in combination with topical therapies and sunscreen isquite high. We put all our patients on pre-procedure protocols with skin care products rangingfrom mild cleansers and moisturizers to products containing active ingredients such asglycolic acid, retinol, Kinerase, or one of the new growth factors (TNS vs. e.g.,). After theprocedure, patients are followed closely, and skin care regimens are restarted about aweek later. Light therapies have recently been introduced. We use IPL for treating lentigos. Wehave not tried IPL on melasma, although several studies have reported success,particularly in Asian patients. IPL provides a more acceptable modality than lasers, asthat there is less photothermal injury and, therefore, less risk of PIH in patientswith melasma. Pigment-specific lasers such as Q-switched Nd-Yag are used for isolated lesionssuch as lentigos, and are only used as a last resort in cases of recalcitrant melasma. When all other measures have failed, combining topical therapies with procedures isa reasonable approach, especially in recalcitrant conditions. The wisdom of this approachis supported by a handful of trials, although solid evidence is lacking. It is possible that thecombination of all available therapies could lead to more rapid and greater improvementand accelerated healing times while reducing the occurrence of PIH.Once their disease hasbeen cleared, patients are always placed on maintenance therapy with a retinoid, a mildlightening agent such as azelaic acid, or a cosmeceutical agent (4,33,56).CONCLUSIONSThe treatment of pigmentary disorders remains a challenge, as there are no standardizedtreatments for melasma, PIH, or pigmentation due to photoaging.

232 Rendon and Gaviria The clinical response to pharmacological monotherapy is frequently slow and, insome cases, suboptimal. Whenever possible, the use of a dual- or triple-combinationproduct as a first approach is recommended. The combination of various pharmacologicagents with chemical peels, microdermabrasion, and/or pigment-specific lasers can lead toaccelerated healing times and a more rapid and greater improvement, and can reduce theoccurrence of PIH. These advantages may enhance compliance. Scientific evidence exists for a few of the pharmacologic agents, but evidencesupporting the use of chemical peels and microdermabrasion for pigmentation disorders isscarce. Lasers have specific uses in the treatment of isolated lesions such as lentigos. Somereports have shown success with light sources including IPL for the treatment of melasmain Asians, specifically dark skinned ones. Pigment-specific lasers should only be reservedfor refractory cases. In general, combining procedural therapy with pharmacologic therapy is logical,although scientific evidence is lacking. Where trials do exist, evidence supports thecombination of modalities. The procedures can also improve or hasten the cosmetic resultsobtained from other conventional therapies. The choice of therapeutic agents involves assessment of the risk-benefit profile, andregimens should be individualized to specific disease and patient characteristics, asmentioned in Table 6. Our success rate in the treatment of pigmentary disorders is quite high with theabove approaches. However, due to the chronicity of some of these disorders, constantfollow-up, patient counseling, and use of sunscreens are critical for long-termimprovement and maintenance of results.REFERENCES 1. Rendon MI. Melasma and post-inflammatory hyperpigmentation. Cosmet Dermatol 2003; 16:9–17. 2. Halder RM, Richards GM. Management of dischromias in ethnic skin. Dermatol Ther 2004; 17:151–157. 3. Klingman A, Willis I. A new formulation for depigmenting human skin. Arch Dermatol 1975; 111:40–48. 4. Rendon MI, Benitez AL, Gaviria JI. Treatment of solar lentigines with Mequinol/Tretinoin in combination with pigment-specific laser: 2 case reports. Cosmetic Dermatol 2004; 17:223–226. 5. Jimbow K, Miura S, Ito Y, et al. Utilization of melanin precursors for experimental chemotherapy of malignant melanoma. Gan To Kagaku Ryoho 1984; 11:2125–2132. 6. Bleehen SS. The treatment of hypermelanosis with 4-isopropylcatechol. Br J Dermatol 1976; 94:687–694. 7. Pathak MA, Ciganek ER, Wick M, et al. An evaluation of the effectiveness of azelaic acid as a depigmenting and chemotherapeutic agent. J Invest Dermatol 1985; 85:222–228. 8. Sugano H, Sugano I, Jimbow K, et al. Tyrosinase-mediated inhibition of in vitro leucine incorporation into mouse melanoma by 4-isopropylcathecol. Cancer Res 1975; 35:3126–3130. 9. Gili A, Thomas PD, Ota M, Jimbow K. Comparison of in vitro cytotoxicity of N-acetyl and N-propionyl derivatives of phenolic thioether amines in melanoma and neuroblastoma cells and the relationship to tyrosinase and tyrosine hydroxylase enzyme activity. Melanoma Res 2000; 10:9–15.10. Inoue S, Hasagawa K, Wakamatsu K, Ito S. Comparison of antimelanoma effects of 4-S-cystaminylphenol and its homologues. Melanoma Res 1998; 8:105–112.

Medical and Surgical Approaches to Skin Lightening 23311. Alena F, Iwashina T, Gili A, Jimbow K. Selective in vivo accumulation of N-acetyl-4-S- cystalminylphenol in B16F10 murine melanoma and enhancement of its in vitro and in vivo antimelanoma effect by combination of buthionine sulfoximine. Cancer Res 1994; 54:2661–2666.12. Jimbow K. N-acetyl-4-S-cystalminylphenol as a new type of depigmenting agent for the melanoderma of patients with melasma. Arch Dermatol 1991; 127:1528–1534.13. Choi S, Lee SK, Kim JE, et al. Aloesin inhibits hyperpigmentation induced by UV radiation. Clin Exp Dermatol 2002; 27:513–515.14. Jones K, Hughes J, Hong M, et al. Modulation of melanogenesis by aloesin: a competitive inhibitor of tyrosinase. Pigment Cell Res 2002; 15:335–340.15. Fitton A, Goa KL. Azelaic acid: a review of its pharmacological properties and therapeutic efficacy in acne and hyperpigmentary skin disorders. Drugs 1991; 5:780–798.16. Balina LM, Graupe K. The treatment of melasma. 20% azelaic acid versus 4% hydroquinone cream. Int J Dermatol 1991; 30:893–895.17. Kakita LS, Lowe NJ. Azelaic acid and glycolic acid combination therapy for facial hyperpigmentation in darker-skinned patients: a clinical comparison with hydroquinone. Clin Ther 1998; 20:960–970.18. Verallo-Rowell VM, Verallo V, Graupe K, et al. Double-blind comparison of azelaic acid and hydroquinone in the treatment of melasma. Acta Derm Venereol Suppl 1989; 143:58–61.19. Rendon MI. Utilizing combination therapy to optimize melasma outcomes. J Drugs Dermatol 2004; 3:S27–S34.20. Lim JT. Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid. Derm Surg 1999; 25:282–284.21. Garcia A, Fulton JE, Jr. The combination of glycolic acid and hydroquinone or kojic acid for the treatment of melasma and related conditions. Dermatol Surg 1996; 22:443–447.22. Kameyama K, Sakai C, Kondoh S, et al. Inhibitory effect of magnesium L-ascorbyl-2- phosphate (VC-PMG) on melanogenesis in vitro and in vivo. J Am Acad Dermatol 1996; 34:29–33.23. Espinal-Perez LE, Moncada B, Castanedo-Cazares JP. A double blind randomized trial of 5% ascorbic acid vs 4% hydroquinone in melasma. Int J Dermatol 2004; 43:604–607.24. Kimbrough-Green Griffiths CEM, Finkel LJ, et al. Topical Retinoic acid (Tretinoin) for melasma in black patients. Arch Dermatol 1994; 130:727–733.25. Griffiths CE, Finkel LJ, Ditre CM, et al. Topical tretinoin (retinoic acid) improves melasma. A vehicle-controlled clinical trial. Br J Dermatol 1993; 129:415–421.26. Rendon MI, Gaviria JI. Skin lightening agents. In: Draelos ZD, Dover JS, eds. Cosmeceuticals. 1st ed. Philadelphia: Elsevier Saunders, 2005:103–109. Chapter, 15.27. Saliou C, Kitazawa M, Mc Laughlin L, et al. Antioxidants modulate acute solar ultraviolet radiation-induced NF-kappa Beta activation in human keratinocyte cell line. Free Radic Biol Med 1996; 26:174–183.28. Lee MH. Therapeutic effect of topical application of linoleic acid and lyncomycin in combination with betamethazone valerate in melasma patients. J Korean Med Sci 2002; 17:518–523.29. Amer M, Metwalli M. Topical liquiritin improves melasma. Int J Dermatol 2000; 39:299–301.30. Eisenberg DM, Davis RB, Ettner SL. Trends in alternative medicine use in the United States, 1990–1997. Results of a follow-up national survey. JAMA 1998; 280:1569–1575.31. Grimes PE, Grambrell-Hunt S. Considerations for cosmetic surgery in the black population. Clin Plast Surg 1993; 20:27–34.32. Javery SM, Handa S, et al. Kaur.Safety and efficacy of glycolic acid facial peel in Indian women with melasma. Int J Dermatol 2001; 40:354–357.33. Sarkar R, Kaur C, Bhalla M, et al. The combination of glycolic acid peels with a topical regimen in the treatment of melasma in dark-skinned patients: a comparative study. Dermatol Surg 2002; 28:828–832.34. Guevara IL, Pandya AG. Safety and efficacy of 4% HQ combined with 10% glycolic acid, antioxidants and sunscreens in the treatment of melasma. Int J Dermatol 2003; 41:966–972.

234 Rendon and Gaviria35. Khunger N, Sarkar R, Jain RK. Tretinoin peels versus glycolic acid peels in the treatment of melasma in dare-skinned patients. Dermatol Surg 2004; 30:756–760.36. Lim JT, Tham SN. Glycolic acid peels in the treatment of melasma among Asian women. Dermatol Surg 1997; 23:177–179.37. Hurley ME, Guevara IL, Gonzalez RM, et al. Efficacy of glycolic acid peels in the treatment of melasma. Arch Dermatol 2002; 138:1578–1582.38. Lawrence N, Cox SE, Brody HJ. Treatment of melasma with Jessner’s solution versus glycolic acid: a comparison of clinical efficacy and evaluation of the predictive ability of Wood’s light examination. J Am Acad Dermatol 1997; 36:589–593.39. Hevia O, Nemeth AJ, Taylor JR. Tretinoin accelerates healing after trichloroacetic acid chemical peel. Arch Dermatol 1991; 127:678–682.40. Tung RC, Bergfeld WF, Vidimus AT, Remzi BK. Alpha-Hydroxy acid-based cosmetic procedures. Guidelines for patient management. Am J Clin Dermatol 2000; 1:81–88.41. Tsai RY, Wang CN, Chan HL. Aluminum Oxide crystal microdermabrasion: a new technique for facial scarring. Dermatol Surg 1995; 21:539–542.42. Rajan P, Grimes PE. Skin barrier changes induced by aluminum oxide and sodium chloride microdermabrasion. Dermatol Surg 2002; 28:390–393.43. Kunachak S, Leelaudomlipi P, Wongwaisayawan S. Dermabrasion: a curative treatment for melasma. Aesthetic Surg 2001; 25:114–117.44. Hamilton MM. Laser treatment of pigmented and vascular lesions in the office. Facial Plast Surg 2004; 20:63–69.45. Angsuwarangsee S, Polnikorn N. Combined ultrapulse CO2 laser and Q-switched alexandrite laser compared with Q-switched alexandrite laser alone for refractory melasma: split-face design. Dermatol Surg 2003; 29:59–64.46. Nouri K, Bowes L, Chartier T. Combination treatment of melasma with pulsed CO2 laser followed by Q-switched alexandrite laser: a pilot study. Dermatol Surg 1999; 25:494–497.47. West TB, Alster TS. Effect of pretreatment on the incidence of hyperpigmentation following cutaneous CO2 resurfacing. Dermatol Surg 1999; 25:15–17.48. Ho C, Nguyen Q, Lowe NJ, et al. Laser resurfacing in pigmented skin. Dermatol Surg 1995; 21:1035–1037.49. Ortonne J, Passeron T. Melanine pigmentary disorders: treatment update. J Dermatol Clin 2005; 23:209–226.50. Ono I, Tateshita T. Phacomatosis pigmentovascularis type IIa successfully treated with two types of laser therapy. Br J Dermatol 2000; 142:358–361.51. Raulin C, Greve B, Hartschuh W, et al. Benign melanosis of lip. Treatment with the Q-switched ruby laser. Hautarzt 2001; 52:116–119.52. Chang CJ, Nelson JS. Q-switched ruby laser treatment of mucocutaneous melanosis associated with Peut-Jeghers syndrome. Ann Plast Surg 1996; 36:394–397.53. Lee PK, Rosenberg CN, Tsao H, et al. Failure of Q-switched ruby laser to eradicate atypical- appearing solar lentigo: report of two cases. J Am Acad Dermatol 1998; 38:314–317.54. Taylor CR, Anderson RR. Ineffective treatment of refractory melasma and postinflammatory hyperpigmentation by Q-switched ruby laser. Dermatol Surg 1994; 20:592–597.55. Lee GY, Kim HJ, Whang KK. The effect of combination treatment of the recalcitrant pigmentary disorder with pigmented laser and chemical peeling. Dermatol Surg 2002; 28:1120–1123.56. Rosenbach A, Lee SJ, Johr H. Treatment of medium-brown solar lentigines using an Alexandrite laser designed for hair removal. Arch Dermatol 2002; 138:547–548.57. Kilmer SL. Laser eradication of pigmented lesions and tattoos. Dermatol Clin 2002; 20:37–53.58. Rashid T, Hussain I, Haider M, et al. Laser therapy of freckles and lentigines with quasi- continuous, frequency-doubled, Nd:YAG (532 nm) laser in Fitzpatrick skin type IV: a 24- month follow up. J Cosmet Laser Ther 2002; 4:81–85.59. Hruza GJ. Laser treatment of epidermal and dermal lesions. Dermatol Clin 2002; 20:147–164.60. Manoloto RMP, Alster T, Erbium: YAG. Laser resurfacing for refractory melasma. Dermatol Surg 1999; 25:121–123.

Medical and Surgical Approaches to Skin Lightening 23561. Huang YL, Liao YL, Lee SH, et al. Intense pulsed light for the treatment of facial freckles in Asian skin. Dermatol Surg 2002; 28:1007–1112.62. Wang CC, Hui CY, Sue YM, et al. Intense pulse light for the treatment of refractory melasma in Asian persons. Dermatol Surg 2004; 30:1196–1200.63. Remington BK, Remington TK. Treatment of facial lentigines in Peutz-Jeghers syndrome with an intense pulse light source. Dermatol Surg 2002; 28:1079–1081.64. Bjerning P, Christiansen K. Intense pulse light source for treatment of small melanocytic nevi and solar lentigines. J Cut Laser Ther 2000; 2:177–181.65. Chan HH, Kono T. The use of lasers and intense pulse light sources for the treatment of pigmentary lesions. Skin Therapy Lett 2004; 9:5–7.66. Tanzi EL, Lupton JR, Alster TS. Lasers in dermatology: four decades of progress. J Am Acad Dermatol 2003; 49:1–31.67. Mordon S, Lagarde JM, Vienne MP, et al. Ultrasound imaging demonstration of the improvement of non-ablative laser remodeling by concomitant daily topical application of 0.05% retinaldehyde. J Cosmet Laser Ther 2004; 6:5–9.68. Halder RM, Nootheti PK. Ethnic skin disorders overview. J Am Acad Dermatol 2003; 48:S43–S148.

15Topical Exfoliation—Clinical Effectsand Formulating ConsiderationsM. Elizabeth BridenAdvanced Dermatology and Cosmetic Institute, Edina, Minnesota, U.S.A.Barbara A. GreenNeoStrata Company, Inc., Princeton, New Jersey, U.S.A.EXFOLIATIONBy definition, to exfoliate is to remove the surface in scales or laminae. Therefore,classical exfoliants are those agents that work at the skin’s surface causing the removalof skin in layers. Exfoliation is characterized, based on its mechanism of action, into3 categories: 1. physical/manual (loofah or microdermabrasion) 2. chemical/keratolytic agents (e.g., salicylic acid) 3. natural/exuviation (e.g., alpha-hydroxy acids) Manual or physical exfoliation involves the use of physically abrasive devices suchas loofahs and could also include instrumental techniques such as microdermabrasion.Manual exfoliants physically scrape and remove surface skin cells. Salicylic acid represents the chemical/keratolytic class of exfoliants. Recent reviewsof salicylic acid propose a change to the term “desmolytics” to more accurately reflect theaction of these materials on skin (1,2); these agents dissolve the desmosomal bondsbetween cells beginning at the uppermost skin layers providing exfoliative effects from thetop of the skin downward in a non-specific manner (1–5). Natural exfoliation, also known as exuviation, is the naturally occurring process ofepidermal turnover, which occurs approximately every 28 days. Compounds that enhancethe natural process of exuviation include, the alpha-hydroxy acids (AHAs), polyhydroxyacids (PHAs), and bionic acids. These agents are frequently considered exfoliants;however, their effects differ from those of conventional keratolytics or desmolytics (6,7).They target the base of the stratum corneum, the layer identified as the stratumdysjunctum, and function by diminishing bonding strength between cells in a specificmanner leading to normalization of cell turnover and, thus, exfoliation (6,8). 237

238 Briden and Green This chapter discusses the mechanisms, effects and formulating considerations ofexfoliants, including physical implements, microdermabrasion, exuviating compounds(AHAs, PHAs, bionic acids), the keratololytic/desmolytic salicylic acid, and finally anewly emerging, non-acid, acetyl amino sugar known as N-acetylglucosamine.PHYSICAL EXFOLIANTS: SCRATCHING THE SURFACEPhysical exfoliants involve the use of manual implements to erode away surface skin cells.Presumably, as rubbing is continued and additional force is exerted, skin cells willcontinue to forcibly desquamate in a non-specific manner. This can continue until thestratum corneum is removed and the “glistening” layer of the live epidermis is reached. Asimilar effect can be observed following repeated tape stripping, which could be thought ofas a process of forced physical exfoliation. Common methods of manual exfoliation include use of physically abrasivematerials such as pumice, loofahs, and buff puffs. The repetitive action of shaving with arazor also serves to physically remove or exfoliate the stratum corneum (9). Newermethods of physical exfoliation, such as microdermabrasion, involve the use ofsophisticated equipment which “sandblasts” the skin surface with particles.Bathing DevicesBuff puffs, loofahs, mesh poofs, and, to a certain extent, washcloths are used by manypeople on a daily basis to provide varying degrees of exfoliation to the face and body. Theamount of exfoliation is dependent on the force of application, the number of passes overthe skin, and abrasiveness of the material being used. There is little information in thepublished literature discussing the effects of washing devices on skin physiology andfunction. A study by Grove showed that use of abrasive fiber sponges stimulates epidermalcell turnover and reduces the size of corneocytes, indicating an exfoliation effect onskin (10). Another study by Bergfeld et al. directly compared the relative effectiveness ofmanual exfoliation with a loofah (controlled application twice daily) in comparison totopical application of the AHA, glycolic acid (10% lotion twice daily to one hand plusweekly, 3-minute 50% peels), in improving the quality of photoaged skin on the back ofhands. Results on 21 women (mean age 44 years) indicated that glycolic acid treatmentwas superior to mechanical exfoliation in improving the quality of photodamaged skin.There was a greater than four-fold improvement in overall photodamage severitycompared to the loofah treatment, and significant improvements (p!0.05) in texture andwrinkling were also observed for the glycolic acid treatment. There were no significantchanges to these characteristics on the loofah treated sites; however, loofah use resulted insignificantly less irritation (11).ShavingShaving with a razor blade removes hair as well as stratum corneum. As a result, there aremany potential detrimental effects to skin including increased risk of irritation from othertopically applied products, such as antiperspirants (9). Moreover, while shaving seems atfirst to make the skin smoother, this process actually generates uplifting scalesand increased dryness, as well as diminished barrier function in the stratum corneum

Topical Exfoliation 239and a pro-inflammatory environment in the epidermis (12). The amount of surface traumaand corresponding potential for irritation is increased with use of new razors, a non-optimalshaving angle, and insufficient use of lubricating products (9). Optimal shaving andminimal skin irritation can be achieved by following a few key steps including: (i) havingclean skin, (ii) allowing warm water to soften hair, (iii) liberal use of shaving cream appliedfor two to three minutes to soften hair, and (iv) use of a wet, warm, sharp razor (13).MicrodermabrasionThe closed, self-contained procedure known as microdermabrasion was first developed inthe mid-1980s by researchers in Italy to eliminate the risk of airborne blood generatedduring conventional dermabrasion treatments (14). Microdermabrasion was approved foruse in the United States by the Food and Drug Administration (FDA) in 1997 and hasbecome one of the most popular procedures used for aesthetic skin care (15). This novel exfoliation technique utilizes a stream of aluminium oxide, sodiumbicarbonate, or sodium chloride crystals that functions by “sandblasting” skin under mildsuction, which serves to collect the aerosolized crystals and skin particulates fordisposal (15,16). Depending on the power of the machine, the number of passes of thehand piece over the skin and/or the speed of the hand piece over the skin, micro-dermabrasion can cause superficial exfoliation of the uppermost layers of the epidermis orreach the dermis, as indicated by signs of bleeding (14). One study reported completeablation of the stratum corneum after two passes with microdermabrasion and a resultingincrease in vitamin C penetration by a factor of 20 compared to non-abraded skin,demonstrating the potential for significant exfoliation effects from microdermabrasion (17). Microdermabrasion has been used to treat a variety of skin conditions includingphotoaged skin, acne, hyperpigmentation, striae distensa, actinic keratosis, and keratosispilaris. Adverse events are infrequent and include pigmentation irregularities, which occurmainly in darker skin (Fitzpatrick skin types V and VI) and prolonged erythema lastingbeyond 24 hours (15). Many microdermabrasion protocols suggest a series of superficialprocedures on a monthly or half-monthly basis in order to achieve skin benefits whileminimizing the likelihood for adverse events (15). Several publications support the safeand effective use of microdermabrasion, with both dermal and epidermal benefits, andcorresponding patient satisfaction (18–21). Due to the perceived benefits of microdermabrasion by patients and its success indermatologist offices and spas/salons, a home care market is emerging. Accordingly,several cosmetic companies have tested and introduced home “microdermabrasion” kits;many of these kits incorporate use of scrubs or exfoliating moisturizers made bysuspending physical particles, such as polyethylene beads or apricot kernels, in a creamemulsion or gel, rather than providing actual exfoliating devices (22,23).CHEMICAL EXFOLIATIONChemical exfoliants are substances that cause superficial skin cells to desquamate at anincreased rate as a result of their ability to disrupt intercellular bonding within the stratumcorneum. This effect on skin occurs through several different mechanisms asdescribed below.

240 Briden and GreenOH OH O OH C CH COOH CH COOH CHH H3C OHGlycolic Acid Lactic Acid Mandelic AcidFigure 1 Alpha-hydroxy acids.Exuviating Compounds: Alpha-Hydroxy Acids—Polyhydroxy Acids,and Bionic AcidsThe alpha-hydroxy acid (AHAs), polyhydroxy acids (PHAs) and bionic acids areexvuviating compounds that enhance desquamation and cell turnover. Because of thedifferences in their molecular structures, these compounds provide some additionalbenefits to skin as described below.Alpha-Hydroxy Acids—Anti-aging Plus ExfoliationAHAs, such as glycolic acid, lactic acid, and mandelic acid (Fig. 1), have many beneficialeffects on skin including enhanced exfoliation as well as reversal of photoaging (24–27).Upon topical application, AHAs have been shown to have a profound effect ondesquamation and exuviation, the natural process of epidermal cell turnover (Fig. 2).When applied to severely hyperkeratotic skin, such as ichthyosis, AHAs at cosmeticstrengths [defined by the Cosmetic Ingredient Review panel as a concentration of 10% orless with a minimum pH of 3.5 (28)] cause separation of abnormally thick stratum corneumat the base of the stratum corneum, the layer known as the stratum compactum (6,29).In severely hyperkeratotic skin, the thickened stratum corneum lifts off as a sheet (6). Thisobservation distinguishes the effects of AHAs from traditional, non-specific exfoliatingagents, such as salicylic acid, which diminish corneocyte cohesion thoughout the entirethickness of the stratum corneum (2).Figure 2 Lamellar ichthyosis before and after four weeks, with twice-daily topical application ofan occlusive 10% AHA cream formulation containing glycolic acid, gluconolactone, tartaric acid,citric acid, and mandelic acid at pH 3.1.

Topical Exfoliation 241 AHAs have been shown to normalize the process of exuviation. As a result,continued use of AHAs results in a normalized rate of desquamation, and skin sheddingbecomes clinically lessened or non-apparent to the product user after two to three weeks(8). Effects of cosmetic strength AHA formulations on skin barrier function have beenstudied; Berardesca reported that twice-daily application of AHAs (8% lactic acid or 8%glycolic acid) over a period of four weeks resulted in maintenance of normal stratumcorneum barrier function as measured by trans epidermal water loss (TEWL) and,therefore, excessive exfoliation of the stratum corneum was not apparent (30). The mechanism of action of AHAs in promoting desquamation is postulated tobe due to activation of the naturally-occurring enzyme steroid sulfatase to facilitateconversion of cholesterol-3-sulfate to cholesterol at the level of the stratum compactum.Exfoliation of normal, healthy skin requires the biochemical conversion of cholesterol-3-sulfate to free cholesterol in skin (31). When present at elevated levels, the more ionicmolecule, cholesterol-3-sulfate, increases desmosomal bonding strength betweencorneocytes, thus prolonging the desquamation process. X-linked ichthyosis is knownto be deficient in this critical enzyme (32). AHAs also have stimulatory effects on dermal components. This, in conjunctionwith normalization of epidermal thickness and morphology, produces the anti-agingbenefits of AHAs (26,33,34). Skin effects of AHAs include: † reduced corneocyte cohesion at the stratum compactum (base of the stratum corneum) corresponding to fewer desmosomal attachments between cells † reduced epidermal thickness especially in the case of abnormally thickened epidermis, e.g., lamellar ichthyosis † more even distribution of melanin † increased epidermal thickness of atrophic, photoaged skin † increased synthesis of glycosaminoglycans (GAGs) and collagen fibers † normalization of elastic tissue distribution and alignment † increased dermal dendrocyte activity (8,33–37) These effects together with their effects on exfoliation and cell turnover enable theAHAs to contribute significantly to the dermatologist’s armamentarium in treatinghyperkeratotic and photodamaged skin.Polyhydroxy Acids and Bionic Acids—Gentler AHAswith Exfoliation EffectsPHAs are organic carboxylic acids that possess two or more hydroxyl groups on an aliphaticor alicyclic molecular structure. When one of the hydroxyl groups occurs in the alphaposition, the PHA is a polyhydroxy AHA. In addition to the anti-aging and cell turnoverbenefits afforded by the alpha-hydroxy structure, the multiple hydroxyl groups of the PHAs,such as gluconolactone (gluconic acid), (Fig. 3) (29,38) and glucoheptonolactone, andpolyhydroxy bionic acids, such as lactobionic and maltobionic acid (Fig. 4), imparthumectant properties to these molecules. Studies indicate that PHA compounds can attractand bind water (38), which, on a practical level, provides moisturization to skin. Aside from their moisturizing effects, PHAs have also been shown to strengthen theskin’s natural barrier against a chemical irritant (30), and provide non-irritating and non-stinging anti-aging skin benefits to clinically sensitive skin including rosacea and atopicdermatitis (39–41). Previous studies of gluconolactone and lactobionic acid havedocumented their ability to provide measurable anti-aging effects including skinsmoothing, reduced appearance of fine lines and wrinkles, and improved clarity, without

242 Briden and Green Carboxylic acid functional groupCOOH Hydroxyl PositionsHC OH alpha αHO C H beta βHC OH gamma γHC OH delta δCH2OH epsilon εFigure 3 Gluconolactone hydrolyzes to gluconic acid in the presence of water in water-basedformulations and skin. Gluconic acid is an alpha-hydroxy acid with additional hydroxyl groups(b, g, d, 3), thereby being a polyhydroxy acid (PHA).causing irritation (42–44). These agents have also been shown to increase skin exfoliationand enhance cell turnover as demonstrated in dansyl chloride cell turnover studies (45).AHA, PHA, and Bionic Acid Use in DermatologyAHAs are used extensively as adjunctive agents in the treatment of hyperkeratoticdisorders including psoriasis, callouses, acne, keratosis pilaris, and keratoses (6,8,27).They are considered among the best therapeutic options for the treatment of most formsof ichthyosis (24,25). These compounds are also used ubiquitously for the treatment ofaging-related skin changes. AHAs are marketed in a variety of forms that are readilyavailable to physicians including superficial peel reagents, cleansers, creams, lotions,and gels. CH2OH CH2OH O OH COOHOHOH O OH OH OHFigure 4 Lactobionic acid, a polyhydroxy bionic acid, is chemically defined as a bionic acid becauseit is comprised of two units: one gluconic acid molecule (right) and one galactose molecule (left).

Table 1 Chemical Exfoliants Topical ExfoliationExfoliation class Ingredient Regulatory status Solubility Bioavailable (non- Common concen- ionized) % at a tration range in topicalAlpha-hydroxy acid Glycolic acid Cosmetic Water-soluble (AHA) Lactic acid selected formulation formulations, % Cosmetic or Rx (12% Water-soluble pKa pH of 3.5a Up to 10%Alpha-hydroxy acid ammonium lactate Water-soluble Up to 10% (AHA) form) 3.83 68% Up to 10% Cosmetic 3.86 70% Up to 10% Up to 10%Alpha- (and beta-) Citric acid Cosmetic Water-/alcohol-soluble 3.13 30% hydroxy acid (AHA) 3.4 44% Up to 15% Cosmetic Slightly soluble in 3.0 24% Up to 15%Alpha-hydroxy acid Mandelic acid Cosmetic water, freely soluble 0.5–2.0% (OTC (AHA) in alcohol, ether monograph) Up to 10%Alpha-hydroxy acid Benzilic acid Water-soluble (AHA)Polyhydroxy acid Gluconolactone/ Cosmetic Water-soluble 3.6 56% (PHA) gluconic acid OTC drug or cosmetic Slightly soluble in 3.8 68%Bionic acid Lactobionic acid 2.97 23%Salicylic acid Salicylic acid depending on claims water, freely soluble in alcohol, etherAcetyl amino sugars N-Acetylglucosamine Cosmetic Water-soluble Neutral N/Aa Calculation based on Henderson-Hasselbalch equation: pKaZpHClog [Acid]/[Base]. 243

244 Briden and Green The PHAs and bionic acids are gaining use in dermatology due to their significantskin normalizing effects and anti-aging benefits in conjunction with their non-irritatingcharacteristics. These non-irritating agents are especially useful on the sensitive skin ofrosacea, atopic dermatitis, and post-procedure (microdermabrasion, peels, non-ablativelaser, etc.) when the skin barrier has been disrupted and irritation or stinging is likely tooccur due to the increased potential for rapid absorption of skin care ingredients (38,44).Formulating Factors for the HydroxyacidsThere are several factors to consider in the formulation process to optimally and safelydeliver hydroxy acids to skin. The AHAs, PHAs, and bionic acids are mild, organic acidsthat are optimally absorbed into skin when present in the free acid, non-ionized form (46).As a result, formulation pH is extremely important. At a defined pH, the concentration ofthe acid and its pKa determine the amount of free acid and, thus, bioavailability, providedby a formulation (Table 1). As the pH of a formulation is reduced below the pKa of theacid, there is a significant increase in the amount of free acid that is available forpenetration. As a result, the potential to cause sensory irritation and erythema increasesand must be considered in the formulation process. Formulation technologies exist tofacilitate the gradual penetration of free acid into skin, thereby diminishing irritationpotential and stinging without reducing skin benefits (46). One such technology utilizesamphoteric amino acids during formulation pH adjustment to temporarily complex freeAHA molecules and allow a more gentle delivery of the AHA with reduced irritationand stinging. Another important factor in the hydroxy acid formulation process involves selectionof the specific AHA ingredient. The relatively broad selection of ingredient optionsprovides the formulator with the ability to customize AHA solubility parameters andmodify potential skin benefits. For example, the more common AHAs, including glycolicacid and lactic acid, are readily soluble in water. In comparison, those with lipophilic sidechains have increased oil solubility and the resultant increased potential to absorb into oilyskin and pores. Examples include mandelic acid (phenyl glycolic acid) and benzilic acid(diphenyl glycolic acid) (Fig. 1).Salicylic Acid—A Topical DesmolyticSalicylic acid (orthohydroxybenzoic acid) (Fig. 5) is an aromatic hydroxyacid with thehydroxyl and carboxyl groups attached directly to a benzene ring (47,48). It is frequentlyreferred to as a beta-hydroxy acid, but a more accurate description is a phenolic aromaticacid because the carboxyl and hydroxyl groups are present on the benzene ring; in thisposition, the hydroxyl group is acidic (2,47,48). This is to be compared to the hydroxylgroup of conventional alpha- or beta- hydroxy acids, which have their attachment on an COOH OHFigure 5 Salicylic acid, orthohydroxybenzoic acid.

Topical Exfoliation 245Figure 6 Mild acne: baseline and after six weeks. Twice-daily application of a topical solutioncontaining 2% salicylic acid in combination with 4% alpha-hydroxy acids (benzilic acid, citric acid,tartaric acid, and O-acetylmandelic acid).aliphatic or alicyclic structure, rendering the hydroxyl group chemically neutral (48). Thischemical difference appears to differentiate the activity of salicylic acid from AHAs on theskin (8). Salicylic acid has been used as a keratolytic since the 1800s, when it was firstderived from the bark of the willow tree (49,50). Its effects on skin have been studied anddetermined to be primarily limited to enhanced shedding of the stratum corneum, with noincrease in mitotic activity of the epidermis (3–5). Salicylic acid reportedly functions bydecreasing corneocyte cohesiveness over the entire thickness of the stratum corneum viadisruption of desmosomal attachments and denaturing glycoproteins, thus the term“desmolytic” (1,3–5). The effects of salicylic acid are reported to be more extensive and clinically relevanton skin exhibiting conditions of increased corneocyte cohesiveness (3–5). As a result,dermatologists have used salicylic acid to treat various conditions of hyperkeratosis,including corns, warts, seborrheic dermatitis, psoriasis, and dandruff (2,51). Topicalsalicylic acid is also a mainstay in home care for acne; this is due to the comedolytic effectof salicylic acid (Fig. 6) (7,52). Aside from OTC formulations, there are products designedfor use in dermatologists’ offices including topical peels with concentrations of salicylicacid up to 30%. These products are primarily targeted for the adjunctive treatment of acne,and are also used in photoaging (53–55). Salicylic acid is frequently also used adjunctivelyin the treatment of psoriasis as a result of its keratolytic effects and its ability to enhancepenetration of topical medications (56,57). The anti-aging benefits of salicylic acid may be limited to the epidermis. Whereasalpha-hydroxy acids have been shown to stimulate biosynthesis of dermal components andincrease dermal skin thickness upon topical application, salicylic acid has been shown todecrease dermal skin thicknness (8). Nonetheless, salicylic acid has been used extensivelyin anti-aging formulations (7), presumably due to its exfoliation effects.

246 Briden and GreenFormulating Factors for Salicylic AcidSalicylic acid is a somewhat stronger acid with a lower pKa compared to most AHAs dueto the electron-withdrawing properties of the benzene ring. As a result, a lower pH shouldbe considered to optimally formulate bioavailable products (Table 1). However, as pH isreduced, and penetration is increased, there is an increased likelihood to cause irritation.The concentration of use of salicylic acid in over-the-counter (OTC) treatments of acne,dandruff, seborrheic dermatitis, psoriasis, and wart formulations is governed by the FDAOTC monographs. These regulatory documents dictate product form, concentration, uses,directions, and warnings. Since these formulations are regulated as OTC drugs, chemicalstability of salicylic acid must be proven over the shelf-life of the formulation. Cosmeticformulations that make cosmetic claims, on the other hand, are free to use varyingstrengths of salicylic acid; however, the upper concentration may be limited byirritation potential.N-Acetylglucosamine—A Non-Acid ChemicalExfoliant for Aging SkinN-acetylglucosamine (NAG) (Fig. 7) is a water-soluble, neutral compound that can easilybe incorporated into skin care formulations. It is found naturally occurring as a repeatingunit of the abundantly available material known as chitin (e.g., shrimp shells). In humanskin, it is a natural component of GAGs, glycolipids, and membrane glycoproteins. Alongwith glucuronic acid (a polyhydroxy acid), NAG is a one of the repeating, alternating unitsin hyaluronic acid, the prominent GAG of skin (29). NAG represents a new class of anti-aging and exfoliation compounds. Its reportedbeneficial effects on exfoliation occur as a result of its interaction with CD44 receptors oncorneocytes, which prevents cross-linking between cells (58,59). Topical application ofNAG has been shown to induce desquamation and epidermal cell turnover, as well asincrease epidermal differentiation. In a pilot (nZ9) dansyl chloride exfoliation study ofNAG (8% cream, native pH 4.9) in comparison to glycolic acid (8%, pH 3.7) and anuntreated control, NAG significantly reduced mean fluorescence scores significantlycompared to the untreated control (82% and 62%, respectively), but not as effectively asthe tested glycolic acid formulation (92%), p!0.05 (60). NAG also provides moisturizing and anti-aging benefits to skin. As a componentmolecule in hyaluronic acid and a potential precursor to its synthesis, NAG has beenshown to stimulate synthesis of hyaluronan in fibroblasts and keratinocytes (61–62).CH2OHHH O OHHO OH H H H NH CO CH2Figure 7 N-acetylglucosamine.

Topical Exfoliation 247Oral supplementation of NAG (1 g orally per day vs. placebo for 60 days) reportedlyreduced skin dryness and roughness, and increased moisturization (63). Topical evaluation of 8% NAG was shown to provide significant, clinically-assessedimprovements on mild to moderate photodamage with substantial improvements in skinfirmness and skin thickness. The latter effect is thought to be due to an increase in theproduction of GAGs, which increases skin volume through water binding and plumping(64). In addition to its desirable cosmetic effects, NAG was shown to be well tolerated onskin (64), and therefore represents a desirable new class of compounds in the growingexfoliation and anti-aging ingredient technology market.CONCLUSIONDermatologists and patients are inundated with products and devices to assist the skin inits natural exfoliation process. The purest form of exfoliation is achieved through use ofphysically abrasive implements on skin. These devices, such as loofahs, buff puffs, andmesh poofs, can provide light exfoliation on a daily basis to slough away excess layers ofstratum corneum, helping to keep the skin smooth and luminous. Additional clinicalbenefits to skin are few, if any, and have not been well documented. Microdermabrasionelevates the physical exfoliation process to the next level. Depending on how it is used,this procedure can simply provide mild exfoliation or, when used as part of acomprehensive skin care regimen, it can help the clinician to achieve meaningfulcosmetic outcomes. Chemical exfoliants have more to offer the dermatologist and patient in terms offlexibility and patient outcomes. When properly formulated for optimal bioavailability andsafety, these agents penetrate the skin and disrupt binding between stratum corneum cellsto facilitate exfoliation. This effect is beneficial in the treatment of various hyperkeratoticdisorders including acne and dry skin. Some chemical exfoliants also provide significantanti-aging effects leading to smoother skin with the reduced appearance of fine lines andwrinkles and an increase in skin firmness. Careful selection of a chemical exfoliantfacilitates customization of the formulation to skin condition including oily, dry, andsensitive skin. Furthermore, the chemical exfoliants can be readily formulated intoproducts that can be used at home or in physicians’ offices and spas/salons. The use ofexfoliating procedures, including topical peels and microdermabrasion, is frequentlycombined with home application of skin benefit ingredients to achieve significanttherapeutic outcomes.REFERENCES 1. Leveque JL, Saint-Leger D. Salicylic acid and derivatives. In: Leyden JJ, Rawlings AV, eds. Skin Moisturization. New York: Marcel-Dekker, 2002:353–364. 2. Del Rosso JQ. The many roles of topical salicylic acid. Skin & Aging 2005; 13:38–42. 3. Roberts DL, Marshall R, Marks R. Detection of the action of salicylic acid on the normal stratum corneum. Br J Dermatol 1980; 103:191–196. 4. Davies M, Marks R. Studies on the effect of salicylic acid on normal skin. Br J Dermatol 1976; 95:187–192. 5. Huber C, Christophers E. Keratolytic effect of salicylic acid. Arch Dermatol Res 1977; 257:293–297.

248 Briden and Green 6. Van Scott EJ, Yu RJ. Hyperkeratinization, corneocyte cohesion and alpha hydroxy acids. J Am Acad Dermatol 1984; 11:867–879. 7. Kligman AM. A comparative evaluation of a novel low-strength salicylic acid cream and glycolic acid products on human skin. Suppl Cosmet Dermatol 1997;11–15. 8. Yu RJ, Van Scott EJ. a-hydroxyacids, polyhydroxy acids, aldobionic acids and their topical actions. In: Baran R, Maibach HI, eds. Textbook of Cosmetic Dermatology. 3rd ed. New York: Taylor & Francis, 2005:77–93. 9. Draelos ZD. The mechanisms of shaving: a complex interaction between the blade and the skin. Cosmet Derm 1993; 6:54–55.10. Grove GL. Effect of daily cleansing with a polyester sponge on epidermal cell renewal. Poster presentation, New Orleans, La, February, 53rd Annual Meeting of the American Academy of Dermatology, 1995:4–9.11. Bergfeld W, Tung R, Vidimos A, et al. Improving the cosmetic appearance of photoaged skin with glycolic acid. J Am Acad Dermatol 1997; 36:1011–1013.12. Marti VPJ, Lee RS, Moore AE, et al. Effect of shaving on axillary stratum corneum. Int J Cosmet Sci 2003; 25:193–198.13. Draelos ZD. Re-evaluating the mechanics of shaving. Cosmet Dermatol 1996; 9:11–14.14. Hopping SB. The power peel: its emergence and future in cosmetic surgery. Int J Cosmet Surg 1988; 6:98–100.15. Sadick NS, Finn N. A review of microdermabrasion. Cosmet Dermatol 2005; 18:351–354.16. Kist D, Flor M, Zelickson B. Vibradermabrasion—new technique for superficial exfoliation. Cosmet Dermatol 2005; 18:131–135.17. Lee WR, Shen SC, Kuo-Hsien W, et al. Lasers and microdermabrasion enhance and control topical delivery of vitamin C. J Invest Dermatol 2003; 121:1118–1125.18. Bridges MA, Chrzanowski DS, Garrett AB, et al. The efficacy of facial microdermabrasion. Cosmet Dermatol 2003; 16:19–21.19. Alam M, Omura NE, Dover JS, et al. Glycolic acid peels compared to mircrodermabrasion: a right-left controlled trial of efficacy and patient satisfaction. Dermatol Surg 2002; 28:475–479.20. Coimbra M, Rohrich RJ, Chao J, et al. A prospective controlled assessment of microdermabrasion for damaged skin and fine rhytides. Plast Reconstr Surg 2004; 113:1438–1443.21. Shim EK, Barnette D, Hughes K, et al. Microdermabrasion: a clinical and histopathologic study. Dermatol Surg 2001; 27:524–530.22. Sparacio RM, Voigt A, Maes D, et al. A study comparing a novel home microdermabrasion system with a standard microdermabrasion procedure. Cosmet Dermatol 2004; 17:431–435.23. J&J study shows home microdermabrasion efficacy on par with professional. The Rose Sheet, March 7, 2005:3.24. Van Scott EJ, Yu RJ. Control of keratinization with alpha hydroxyacids and related compounds. Arch Dermatol 1974; 110:586–590.25. Bond M, Van Scott EJ. New hydroxy acid formula for ichthyosis and other severe dry skin. Cosmet Dermatol 1998; 11:32–33.26. Edison BL, Green BA, Wildnauer RH, et al. A polyhydroxy acid skin care regimen provides antiaging effects comparable to an alpha-hydroxyacid regimen. Cutis 2004; 73:14–17.27. Yu RJ, Van Scott EJ. Alpha-hydroxyacids and carboxylic acid. Cosmet Dermatol 2004; 3:76–87.28. 34th Report of the CIR Expert panel—safety of alpha hydroxy acid ingredients. Int J Toxicol 1998; 17.29. Yu RJ, Van Scott EJ. Hydroxycarboxylic acids, N-acetylamino sugars, and N-acetylamino acids. Skin Med 2002; 2:117–122.30. Berardesca E, Distante F, Vignoli GP, et al. Alpha hydroxyacids modulate stratum corneum barrier function. Br J Dermatol 1997; 137:934–938.31. Williams ML. Lipids in normal and pathological desquamation. In: Elias PM, ed. Advances in Lipid Research. New York: Academic Press, 1991:211–262.

Topical Exfoliation 24932. Shapiro LJ, Weiss R, Webster D, et al. X-linked ichthyosis due to steroid sulphatase deficiency. Lancet 1978; 1:70–72.33. Ditre CM, Griffin TD, Murphy GF, et al. Effects of alpha hydroxyacids on photoaged skin: a pilot clinical, histologic and ultrastructural study. J Am Acad Dermatol 1996; 34:187–195.34. Bernstein EF, Underhill CB, Lakkakorpi J, et al. Citric Acid increases viable epidermal thickness & glycosaminoglycan content of sun-damaged skin. Dermatol Surg 1997; 23:689–694.35. Bernstein EF, Uitto J. Connective tissue alterations in photoaged skin and the effects of alpha hydroxy acids. J Geriatr Dermatol 1995; 3:7A–18A.36. Bernstein EF. Dermal effects of alpha hydroxyl acids. In: Moy R, Luftman D, Kakita L, eds. Glycolic acid peels. New York, NY: Marcel Dekker, 2002:71–113.37. Griffin TD, Murphy GF, Sueki H, et al. Increased factor XIIIa transglutaminase expression in dermal dendrocytes after treatment with a-hydroxyacids. Potential physiologic significance. J Am Acad Dermatol 1996; 34:196–203.38. Bernstein EF, Green BA, Edison B, et al. Poly hydroxy acids (PHAs): clinical uses for the next generation of hydroxy acids. Supplement to Skin & Aging. Skin Aging 2001; 9:4–11.39. Bergfeld WF, Remzi BK, Green B. An evaluation of the gluconolactone sensitive skin care products. Poster presentation. February 1998: 56th Annual Meeting of the American Academy of Dermatology. FL: Orlando, 1998.40. Rizer R, Turcott A, Edison B, et al. An evaluation of the tolerance profile of a complete line of gluconolactone-containing skin care fomulations in atopic individuals. Suppl Skin Aging 2001; 9:18–21.41. Rizer R, Turcott A, Edison B, et al. An evaluation of the tolerance profile of gluconolactone- containing skin care fomulations in individuals with rosacea. Suppl Skin Aging 2001; 9:22–25.42. Green BA, Edison BL, Wildnauer RH, et al. Lactobionic acid and gluconolactone: PHAs for photoaged skin. Cosmet Dermatol 2001; 9:24–28.43. Grimes PE, Green BA, Wildnauer RH, et al. The use of polyhydroxy acids (PHAs) in photoaged skin. Cutis 2004; 73:3–13.44. Briden ME, Green BA. The next generation hydroxyacids. In: Draelos Z, Dover J, Alam M, eds. Procedures in Cosmetic Dermatology: Cosmeceuticals. Philadelphia, PA: Elsevier Saunders, 2005:205–212.45. Outwater S, Kohut BE, Greenspan AH, et al. An evaluation of the exfoliation efficacy of skin care formulations containing the poly hydroxy acid, gluconolactone. Suppl Skin Aging 2001; 9:26–30.46. Van Scott EJ, Yu RJ. Bioavailability of alpha-hydroxy acids in topical formulations. Cosmet Dermatol 1996; 9:54–62.47. Brackett W. The chemistry of salicylic acid. Therapeutic use of salicylic acid. Suppl Cosmet Dermatol 1997; 9:5–6.48. Yu RJ, Van Scott EJ. Salicylic acid: not a beta-hydroxy acid. Cosmet Dermat 1997; 10:27.49. Goldsmith LA. Salicylic acid. Int J Dermatol 1979; 18:32–36.50. Lin AN, Nakatsui T. Salicylic acid revisited. Int J Dermatol 1998; 37:335–342.51. Draelos ZD. Salicylic acid in the dermatologic armamentarium. Suppl Cosmet Dermatol 1997;7–8.52. DiNardo JC. A comparison of salicylic acid, salicylic acid with glycolic acid and benzoyl peroxide in the treatment of acne. Cosmet Dermatol 1995; 8:43–44.53. Elson ML. Salicylic acid peels in a new formulation for use in dermatologic surgery. J Clin Dermatol 1998; 1:36–39.54. Lee HS, Kim IH. Salicylic acid peels for the treatment of acne vulgaris in asian patients. Dermatol Surg 2003; 29:1196–1199.55. Kligman D, Kligman AM. Salicylic acid peels for the treatment of photoaging. Dermatol Surg 1998; 24:325–328.56. Medansky RS, Duffie CA, Tanner DJ. Mometasone furoate 0.1% salicylic acid 5% ointment twice daily versus fluocinonide 0.05% ointment twice daily in the management of patients with psoriasis. Clin Ther 1997; 19:701–709.

250 Briden and Green57. Tost A, Piraccini BM, Cameli N, et al. Calcipotriol ointment in nail psoriasis: a controlled double-blind comparison with betamethasone dipropionate and salicylic acid. Br J Dermatol 1998; 139:655–659.58. Brysk MM, Rajaraman S, Penn P, et al. Glycoproteins modulate adhesion in terminally differentiated keratinocytes. Cell Tissue Res 1988; 225:657–663.59. Hudson DL, Sleeman J, Watt FM. CD44 is the major peanut lectin-binding glycoprotein of human epidermal keratinocytes and plays a role in intercellular adhesion. J Cell Sci 1995; 108:1959–1970.60. Data on file, NeoStrata Company, Inc., 2004.61. Sayo T, Sakai S, Inoue S. Synergistic effect of N-acetylglucoseamine and retinoids on hyaluronan production in human keratinocytes. Skin Pharmacol Physiol 2004; 17:77–83.62. Breborowicz A, Kuzlan-Pawlaczyk M, Wieczorowska-Tobis K, et al. The effect of N-acetylglucosamine as a substrate for in vitro synthesis of glycosaminoglycans by human peritoneal mesothelial cells and fibroblasts. Adv Perit Dial 1998; 14:31–35.63. Kikuchi K, Matahira Y. Oral N-acetylglucosamine supplementation improves skin conditions of female volunteers: Clinical evaluation by a microscopic three-dimensional skin surface analyzer. J Appl Cosmet 2002; 20:143–152.64. Green BA, Edison BL, Wildnauer RH, et al. Derivatives of sugar compounds provide anti- aging effects. Poster presentation, Washington DC, February 2004: 62nd Annual Meeting of the American Academy of Dermatology.

16Over-the-Counter Acne MedicationsTheresa Chen and Yohini AppaNeutrogena Skincare Institute, Los Angeles, California, U.S.A.INTRODUCTIONAcne vulgaris is an extremely common condition affecting more than 80–90% ofadolescents and young adults (1,2). It typically starts in late childhood or early teens, butonset may be delayed in some people well into their 20s and 30s (3). The incidence rate ofacne is roughly the same in males and females but, males tend to have more seriousconditions (4). Even later in adulthood, roughly 25% of adult men and 50% of adultwomen can have acne at some time in their adult lives. Acne can be difficult to cope with no matter what age, and can cause depressionand social anxiety in an adult the same way it can in a teen. Kellett and Gawkrodger (5)found that acne patients reported levels of social, psychological, and emotional problemsas great as those reported by patients with chronic disabling asthma, epilepsy, diabetes,back pain, or arthritis. This study also reported that the impact on quality of life did notcorrelate with acne severity. To a teenager, acne can be one of the worse things that everhappened. Acne frequently makes teens feel embarrassed and lowers their self-esteem. Arecent survey of British teenagers found that the emotional toll could be significant (6).This survey found: † About two out of five teenagers with acne claimed to have skipped school because of embarrassment. † Between 11- to 18-year-olds, over half said acne prevented them from having a boyfriend or a girlfriend. † One-third indicated acne hurt their ability to make friends. Proper care and intervention help improve the life quality by alleviating the negativeemotional impacts and building up self-esteem. Treatment can also prevent acne fromgetting worse and deter scarring. 251

252 Chen and Appa When it comes to treatment, one study conducted in 2000 indicated that 75% ofpatients waited about one year before seeking professional help for acne (7). Anothersurvey estimates that only a third of acne sufferers consult their physicians at all. Thus, themajority of acne sufferers apparently opt for the over-the-counter (OTC) acne products totreat their acne. This is most likely due to the fact that most acne cases are mild tomoderate in severity for which OTC acne products—readily available and not requiring aprescription and an appointment to the doctor’s office—are perfectly suited. And many oftoday’s new OTC acne products are not only clinically effective and safe butalso aesthetically elegant and pleasant to use. Non-prescription products tried mostfrequently were medicated cleansers, washes, pads, gels, and lotions (8). A 2001 reportestimates that consumers of all ages spend approximately $100 million per year on OTCremedies for acne (9). The actual market figure today is probably much higher than thatas evidenced by the sheer number of OTC acne products that have since come on themarket in the recent years. Given the large variety of acne OTC products, this chapterattempts to provide a comprehensive overview while focusing on the recent OTCadvances of the two most-widely used acne OTC medications, salicylic acid (SA) andbenzoyl peroxide (BPO).CLINICAL CONSIDERATIONSAcne affects mainly the face, although other regions rich in sebaceous glands can also beaffected (chest, back, upper arms). The lesions can be distinguished into non-inflammatory(open and closed comedones or blackheads and whiteheads) and inflammatory lesions(papules, pustules and nodules). Four main factors are known to influence the development of acne, namely: (i)sebaceous gland hyperplasia with excess sebum production (seborrhea); (ii) follicularepidermal hyperproliferation and altered differentiation; (iii) follicular colonization byPropionibacterium acnes (P. acnes); and (iv) inflammation and immune response. Alteredepidermal growth and differentiation, combined with seborrhea, is responsible for theformation of the primary lesion in acne: The microcomedo. The development ofinflammatory lesions, instead, is often triggered by the effects of P. acnes with release ofinflammatory mediators. The first entity in the development of an acne lesion is a tiny invisible plug(microcomedone) of the pilosebaceous duct; skin that is at one time apparently unaffectedmay subsequently develop lesions if not treated. Generally speaking, it may take up to fourweeks for an untreated papule or pustule to complete its life cycle from start to end.Therefore, an acne therapy that significantly reduces lesion counts during the first fourweeks is recognized as having treated existing lesions, while therapies effective inreducing acne lesions count during the following four weeks are considered also effectivein preventing the appearance of new lesions. Because of the multiple pathogenetic factors, dermatologists recommend treatingacne with combinations of agents that act at different levels. It is widely recognized that aneffective acne treatment should not only clear current acne lesions but also prevent theappearance of new ones.

Over-the-Counter Acne Medications 253HIGHLIGHTS OF OVER-THE-COUNTERACNE MONOGRAPHThe Food and Drug Administration (FDA) is the regulatory agency that oversees themarketing of non-prescription acne products. In the Final Acne Monograph, an “acne drugproduct” is defined as: “A drug product used to reduce the number of acne blemishes, acnepimples, blackheads and whiteheads” (10). The following ingredients and concentrations are currently allowed in OTC acneproducts. † Salicylic acid 0.5–2% † Sulfur 3–10% alone, or 3–8% in combination with resorcinol † Resorcinol 2% or resorcinol monoacetate 3% in combination with sulfur 3–8% † Benzoyl peroxide 2.5–10% Salicylic acid, sulfur alone, or sulfur in combination with resorcinol are included inthe Final Monograph for meeting the monograph conditions of being “generallyrecognized as safe and effective and not misbranded (Category I)” for the treatment ofacne. Although the final rule on benzoyl peroxide is still pending, FDA has allowed itscontinued use in OTC acne products (11). In the Final Acne Monograph, it also lays down the requirements for the labelingof OTC acne products. The labeling requirements include a statement of identity thatcontains the established name of the drug and identifies the product as an acnemedication or treatment and the dosage form, a statement for the indications that thedrug product is intended to treat; additional statements of treatment benefits; appropriatewarnings; and directions of product usage. In the absence of a final ruling on the use ofbenzoyl peroxide in OTC acne products, manufacturers are referred to the proposed rules(12,13).FORMULATION OF OVER-THE-COUNTERACNE PRODUCTSManufacturing of OTC acne products is both a science and an art. An OTC acne productmust abide by the rules and regulations set in the Acne Monograph in the choice of anallowed active ingredient or combination of active ingredients and the allowableconcentration ranges. Amongst the approved OTC acne ingredients, BPO and SA are the most widelyused. Both are topical comedolytics that help dry excess sebum and make the excretedsebum less sticky. This prevents occlusion of the pores and consequent formation ofcomedones. Topical comedolytics also cause sloughing of the stratum corneum andhelp remove existing sebum plugs along with loose keratinocytes. They also helpnormalize keratin turnover in the follicle (14). Interestingly, in the Final AcneMonograph, the agency notes that only BPO has known comedolytic activity andconsiders the other monograph ingredients as exfoliating agents that can evokesuperficial peeling, thereby “aiding in unroofing superficial pustular lesions and causingspontaneous drainage” (15).

254 Chen and Appa Benzoyl peroxide and SA come in a variety of products and in several differentdelivery systems, such as creams, washes, gels, and cleansing pads (16). Skin reactions totopical treatments may vary depending on the skin types. Thus, formulating the right OTCproduct that can work best for the majority of acne population is a formidable task. Themain concern should be minimization of irritation on all skin types. The formulator shouldalso take into account the time an individual has to care for the skin, the lifestyles ofconsumers, and the cost of individual products. Another important consideration for formulation is the effects of the vehicle onthe skin. Gels and solutions such as astringents can have higher alcohol contents andmay increase the drying effect, while creams and lotions delivered in an emollientbase tend to be moisturizing to the skin. “A proper vehicle is one that will deliver thedrug to the site of action at a rate that will allow maximum benefit without causing orallowing toxic effects” (17). Given that all OTC acne drugs are keratolytics and canbe somewhat drying and irritating, the ability of a vehicle that can mitigate theirritancy potential and allow delivery of the maximum drug benefits is all themore important. What this also translates into is that in order to provide sustainable treatmentbenefits, OTC acne treatment should be developed in such a way that the consumers canand will like to use on a consistent, long-term basis. In other words, OTC acne productsshould be effective in delivering the clinical improvements as indicated, cause little or noirritation, be aesthetically pleasant, and be easy to use.TRENDS IN OVER-THE-COUNTER ACNE FORMULATIONSIn the last decade, no new OTC ingredient has been approved for the treatment of acne.However, much research effort has led to the development of better vehicles and deliveryforms designed to reduce skin irritation and improve efficacy. The common product formsare gel, lotion, cream, and cleanser. In addition, other delivery methods have appeared, which include masks, scrubs,pads and even makeup foundation and concealing sticks. Body acne has also beengaining notices: Body washes and leave-on sprays have been developed to addressdelivery to hard-to-reach areas such as the back. The varieties in forms and deliverysystems make it possible to design OTC treatment programs that are tailored to anindividual’s needs. At the same time, there is an increasing desire to provide patients with acomprehensive product system or regimen that is easy to follow on a daily basis. Thisapproach has two potential advantages: Encouraging usage compliance by consumers,and ensuring a product system that has been tested and proven to be compatible andmay even be synergistic to deliver optimal efficacy and safety profiles. Multi-stepsystems that consist of combinations of products from cleanser to lotion or cream havebeen designed to provide a full range of products to use in daily routines. Typically oneor two of the products in the system contain an OTC active ingredient. Cleansers,toners, masks, cosmoceuticals, emollients and sunscreens can be incorporated asadjunctives in the system. Some products even go beyond acne to try to address bothacne and aging, targeting those adults who are concerned about both conditions ontheir skin.

Over-the-Counter Acne Medications 255ADVANCES IN OVER-THE-COUNTER ACNE FORMULATIONSSalicylic AcidSA is a keratolytic agent. It is used to treat a variety of hyperkeratotic skin disorders suchas psoriasis, ichthyoses, seborrheic dermatitis, palmoplantar keratosis, keratosis pilaris,and pityriasis rubra pilaris (18). In acne, SA may reduce comedones (comedolytic) andprevent the formation of new ones by breaking down the comedonal follicular plug and byreducing follicular desquamation. It is an effective alternative for patients who do nottolerate topical retinoids. SA is approved for use in pediatric acne. Concentrations of SA ranging from 0.5–10% from various manufacturers have beenrecommended for acne, but 2% is the maximum strength allowed in non-prescription acneproducts in the U.S. It is commonly found in acne cleansers. The effectiveness of 0.5–2% SA as an acne treatment was originally demonstrated intwo studies submitted to the FDA during the OTC approval phase (50 FR 2174, 1/15/85).The first study was a 12-week, double-blind investigation on 180 subjects comparing theefficacy of 2% SA solution versus vehicle solution and active control (5% benzoylperoxide) in the treatment of acne. Forty percent of the subjects treated with 2% SAshowed a good or excellent decrease in total lesions compared to 5% of the subjects in thevehicle group and 2% of the subjects in the benzoyl peroxide group. The study reportedthat SA was significantly more effective than vehicle and benzoyl peroxide in thereduction of total lesions, inflammatory lesions, and open comedones (but not closedcomedones) (19). The second study was conducted on 187 subjects. Two SA formulationsat 0.5% and 2% were tested against the vehicle. The results showed that both 0.5% SA and2% SA were superior to the vehicle in reducing inflammatory lesions, open and closedcomedones, and total lesions (20). The efficacy of the cleanser form was investigated by Shalita in a cross-over study.He compared a 2% SA cleanser and a 10% benzoyl peroxide wash in 30 acne subjects.Subjects were randomly treated for two weeks with either SA or benzoyl peroxide. Atthe end of the first two weeks they switched treatment. The study concluded that only SAcleanser induced a significant reduction in comedones (21). More recently, a study byPagnoni et al. (22) showed a significant reduction from baseline in open comedonescount after four weeks of treatment using a 2% SA scrub or a 0.5% SA toner with 1%glycolic acid. The scrub induced a significant improvement as early as two weeksafter treatment. SA pads were investigated by Eady et al. (23). They compared 2% SA lotion versusplacebo impregnated into pads. They found that the SA pads were significantly better thanthe control in reducing the total lesion count, starting at the fourth week of treatment. Thesuperiority in improving comedones was also noted. Zander and Weisman reviewed threeplacebo-controlled studies and reported that SA pads were effective in reducing thenumber of primary lesions and thereby the number and severity of all lesions associatedwith acne (24). They also reported that SA was superior to benzoyl peroxide in reducingthe total number of acne lesions. Based on these previous studies, SA is generally considered less effective thanbenzoyl peroxide in the treatment of inflammatory acne but more effective in the treatmentof comedonal acne. Recently a new paradigm on SA has been ushered in when an acne treatment gelcontaining 2% SA was shown to be as effective as a 10% benzoyl peroxide lotion in allacne-related parameters. Because of the drying and irritating potentials of acne active

256 Chen and AppaTable 1 Anti-acne Efficacy Comparison of a 2% Salicylic Acid Treatment Gel Containing SkinSoothing Naturals with a 10% Benzoyl Peroxide Lotion Mean change from baseline (%) 2% Salicylic acid gel 10% Benzoyl peroxide (NZ44) lotion (NZ46)Acne lesion type Week 2 Week 4 Week 2 Week 4Open comedones K31 K43 K34 K56Closed comedones K30a K26a K13 K6Inflammatory (papuleCpustules) K26a K23 K15 K6Total lesions K28a K27 K17 K15Shading indicates a significant change from baseline (p !0.05).a Significantly higher improvement compared to the other treatment (p !0.05).ingredients, some of today’s acne treatment products are formulated with cosmeticingredients or cosmoceuticals that can help soothe the skin and reduce irritation. Thisapproach has proven very effective in optimizing efficacy for OTC acne productscontaining SA. A SA gel formulated with a proprietary soothing blend of naturals was compared to a10% benzoyl peroxide treatment lotion, to the vehicle and also to no treatment control indouble-blind and randomized clinical studies (25,26). The 2% SA treatment gel was foundto be at parity to 10% benzoyl peroxide in target lesion resolution and on par or evensuperior in reducing closed comedones and inflammatory lesions (Table 1). The effects on the target lesion resolution was evaluated by assessing lesionerythema, size and elevation and surrounding erythema. Significantly faster resolution wasobserved with the active treated group versus the vehicle group and the untreated group inblinded and randomized clinical evaluation (Fig. 1). When it comes to irritancy, the 2% SA gel was superior to the 10% benzoylperoxide lotion in mildness. Skin soothing benefits were evidenced in the reduction ofpimple associated discomfort and the lessening of global erythema. These effectswere observed in the majority (70–90%) of the study subjects. Similar gentleyet effective treatment benefits were also noted with another SA treatment in a lotionbase (27). Yamamoto et al. (28) have reported diminished water barrier function in acnepatients. The strong vehicle effects often observed in acne clinical studies might be due tothe vehicles being less drying. Thus, having a delivery vehicle that helps improve skinmoisturization can have a positive impact in the treatment. Recently, Chantalat et al. (29) reported the use of a microgel complex to optimizeSA’s anti-acne efficacy through solubilizing sebum and enhancing the delivery of SA.This microgel complex is a multiple-phase system consisting of micro-droplets in anaqueous phase. High-performance liquid chromatography (HPLC) analysis of

Over-the-Counter Acne Medications 257(A) Surrounding Erythema of Acne Lesions 40.0Percent Change of Mean 20.0 from Baseline (%) 0.0 -20.0 8 Hours -40.0 -60.0 -80.0 345 6 7 8 Improvement Region Days of Treatment -100.0 012 Active, N = 32; Placebo, N = 31(B) Lesion SizePercent Change of Mean from 0.0 8 Hours Baseline (%) -20.0 -40.0 -60.0 -80.0 Improvement Region -100.0 012345678 Days of Treatment Active, N = 32; Placebo, N = 31Figure 1 Blinded clinical expert grading of (A) surrounding erythema and (B) lesion sizecomparing a salicylic acid gel with a synergistic blend of skin soothing naturals (active) and itsvehicle control (placebo). Note: open symbols denote mean values that are significantly differentfrom baseline (p !0.025). Asterisks next to the data points denote between treatments difference infavor of the labeled treatment (p !0.01).

258 Chen and Appamicrogel complex formulations with SA shows that the distribution of SA issignificantly higher in the hydrophobic phase than the aqueous phase. In vitroinvestigations with model sebum compositions showed that certain components ofthe microgel complex solubilize sebum. Using fluorescence spectroscopy, ultraviolet(UV) light imaging, and confocal microscopy, they demonstrated in vivo that the depthof SA penetration in the skin was increased, as was the extent of deposition.Furthermore, skin conductance and transepidermal water loss (TEWL) measurementsshowed that formulations with the microgel complex delivered greater moisturizationbenefits versus placebo. This microgel formulation containing SA was shown to behighly effective not only at treating existing acne lesions but also at amelioratingemerging acne pimples—the sub-surface acne lesions that are not yet visible on the skinsurface (30).Benzoyl PeroxideBenzoyl peroxide has been one of the most important topical acne agents for a long time.It has a combination of antibacterial, anti-inflammatory and comedolytic properties.Benzoyl peroxide can penetrate through the follicular duct deeply into the infundibulumwhere it then releases oxygen to inactivate anaerobic bacteria that cannot live in itspresence, P. acnes being one of those bacteria. A study by Bojar et al. (31) reported analmost 2-log10 decrease in the density of P acnes after two days of 5% benzoyl peroxidetreatment. Pagnoni et al. (32) confirmed this rapid effect in their investigation that showedP. acnes count decreased by an average of 2-log after a three-day treatment with a 10%benzoyl peroxide cream, without any further decline by day 7. In contrast to the bacterialresistance known to be associated with the use of oral and topical antibiotics, theantibacterial activity of benzoyl peroxide occurs without the induction ofbacterial resistance. The anti-inflammatory effect of benzoyl peroxide is probably directly related to thedecrease of P. acnes density in the sebaceous follicles. It is known that P. acnes inducesmonocytes to secrete pro-inflammatory cytokines such as tumour necrosis factor a(TNF-alpha), interleukin-1b (IL-1b), and IL-8 through a Toll-like receptor 2-dependentpathway (33,34). Benzoyl peroxide is commonly available as a liquid cleanser (2.5–10%), barcleanser (5–10%), pads (3–9%), mask (2.5–5%), lotion (5–10%), cream (5–10%), and gel(2.5–20%). A report from the Global Alliance to Improve Outcomes in Acne (35) indicatesthat gel formulations may be more stable and may release benzoyl peroxide moreconsistently than creams and lotions. Specific cleanser forms of benzoyl peroxide (5% and 10%) have been shown toreduce P. acnes density and inflammatory lesion counts. To increase the cleanser’sbenefits, patients should be instructed to gently massage the cleanser into moistenedskin and allow a 20-second contact time followed by a 10-second gentle rinse (36).Recently a benzoyl peroxide cleanser mask takes this one step further by allowing thepatients to use the product either as a cleanser or as a mask that allows for even longercontact time (37). Benzoyl peroxide can enhance the efficacy of concomitant antibiotic therapy andreduces the development of antibiotic-resistant P. acnes. When used in combination withoral antibiotics, it has been shown to reduce the resistance of bacteria to the systemic drug.Recently, new drugs have combined benzoyl peroxide with other topical antibiotics. These

Over-the-Counter Acne Medications 259formulations are available only by prescriptions and include erythromycin 3%–benzoylperoxide 5% and clindamycin 1%—benzoyl peroxide 5% combinations. These productshave been shown to have some additive effect compared to either drug alone and to reducethe resistance to the antibiotic. Once absorbed by the skin, benzoyl peroxide is metabolized to benzoic acid andexcreted in the urine as benzoate. There is no evidence of systemic toxicity caused bybenzoyl peroxide in humans (38). Side effects of benzoyl peroxide may include mild tomoderate irritation and skin dryness. Contact allergy has been reported in approximately1% of patients. Additionally, benzoyl peroxide formulations may bleach fabrics and hair.It is the controversy over tumor-promoting reports from animal studies on benzoylperoxide that caused the FDA to delay ruling on its monograph status. In the interim, theagency has issued proposed rules that recommend sun avoidance and the use of asunscreen when using a benzoyl peroxide product to treat acne (39). Many peer-reviewed studies have been published supporting the efficacy and safetyof benzoyl peroxide in acne. This ingredient is the main OTC treatment suggested bydermatologists because of its undisputed efficacy in inflammatory lesions. In fact, areview of the literature by Eady et al. (40) showed that none of the topical antibioticsused in various studies was clinically better than benzoyl peroxide. A direct comparisonbetween a 10% benzoyl peroxide gel, a 1% clindamycin lotion, and a 20% azelaic acidcream found that the 10% benzoyl peroxide gel was significantly superior in reducing P.acnes at two and four weeks of treatment (41). Clinically, benzoyl peroxide has alsoadditive benefits when combined with other topical antibiotics (such as clindamycin orerythromycin) (42,43). Several previous studies have originally documented the efficacy of 2.5–10%benzoyl peroxide, which were reported in the Advance Notice of Proposed Rulemakingfor Topical OTC Acne Drugs and accepted as support for the efficacy of benzoylperoxide in acne (44). It is interesting to note that higher concentrations of benzoylperoxide have not been shown to be more effective in acne, but may actually increasethe risk of irritation. An eight-week study (45) compared the efficacy of 2.5% benzoylperoxide versus 10% benzoyl peroxide in 50 acne subjects. The results showed that bothtreatments significantly decreased the total number of papules and pustules, with nodifference in effectiveness between the two concentrations. There was also basically nodifference in the reduction of total lesions between the two concentrations, while theincidence and severity of adverse events was much higher in the 10% benzoyl peroxidegroup. Similar findings were reported by Mills et al. (46), in which they compared a2.5% benzoyl peroxide against its vehicle, and against a 5% and a 10% benzoylperoxide gel in three double-blind studies involving 153 patients with mild tomoderately severe acne vulgaris. The 2.5% benzoyl peroxide formulation was moreeffective than its vehicle and equivalent to the 5% and 10% concentrations in reducingthe number of inflammatory lesions. Orth et al. (47) investigated the penetration of a 2.5% and a 10% benzoyl peroxideformulation into the sebaceous follicles using cyanoacrylate follicular biopsy. The resultsshowed that benzoyl peroxide penetrated into the follicles within a few hours and that the2.5% formulation delivered a similar amount of benzoyl peroxide as the 10% product. Theauthors suggested that the vehicle of the 2.5% formulation played a significant role inenhancing the delivery of benzoyl peroxide. One of the few studies comparing benzoyl peroxide to topical retinoids wasconducted by Belknap (48). He compared 5% benzoyl peroxide twice daily versus 0.05%

260 Chen and Apparetinoic acid once daily in an eight-week study. Both treatments were “extremelyeffective” for all types of lesions and significantly reduced open and closed comedonesafter two weeks of treatment. Somewhat higher number of patients in the benzoyl peroxidegroup showed excellent results. A study by Shalita et al. showed the additive effect of the cleanser in acne treatment(49). They compared the efficacy of a combination of benzoyl peroxide 6% cleanser andtretinoin 0.1% microsphere gel versus tretinoin alone during a 12-week study. Fifty-sixsubjects with moderate acne completed the study. Both treatments showed a significantreduction in inflammatory and non-inflammatory lesions from baseline. However, thecombination regimen produced a greater reduction of inflammatory acne lesions than themonotherapy without increasing local irritation. Recently, a British study compared the efficacy and treatment costs of benzoylperoxide versus oral antibiotics (50). This 18-week study evaluated five antimicrobialacne treatments in approximately 650 participants: oral oxytetracycline; oral minocy-cline; benzoyl peroxide; separate administration of topical erythromycin and benzoylperoxide; and a combination of topical erythromycin and benzoyl peroxide. The authorsfound that topical 5% benzoyl peroxide used twice daily as single active agent wassimilar in efficacy to 100 mg minocycline once daily. The analysis of cost-effectivenessfound that the cheapest treatment (benzoyl peroxide) was 12 times more cost-effectivethan minocycline. Additionally, the authors noted that pre-existing propionibacterialresistance compromised the clinical efficacy of oral tetracyclines. In contrast, regimenscombining benzoyl peroxide with erythromycin were unaffected by resistance. Theauthors concluded that topical benzoyl peroxide and benzoyl peroxide/erythromycincombinations are similar in efficacy to oral antibiotics (oxytetracycline and minocycline).The more significant message is that the clinical equivalence comes without beingaffected by propionibacterial antibiotic resistance.Sulfur and Sulfur/Resorcinol CombinationsSulfur has been used to treat acne for hundreds of years for its peeling and dryingactions, and it is found in various washes, soaps, and creams. It is an antifungal andantibacterial agent. Its keratolytic activity is somewhat controversial, with some authorsshowing even a comedogenic effect (51). It is not fully understood how sulfur works inthe treatment of acne lesions. The claimed keratolytic properties may derive from theinteraction between sulfur and keratinocytes, producing hydrogen sulfide. Smaller sulfurparticles could allow greater interaction with keratinocytes and, therefore, producegreater therapeutic efficacy (52). Because of its unpleasant odor, sulfur is rarely usedalone. As an OTC ingredient, it is most frequently found in combination with resorcinol.Sulfur is also present in prescription acne products in combination withsodium sulfacetamide. Resorcinol has antibacterial, antifungal and mild keratolytic activity. When used asresorcinol monoacetate, this slowly liberates resorcinol, generating a milder but longerlasting effect. In the Acne Monograph, the OTC panel concluded that resorcinol is safe forhuman applications but did not find it efficacious in acne as a single ingredient (53).Therefore, resorcinol and resorcinol monoacetate are currently approved as OTC acneingredients only in combination with sulfur. Side effects of sulfur and of resorcinol include

Over-the-Counter Acne Medications 261mostly mild irritation. Unpleasant odor (sulfur) of the formulation may also be a problemfor patients. Sulfur preparations for acne treatments are not as popular as they were in the pastdecades. Although sulfur is found in the forms of cream, lotion, ointment, spot-treatmentmask, and bar soap, the more common use is in its prescription combination withsodium sulfacetamide. Published peer-reviewed studies on the efficacy of sulfur, alone or in combinationwith resorcinol, are basically non-existent. Few controlled efficacy studies are, however,described in the OTC Acne Monograph and were presented to the OTC panel assubstantiating material for the approval of these ingredients (54). Based on these studies,sulfur was approved as an acne ingredient in the concentrations of 3–8%. Resorcinol (2%)and resorcinol monoacetate (3%), however, were not found to be effective as singleingredients, and they were approved only in combination with sulfur 3–8% (55). The AcneMonograph reports that in a 12-week study (56), more subjects treated with 3% sulfurshowed a good to excellent response, compared to the vehicle group, although nostatistical analysis was conducted. A series of split-face, vehicle-controlled studies (57)showed a better reduction in lesion count in the subjects treated with a 5% sulfur productcompared to vehicle. Another study compared an 8% sulfur-2% resorcinol cream against placebocream in 25 subjects using a split-face design (58). After eight weeks of treatmentsulfur-resorcinol was significantly better in reducing open comedones, papules andpustules compared to placebo. A third study compared four treatment cells of 60 acnesubjects each. The treatments were applied three times daily for eight weeks andconsisted of: (i) 2.66% sulfur–1% resorcinol; (ii) 8% sulfur–2% resorcinol; (iii) 2.66%sulfur; and (iv) placebo. The two combinations of sulfur-resorcinol were foundequivalent and were superior to both the placebo and the sulfur alone in the reductionof papules and “whiteheads” (59). While the effect of sulfur on non-inflammatory lesions is not clear, itscombination with resorcinol seems to increase its efficacy in both inflammatory andcomedonal lesions.Adjunctive Acne ProductsA few adjunctive products have been promoted for the treatment of acne. Since these arenot sold as OTC drugs, well-controlled studies are usually missing and it is difficult tointerpret their true benefit as acne treatments.Tea Tree OilTea tree oil (TTO) is extracted from the Melaleuca alternifolia and in the past decade hasbecome a popular topical antimicrobial for skin conditions such as tinea pedis and acne.The three major components of TTO responsible for anti-P. acnes activity have beenfound to be alpha-terpineol ! terpinen-4-ol ! alpha-pinene (listed in order or increasedminimum inhibitory concentration (MIC) values) (60). Besides its anti-P. acnesproperties, TTO has been found to have a significant and rapid (within 10 minutes)anti-inflammatory activity when applied to histamine-induced weals (61). This could be anadditional pathway through which TTO improves inflammatory acne.

262 Chen and Appa One of the few clinical studies conducted in acne compared a 5% TTO gel with a5% benzoyl peroxide lotion in 124 acne patients. Both treatments had a significanteffect in improving both inflamed and non-inflamed acne lesions, although benzoylperoxide produced faster results. Fewer side effects, though, were experienced in theTTO group (62).BotanicalsAlthough products cannot be sold bearing an anti-acne label unless they contain an OTCapproved ingredient, many botanical formulations are marketed towards the acne-proneconsumer claiming to “heal,” “purify,” or “cleanse” the skin and pores. Companiespromote their proprietary formula of herb extracts, but well-conducted clinical studies arelacking, and therefore it is difficult to understand the true efficacy of these products. Theformulation may include different herb extracts with various activities (antimicrobial, anti-oxidant, anti-inflammatory, soothing, etc.).RetinaldehydesA novel European acne formulation combines 6% glycolic acid and 0.1% retinaldehyde.In a study on mild to moderate acne patients, the combination led to “important/veryimportant” global improvement at two months (63). This formulation has been alsosuggested to prevent post-inflammatory pigmentation (64).Capryloyl Salicylic AcidA lipophilic derivative of SA (capryloyl SA or LHA) has been proposed as a new anti-acneagent by a European firm. In a recent study, they showed that the LHA cream was welltolerated and significantly more effective than a control moisturizing cream throughout the87-day period as per the global evaluation scale (65). However, no comparison with itsvehicle cream or with any approved SA drug was presented.Oral Supplements (Nutraceuticals)Oral supplements have recently become more popular as a way of promoting total well-being. Some supplements are marketed as part of a multi-step aging or acne treatment.Nutraceuticals marketed for acne typically contain either herb extracts or specific vitamins(especially vitamin A and vitamin B-complex).Alpha-Hydroxyl AcidsAlpha-hydroxy acids (AHAs) such as glycolic acid and lactic acid have been used formany years by dermatologists at concentrations of 20% to 30% for facial peelprocedures. More recently, AHAs have been added to OTC washes and moisturizers atconcentrations of 4% to 6%. AHAs have been found to soften the stratum corneum,remove dead cells, and change free radicals on the skin. These products combine wellwith both topical comedolytics and topical antibiotics. They can be used as the dailyfacial cleanser or moisturizer before application of prescription medication. AHAs in the20% to 30% strength help to improve discoloration and scarring. Mild benefit can also beseen at the 4% to 6% strength. As with all other topical products, irritation may be aproblem, especially during the initial few weeks of usage. AHAs are sometimes used

Over-the-Counter Acne Medications 263alone in mild acne. Various products, though, add glycolic acid to SA formulationsclaiming an increase in the exfoliation benefits. A 2% lactic acid cream gel preparationhas been reported to be effective in both inflammatory and non-inflammatory acnelesions compared to placebo (66).Over-the-Counter Combination TherapySince acne is a multi-factorial disorder, dermatologists recommend the use of combinationtherapy. In analogy, an OTC combination therapy was recently developed to treat multiplepathogenic factors of acne. This system combines a 2.5% benzoyl peroxide lotion with anSA cleaner that also contains glycolic acid. A daytime broad-spectrum sunscreencontaining a proprietary blend of skin soothing naturals is included in the system as perFDA recommendation (67). This OTC combination therapy system was compared to a benzoyl peroxide onlysystem in a double-blind, randomized, placebo-controlled clinical study on 90 subjectswith mild to moderate acne. Both systems were well tolerated, although the benzoylperoxide–only system had slightly higher irritation. The clinical results showed that theOTC combination therapy system with both SA and benzoyl peroxide treatmentproducts rapidly improved acne within one week and continued to further ameliorateover the course of treatment. Target pimple size, edema and erythema weresignificantly reduced within two days (first time point). Significant reduction of full-face total acne lesion counts was seen as early as day 4. In contrast, the benzoylperoxide only system did not show significant reduction of full face acne lesions untilweek 2 and global acne severity until week 4 (68). The time course kinetics of thetreatments (charts in Fig. 2) show that the main difference clinically appeared to be inthe superior reduction of the closed comedones or the primary lesions by the SACBPOOTC combination therapy system. These results demonstrate the value of using the combination therapy approach inOTC acne treatments as in Rx.Clinical Imaging in the Development and Evaluationof Over-the-Counter Acne ProductsPhotography has been a useful tool for evaluating and documenting treatment benefits(Fig. 3 for example). Several acne-grading methods have even been proposed based onphotographs. Recent advancement in digital imaging has made image capture andevaluation much more convenient. The techniques that have been applied to clinicalimaging go beyond just regular photography that mainly utilizes the visible lightspectrum. Photographers have used polarized filters to either cut through the surfacespecula for a matted appearance with cross-polarized light (Fig. 4 for example), or toenhance the surface specula to make the shine shinier or the surface texture more3-dimensional–like with the help of parallel-polarized light. Skin redness andpigmentation are highlighted in cross-polarized light images, while parallel-polarizedlight images bring out the surface luminosity and make the height of a pimple or thedepth of a wrinkle more distinctive.

264 Chen and Appa(A) Whole Face Inflammatory Lesion Counts 20% 10%Mean Change from Baseline 0% 10 20 30 40 50 60 0 -10% -20% -30% SA+BPO System -40% BPO Only System -50% Untreated Treatment Time (Days)(B) Closed Comedone Counts 30% 20%Mean Change from Baseline 10% 0% 10 20 30 40 50 60 0 SA+BPO System -10% BPO Only System Untreated -20% -30% -40% -50% Treatment Time (Days)Figure 2 Treatment effects of an over-the-counter regimen containing salicylic acid and benzoylperoxide versus a regimen containing only benzoyl peroxide. Upper chart (A) shows the changes inthe total inflammatory lesion counts and the lower chart (B) shows the changes in closed comedonecounts. Asterisks denote significantly greater reduction among treatments in favor of the labeledtreatment.

Over-the-Counter Acne Medications 265Figure 3 Acne skin images from visible light photography comparing the skin conditions before,during and after treatment with an over-the-counter combination therapy system (salicylic acid Cbenzoyl peroxide). Note the marked improvements in skin texture, bumpiness and clarity. Skinredness was also reduced (data not shown).Figure 4 Cross-polarized light images tracking pimple resolution and redness reduction of a pimpletreated with a 2% SA gel (active) and of an untreated pimple. Blinded analysis of individual pimple imagesshowed pimple resolution by the 2% SA gel was faster than by the placebo (the vehicle gel) and theuntreated control, and similar to that of a 10% benzoyl peroxide lotion. Abbreviation: SA, salicylic acid.

266 Chen and Appa(A) ERYTHEMA CHANGE ACTIVE 5 FROM BASELINE PLACEBO 0 10 20 30 40 50 60 −5 TIME (HRS) −10 −15 −20 −25 0(B) 5EDEMA CHANGE 0 FROM BASELINE ACTIVE PLACEBO −5 −10 10 20 30 40 50 60 0 TIME (HRS)Figure 5 Time Course of target Lesion resolution as measured by hyper-spectral image analysisquantifying (A) Erythema, and (B) Edema (water). Another imaging technique involves the use of UV-enriched lamp or blue light.When the skin is illuminated in this manner, the pilosebaceous glands glow as intenselyyellow-green or orange-red fluorescent spots (69). Partially or totally cloggedpilosebaceous glands all show particularly intense fluorescence of different sizes andbrightness, reflecting the degrees to which they are blocked. While the yellow-greenfluorescence is associated with the pore plug materials, the orange-red fluorescenceis shown to be the emission at wavelengths of 620 and 680 nm by the P. acnes under

Over-the-Counter Acne Medications 267385–415 nm light (70–73). The intensity of this orange-red fluorescence is proportional tothe density of P. acnes and declines under effective antibiotic treatment (74,75).Fluorescence photography is thus a quick way to assess the antibacterial efficacy ofbenzoyl peroxide formulations (76). A powerful method has recently been developed that incorporates all of the aboveimaging techniques to enable concurrent evaluation of clinical and sub-clinical conditionsin the skin (77,78). The most recent advancement in the clinical digital imaging field is the hyper-spectral imaging technique (79). This technique uses narrow-band filters in front of thecamera to acquire a series of images (called a hyper-spectral cube). The narrow band filtersare selected to detect different chromophores in the skin, the distribution of which iscaptured in the corresponding images. Each pixel in an image, thus, contains spectralinformation of the corresponding imaged site on the skin. Reflectance data can be analyzedon a pixel-by-pixel basis to yield chromophore concentrations (oxy-hemoglobin, deoxy-hemoglobin, melanin, water, and light scattering). Increased local oxy-hemoglobinconcentrations are manifested as erythema. Increased local water concentrations arerelated to interstitial fluid accumulation due to edema. Chen et al. (80) studied theprogression of acne lesion maturation by monitoring lesion erythema and edema withhyperspectral imaging. An example of the results that can be obtained is shown in Fig. 5.Chantalat et al. (81) applied hyperspectral imaging to detect sub-clinical acne lesions thatwere not yet visible on the skin surface, and tracked the effects of treatments on resolvinginflammation associated with the sub-clinical lesions. These studies demonstrate theunique potential of hyperspectral imaging in the evaluation of clinical and sub-clinicalacne non-invasively.SUMMARYMajority of acne sufferers rely upon OTC acne medication to treat their acne. Therefore itis incumbent upon the OTC manufacturers to improve OTC formulations in response tothe unmet needs of the average acne patients. While no new OTC acne ingredients haveemerged since FDA issued the Final Acne Monograph in 1991, step change has takenplace in terms of improved delivery of actives, the choices of vehicles, and the forms oftreatments. This is particularly true with daily regimen. It has changed the paradigm ofOTC acne therapy from reactive, occasional and irregular usage to routine daily treatmentproviding the ultimate acne control. The body of works mentioned in this chapter clearly demonstrates that both benzoylperoxide and SA are two powerful acne-fighting ingredients. Even though benzoylperoxide has been the mainstay in OTC acne therapy, our recent work indicates that SAhas been under-appreciated. With proper formulation, SA can provide rapid acneclearance with overall efficacy comparable to a 10% benozyl peroxide treatment, whileproviding high degree of skin compatibility. In parallel, we have developed powerful, non-invasive imaging and spectraltechniques to track acne clinically and sub-clinically at the follicular level.These advanced acne diagnostic methods will enable dermatologists and scientiststo develop a much clearer understanding of the acne life cycle in vivo and controlits emergence.

268 Chen and AppaREFERENCES 1. White GM. Recent findings in the epidemiologic evidence, classification, and subtypes of acne vulgaris. J Am Acad Dermatol 1998; 39:S34–S37. 2. Krowchuk DP, Stancin T, Keskinen R, Walker R, Bass J, Anglin TM. The psychosocial effects of acne on adolescents. Pediatr Dermatol 1991; 8:332–338. 3. Pochi PE. The pathogenesis and treatment of acne. Ann Rev Med 1990; 41:187–198. 4. Kraning KK, Odland GF. Analysis of research needs and priorities in dermatology. J Invest Dermatol 1979; 73:395–513. 5. Kellett SC, Gawkrodger DJ. The psychological and emotional impact of acne: the effect of treatment with isotretinoin. Br J Dermatol 1999; 140:273–282. 6. Jancin B. Teens with acne cite shame, embarrassment about skin. Skin Allergy News 2004; January:28. 7. Woodard I. Adolescent acne: a stepwise approach to management. Topics in Advanced Practice Nursing eJournal 2002; 2(2). 8. Malus M, LaChance PA, Lamy L, Macaulay A, Vanasse M. Priorities in adolescent health care: the teenager’s viewpoint. J Fam Pract 1987; 25:159–162. 9. Agency for healthcare research and quality. Management of acne. Evidence report/technology assessment: number 17. Agency for healthcare research and quality (AHRQ) publication No 01-E018; March 2001.10. 21CFR Part 333.350(b)(2), Federal Register, 1991; 56:41020.11. Federal Register, 1995; 60:9555.12. Federal Register, 1982; 60:9554–9558.13. Federal Register, 1982; 47:12443–12447.14. Fitzpatrick TH, Freedberg IM, Eisen AZ, et al. In: Dermatology in General Medicine. New York: McGraw-Hill, 1999:769–784.15. Federal Register, 1991; 56:41015.16. Scheman AJ, Severson DL. 6th ed Pocket Guide to Medications Used in Dermatology. New York: Lippincott Williams & Wilkins, 1999.17. 21 CFR Part 333 Section II.I.3, Federal register, 1982; 47:12443.18. Olin B, ed. Facts and Comparisons. St. Louis (MO): JB Lippincott Co., 1990.19. Shalita AR. “Double-blind investigation of 2% salicylic acid solution versus vehicle solution and active control (benzoyl peroxide 5%) in the treatment of acne vulgaris Pillsbury grades I to III,” included in Comment No C00002, Docket No.81N-0114, Dockets Management Branch.20. Leyden J. “Double-blind investigation of 0.5% and 2% salicylic acid solutions (medicated pads) versus vehicle solutions (pads) in the treatment of acne vulgaris pillsbury grades I to III,” included in comment No SUP, docket No.81N-0114, dockets management branch.21. Shalita AR. Comparison of a salicylic acid cleanser and a benzoyl peroxide wash in the treatment of acne vulgaris. Clin Ther 1989; 11:264–267.22. Pagnoni A, Chen T, Duong H, Wu IT, Appa Y. Clinical evaluation of a salicylic acid containing scrub, toner, mask and regimen in reducing blackheads. 61st meeting, American academy dermatology, Feb 2004, Poster#97.23. Eady EA, Burke BM, Pulling K, Cunliffe WJ. The benefit of 2% salicylic acid lotion in acne—a placebo-controlled study. J Dermatol Treat 1996; 7:93–96.24. Zander E, Weisman S. Treatment of acne vulgaris with salicylic acid pads. Clin Ther 1992; 14:247–252.25. Herndon JH, Stephens TJ, Singler M, Asuncion A, Chen T, Appa Y. Rapid acne resolution by a 2% salicylic acid gel containing a complex of naturals. J Am Acad Dermatol 2004; 50:23.26. Ok Kim H, Galzote CJ, Estanislao RB, Asuncion A, Chen T, Appa Y. Clinical assessment of a salicylic acid formulation containing a complex of naturals for the treatment of acne vulgaris in Asian subjects. J Am Acad Dermatol 2004; 50:24.

Over-the-Counter Acne Medications 26927. Miller D, Smith G, Kurtz ES, Berger RS. Gentle and fast-acting relief from a salicylic acid acne treatment with soothing natural extracts. J Am Acad Dermatol 2004; 50:12.28. Yamamoto A, Takenouchi K, Ito M. Impaired water barrier function in acne vulgaris. Arch Dermatol Res 1995; 287:214–218.29. Chantalat J, Wu J, Lu JC. Characterization of a synergistic microgel complex that improves acne treatment efficacy. Presented at the annual meeting of American academy of dermatology, San Francisco, CA, 2006.30. Chantalat J, Lu JC, Chen T, Appa, Y. Treating emerging acne. Presented at the annual meeting of American academy of dermatology, San Francisco, CA, 2006.31. Bojar RA, Cunliffe WJ, Holland KT. Short-term treatment of acne vulgaris with benzoyl peroxide: effects on the surface and follicular cutaneous microflora. Br J Dermatol 1995; 132:204–208.32. Pagnoni A, Kligman AM, Kollias N, et al. Digital fluorescence photography can assess the suppressive effect of benzoyl peroxide on Propionibacterium acnes. J Am Acad Dermatol 1999; 41:710–716.33. Kim J, Ochoa MT, Krutzik SR, et al. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol 2002; 169:1535–1541.34. Vowels BR, Yang S, Leyden JJ. Induction of proinflammatory cytokines by a soluble factor of Propionibacterium acnes: implications for chronic inflammatory acne. Infect Immun 1995; 63:3158–3165.35. Gollnick H, Cunliffe W, Berson D, et al. Management of acne. A report from a global alliance to improve outcomes in acne. J Am Acad Dermatol 2003; 49:S1–S37.36. Del Rosso J. Keeping it clean. Skin Aging 2003; August:82–87.37. Neutrogena corporation clear pore cleanser mask.38. TRIAZw (Medicis) prescribing information.39. Federal Register, 1995; 60:9554.40. Eady EA, Cove JH, Joanes DN, Cunliffe WJ. Topical antibiotics for the treatment of acne vulgaris: a critical evaluation of the literature on their clinical benefit and comparative efficacy. J Dermatol Treat 1990; 1:215.41. Leyden JJ, Gans EH. Evaluation of the antimicrobial effects in vivo of triaz gel (benzoyl peroxide special gel), Cleocin-Tw lotion (clindamycin phosphate lotion), and Azelexw cream (azelaic acid cream) in humans. J Dermatolog Treat 1997; 8:S7–S10.42. Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and vehicle gel: combined results of two double-blind investigations. J Am Acad Dermatol 1997; 37:590–595.43. Chalker DK, Shalita A, Smith JG, Jr, Swann RW. A double-blind study of the effectiveness of a 3% erythromycin and 5% benzoyl peroxide combination in the treatment of acne vulgaris. J Am Acad Dermatol 1983; 9:933–936.44. FR 1982, 12445–12446.45. OTC Volume 070270.46. Mills OH, Jr., Kligman AM, Pochi P, Comite H. Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris. Int J Dermatol 1986; 25:664–667.47. Orth DS, Widjaja J, Wortzman MS. Benzoyl peroxide concentration in follicular casts. Cosmetics Toiletries Mag 1997; 112:87–90.48. Belknap BS. Treatment of acne with 5 percent benzoyl peroxide gel or 0.05 percent retinoic acid cream. Cutis 1979; 18:485–488.49. Shalita AR, Rafal ES, Anderson DN, Yavel R, Landow S, Lee WL. Compared efficacy and safety of tretinoin 0.1% microsphere gel alone and in combination with benzoyl peroxide 6% cleanser for the treatment of acne vulgaris. Cutis 2003; 72:167–172.50. Ozolins M, Eady EA, Avery AJ, et al. Comparison of five antimicrobial regimens for treatment of mild to moderate inflammatory facial acne vulgaris in the community: randomised controlled trial. Lancet 2004; 364:2188–2195.

270 Chen and Appa51. Mills O, Kligman A. Drugs that are ineffective in the treatment of acne vulgaris. Br J dermatol 1983; 108:371–374.52. Lin AN, Reimer RJ, Carter DM. Sulfur revisited. J Am Acad Dermatol 1988; 18:553–558.53. FR 1982; 12459–12460.54. FR 1982; 12447–12448.55. FR 1982; 12468–12469.56. OTC Volume 070099.57. OTC Volume 070168.58. OTC Volume 070236.59. OTC Volume 070256.60. Raman A, Weir U, Bloomfield SF. Antimicrobial effects of tea-tree oil and its major components on Staphylococcus aureus, Staph epidermidis, and Propionibacterium acnes. Lett Appl Microbiol 1995; 21:242–245.61. Koh KL, Pearce AL, Marshman G, Finlay-Jones JJ, Hart PH. Tea tree oil reduces histamine- induced skin inflammation. Br J Dermatol 2002; 147:1212–1217.62. Bassett IB, Pannowitz DL, Barnetson RS. A comparative study of tea-tree oil versus benzoyl peroxide in the treatment of acne. Med J Aust 1990; 153:455–458.63. Poli F, Ribet V, Lauze C, Adhoute H, Morinet P. Multicentre, double-blind, randomized, vehicle-controlled trial. Dermatology 2005; S1:14–21.64. Boisnic S, Branchet-Gumila MC, Nocera T, Verriere F. RALGA (Diacneal) decreases melanin content in a human skin model. Dermatology 2005; S1:35–38.65. Rougier A, Richard A, Stengel F, Cannavo A. New advances in the treatment of inflammatory acne. J Am Acad Dermatol 2005; 52:11.66. Presto S, Wehmeyer A, Rippke F, et al. In vivo assessment of the efficacy of an innovative face care system (Eucerinw impure skin) in subjects with mild acne vulgaris. J Eur Acad Dermatol Venereol 2000; 14:207.67. Federal Register, 1995; 60:9554.68. Chen T, Herndon JH, Stephens T, Appa Y. Constant attenuation of acne by a 2-step regimen containing both salicylic acid and benzoyl peroxide treatments. J Am Acad Dermatol 2005; 52:P16.69. Bommer S. Hautuntersuchungen im gefilterten quarzlicht. Klin Wochenschr 1927; 6:1142–1144.70. Cornelius CE, III, Ludwig GD. Red fluorescence of comedones: production of porphyrins by Corynebacterium acnes. J Invest Dermatol 1967; 49:368–370.71. Melo¨ TB, Johnsson M. In vivo porphyrin fluorescence from Proprionibacterium acnes. A characterization of the fluorescing pigments. Dermatology 1982; 164:167–174.72. Lee WL, Shalita AR, Poh-Fitzpatrick MB. Comparative studies of porphyrin production in Propionibacterium acnes and Propionibacterium granulosum. J Bacteriol 1978; 13:811–815.73. Sauermann G, Ebens B, Hoppe U. Analysis of facial comedos by porphyrin fluorescence and image analysis. J Toxicol Cutan Ocular Toxicol 1989; 8:369–385.74. McGinley KJ, Webster GF, Leyden JJ. Facial follicular porphyrin fluorescence: correlation with age and density of Propionibacterium acnes. Br J Dermatol 1980; 102:437–441.75. Martin RJ, Kahn G, et al. Cutaneous porphyrin fluorescence as an indicator of antibiotic absorption and effectiveness. Cutis 1973; 12:758–764.76. Pagnoni A, Kligman AM, Kollias N, et al. Digital fluorescence photography can assess the suppressive effect of benzoyl peroxideon Propionibacterium acnes. J Am Acad Dermatol 1999; 41:710–716.77. Merola K, Chen T, Appa Y. U.S. patent, filed Nov. 2001, serial no. 10/008 579.78. Chen T, Stamatas G, Kollias N, Appa Y. High resolution imaging of acne. J Am Acad Dermatol 2005; 52:P22.79. Stamatas GN, Balas C, Kollias N. Hyperspectral image acquisition and analysis of skin. Proc SPIE 2003; 4959:77–82.

Over-the-Counter Acne Medications 27180. Chen T, Stamatas G, Kollias N, Appa Y. High resolution imaging evaluation of acne. Poster #22 presented at the 63rd annual meeting of American academy of dermatology, Febuary 18– 22, 2005, New Orleans, LA. Abstract published in J Am Acad Dermatol 2005; 52:P22.81. Chantalat J, Lu JC, Chen T, Appa Y. Treating emerging acne. Poster #128 presented at the 64th annual meeting of American academy of dermatology, San Francisco, CA, March 3–7, 2006.

17Acne Treatment MethodologiesEmmy M. Fernandez, Andrea L. Zaenglein, and Diane M. ThiboutotDepartment of Dermatology, Pennsylvania State University Milton S. Hershey MedicalCenter, Hershey, Pennsylvania, U.S.A.INTRODUCTIONAcne is an exceedingly common condition affecting millions of adolescents and youngadults. Not surprisingly, the psychological and economic impact of acne is reflected inthese vast numbers. The prevalence in teenage girls ranges from 16–80%, while teenageboys are even more likely to be affected with prevalence ranging from 29–90% (1–4).These large variations in prevalence are due to differences in acne grading scales used inthe various studies. Adult acne, although less common than adolescent acne, continues tobe a significant problem for 3–6% of adult men, and 5–12% of adult women well into theirthirties and forties (5,6). With so many persons affected, the economic impact of acne isimmense. In 1999 there were approximately 35 million Americans with acne generating7.9 million physician visits. That same year approximately 1.2 billion dollars was spent onprescription acne medications (7). In addition to the economic impact, acne also has a significant psychological impact inboth adolescents and adults.Thirty to fifty percent of adolescents experience psychiatricdisturbances due to acne (8). Studies have shown that acne causes similar levels of social,psychological, and emotional impairment as asthma and epilepsy (9). Studies have also shownthat unemployment is higher among adults with acne than among adults without acne (10). In order to implement effective treatment strategies for patients with acne, a solidunderstanding of the physiology of the pilosebaceous unit and the pathological events thatlead to acne are essential. The pathogenesis of acne is very complex, but four basic stepshave been identified. These key elements (Fig. 1) are: (i) follicular epidermal hyper-proliferation, (ii) excess sebum production, (iii) inflammation, and (iv) the presence andactivity of Propionibacterium acnes (P. acnes).Follicular Epidermal HyperproliferationFollicular epidermal hyperproliferation results in the formation of the primary lesion ofacne, the microcomedo. The epithelium of the upper hair follicle, the infundibulum,becomes hyperkeratotic with increased cohesion of the keratinocytes. The excess cells andtheir tackiness result in a plug in the follicular ostium. This plug then causes downstreamconcretions of keratin, sebum, and bacteria to accumulate in the follicle. These packedconcretions cause dilation of the upper hair follicle producing a microcomedo. Thestimulus for keratinocyte hyperproliferation and increased adhesion is unknown. However, 273

274 Fernandez et al.(A) (B) PATHOGENESIS OF ACNE (D)Epidermis Sebaceous (C) lobuleEpitheliumEarly comedone Later comedone Inflammatory papule/pustule Nodule/cyst Infundibulum Accumulation of shed keratin Propionibacterium acnes Marked inflammation −hyperkeratosis and sebum proliferation Scarring − ↑ corneocyte cohesiveness Formation of whorled lamellar Sebaceous lobule regression Androgen stimulation concretions Mild inflammation of sebum secretionFigure 1 Acto Pathogenesis. The four key steps in acne pathogenesis: (A) follicular epidermalhyperproliferation, (B) excess sebum production, (C) inflammation, and (D) the presence andactivity of Propionibacterium acnes. Source: Adapted from Ref. 11.several proposed factors in keratinocyte hyperproliferation include: androgen stimulation,decreased linoleic acid, and increased interleukin-1 alpha (IL-1 alpha) activity. Androgenic hormones may act on the follicular keratinocytes stimulatinghyperproliferation. Dihydrotestosterone (DHT) is a potent androgen that may play a rolein acne. Figure 2 demonstrates the physiologic pathway for dehydroepiandrosterone sulfate(DHEA-S) conversion to the androgen DHT. 17-beta HSD and 5-alpha reductase, areenzymes responsible for converting DHEA-S to DHT. When compared to epidermalkeratinocytes, follicular keratinocytes have increased 17-beta HSD, and 5-alpha reductasethus enhancing DHT production (12,13). DHT may stimulate follicular keratinocyteproliferation. Also supporting the role of androgens in acne pathogenesis is the evidence thatthe individuals with complete androgen insensitivity do not get acne (14). Follicular keratinocyte proliferation may also be regulated by linoleic acid. Linoleicacid is an essential fatty acid in the skin that is decreased in subjects with acne. The quantityof linoleic acid normalizes after successful treatment with isotretinoin. Subnormal levelsof linoleic acid may induce follicular keratinocyte hyperproliferation, and produce pro-inflammatory cytokines. It has also been suggested that regular quantities of linoleic acid areactually produced but are simply diluted by increased sebum production (15). In addition to androgens and linoleic acid, IL-1 may also contribute to keratinocytehyperproliferation. Human follicular keratinocytes demonstrate hyperproliferation andmicrocodemo formation when IL-1 is added. IL-1 receptor antagonists inhibitDHEA 3-beta-HSD androstenedionearomatase 17-beta-HSDestrone testosterone17-beta-HSD 5-alpha-R aromataseestradiol dihydrotestosterone androstanediols 3-beta and 3-alpha-HSDsFigure 2 Steroid metabolic pathway. DHEA is a weak androgen that is converted to the morepotent testosterone by 3-beta-HSD and 17-beta-HSD. Five-alpha-reductase then convertstestosterone to dihydrotestosterone, the predominant hormonal effector on the sebaceous gland.Both DHEA and testosterone can be metabolized to estrogens by the enzyme aromatase. Thesebaceous gland expresses each of these enzymes. Source: Adapted from Ref. 11.

Acne Treatment Methodologies 275microcodemo formation providing additional support for the cytokine’s role in acnepathogenesis (16,17).Excess Sebum ProductionThe second key feature in the pathogenesis of acne is excess sebum production from thesebaceous gland. Patients with acne produce more sebum than those without acne althoughthe quality of sebum is the same between the two groups (18). One of the components ofsebum, triglycerides, may play a role in acne pathogenesis. Triglycerides are broken downinto free fatty acids by P. acnes, normal flora of the pilosebaceous unit. These free fatty acidspromote further bacterial clumping and colonization of P. acnes, incite inflammation, andmay be comedogenic (19). Androgenic hormones also influence sebum production. Similar to their action onthe follicular infundibular keratinocytes, androgen hormones bind to and influencesebocyte activity (20). Those with acne have higher average serum androgen levels(although still within normal range) than unaffected controls (21,22). 5-alpha reductase,the enzyme responsible for converting testosterone to the potent DHT, has greatest activityin areas of skin prone to acne, the face, chest, and back (23). The role of estrogen on sebum production is not well defined. The dose of estrogenrequired to decrease sebum production is greater than the dose required to inhibit ovulation(24). The mechanisms by which estrogens may work include: (i) directly opposing theeffects of androgens within the sebaceous gland; (ii) inhibiting the production of androgensby gonadal tissue via a negative feedback loop on pituitary gonadotrophin release; and (iii)regulating genes that suppress sebaceous gland growth or lipid production (25).InflammationThe microcomedo will continue to expand with densely packed keratin, sebum, andbacteria. Eventually this distension will cause follicular wall rupture. The extrusion of thekeratin, sebum, and bacteria into the dermis results in a brisk inflammatory response. Thepredominant cell type within 24 hours of comedo rupture is the lymphocyte. CD4Clymphocytes are found around the pilosebaceous unit while CD8C cells are foundperivascularly. One to two days after comedo rupture, the neutrophil becomes thepredominant cell type surrounding the burst microcomedo (26).Propionibacterium AcnesAs mentioned above, P. acnes also plays an active role in the process of inflammation.P. acnes is a gram-positive, anaerobic, and microaerobic bacterium found in the sebaceousfollicle. Adolescents with acne have higher concentrations of P. acnes compared to non-acne controls. However, there is no correlation between the raw number of P. acnesorganisms present in a sebaceous follicle and the severity of the acne (27). The cell wall of P. acnes contains a carbohydrate antigen that stimulates antibodydevelopment. Those patients with the most severe acne have the highest titers of antibodies(28). The anti-P. acnes antibody enhances the inflammatory response by activating thecomplement cascade and thus initiating pro-inflammatory events (29). P. acnes alsofacilitates inflammation by eliciting a delayed type hypersensitivity response (30) and byproducing lipases, proteases, hyaluronidases, and chemotactic factors (31). Additionally,P. acnes has been shown to stimulate an upregulation of cytokines by binding to toll-likereceptor 2 (TLR-2) on monocytes and polymorphonuclear cells surrounding the sebaceousfollicle (32). After binding TLR-2, pro-inflammatory cytokines such as IL-1, IL-8, IL-12,and TNF-alpha are released (33,34).

276 Fernandez et al. The four elements of acne pathogenesis—follicular keratinocyte hyperproliferation,seborrhea, inflammation, and P. acnes—are intertwined steps in the formation of acne.Various acne treatments target different elements in acne pathogenesis. Understanding themechanisms of action of the multitude of therapeutic options in treating acne will helpassure better therapeutic results.MORPHOLOGYClinically, acne can present as non-inflammatory or inflammatory lesions or both. Non-inflammatory acne is marked by the presence of codemos. Codemos are follicular-basedpapules that may be either open or closed. Open codemos, commonly called blackheads, arepapules with prominent dilated follicular ostia. Closed codemos, or whiteheads, are fleshcolored papules without an evident follicular opening. Inflammatory acne can include lesionssuch as erythematous papules, pustules, nodules, cysts, or plaques. Post-inflammatory hyper-or hypopigmentation are common sequelae of inflammatory acne. However, scarring can be acomplication of both inflammatory and non-inflammatory acne.TOPICAL RETINOIDAll acne lesions begin as non-inflammatory lesions, either open or closed codemos. Topicalretinoids are a mainstay of acne treatment due to their ability to hamper the primary acnelesion, the microcodemo. Additionally, retinoids have fairly potent anti-inflammatoryeffects. Retinoids are structural and functional analogs of vitamin A that exist in both topicaland systemic forms. They act by binding to two nuclear receptor families withinkeratinocytes: the retinoic acid receptors (RAR), and the retinoid X receptors (RXR). Eachof the receptor families contains three receptor isotypes: alpha, beta, and gamma. In thehuman epidermis RXR receptors are by and large the alpha isotype and RAR are generallythe gamma isotype (35). Both families of receptors act as ligand-activated transcriptionfactors. The RAR receptors function as a heterodimer by binding to RXR. The RXRreceptors may act as homodimers or may bind to other nuclear receptors such as: vitaminD3, thyroid hormone, and peroxisome proliferator-activated receptors. The retinoidreceptors bind to specific regulatory DNA sequences called retinoid hormone responseelements (HREs) where transcription is activated. The retinoid HREs activate thetranscription of genes that normalize follicular keratinization, and decrease cohesiveness ofkeratinocytes. This prevents the formation of microcodemos. The retinoid-receptorcomplex also antagonizes genes that do not contain retinoid HRE. AP-1 and NF-IL6 arekey transcription factors in inflammatory responses. The retinoids suppress thesetranscription factors by competing for the co-activator proteins needed to activate AP-1and NF-IL6 (36). These combined anti-comedogenic and anti-inflammatory propertiesmake retinoids beneficial for patients with either non-inflammatory or inflammatory acne.TretinoinTretinoin, the original topical retinoid, has been formulated in different vehicles in anattempt to decrease the irritation associated with the original formulations (Table 1). Onedelivery system involves the use of inert microspheres impregnated with tretinoin to allowfor a slower delivery of tretinoin (Retin-A Microw 0.04%, and 0.1% gel). Anotherformulation involves the combination of tretinoin with polyolprepolymer-2 (Avitaw).Polyolprepolymer-2 prevents rapid percutaneous absorption of tretinoin, thus lesseningsome of the early irritation experienced with pure tretinoin products (37). Less peeling and

Acne Treatment Methodologies 277Table 1 Topical Retinoid Preparations Used for Treatment of Acne VulgarisDrug Trade Vehicle ConcentrationTretinoin Retin-A Cream 0.025%, 0.05%, 0.1% Gel 0.01%, 0.025%Adapalene Retin-A Micro Solution 0.05%Tazarotene Gel with 0.04%, 0.1% Avita Altinac microsponge 0.025% Renova system 0.025% Generic Cream 0.025%, 0.05%, 0.1% Differin Gel Cream 0.025%, 0.05%, 0.1% Tazorac Cream 0.025% Cream 0.1% Gel 0.1% Cream 0.1% Gel 0.05%, 0.1% Solution 0.05%, 0.1% Gel CreamMany topical retinoids are available in different vehicles and varying concentrations.Source: Adapted from Ref. 11.drying can be seen in patients using Avitaw (37,38). A multi-center, double-bind, parallelstudy demonstrated comparable efficacy between Avitaw and tretinoin 0.025% cream in215 patients after 12 weeks of treatment (38).AdapaleneAdapalene and tazarotene are topical medications that are formulated to bind the to theRAR without affinity for the RXR. Adapalene is a naphthoic acid derivative that wasmanufactured to be structurally similar to a naturally occurring hormone, retinoic acid. Itworks by directly binding to the RAR gamma and beta. A multi-center trial comparingadapalene 0.1% gel to tretinoin 0.025% gel found adapalene to produce a greater decreasein inflammatory and non-inflammatory lesions over a 12-week period. The adapalenegroup also had significantly less side effects of erythema, scaling, dryness, and burning(39). Adapalene is light stable allowing for daytime use. Adapalene is also resistant tooxidation by benzoyl peroxide. It is available in 0.1% concentration in a cream, solution,pledget, and propylene glycol-based gel.TazaroteneTazarotene, a synthetic retinoid, exerts it action through its metabolite tazarotenic acid thatbinds RAR-beta and gamma. Studies have shown that tazarotene 0.1% gel is moreeffective than tretinoin 0.025% gel (40) or tretinoin 0.1% microspheres (41). Tazarotenecan be used once daily overnight similarly to tretinoin or it can be applied for a briefperiod, and then washed off. This latter method minimizes irritation but maintains efficacyby exposing the skin to the retinoid for only five minutes once a day (42). It is available in0.05% or 0.1% cream or gel formulations. While the other topical retinoids are classified as pregnancy category “C,”tazarotene is category “X” (Table 2). In two surveys of patients with first trimesterexposures to tretinoin, there was no increased incidence of congenital malformations

278 Fernandez et al.Table 2 Comparison of Topical RetinoidsGeneric Required nighttime use? Inactivated by benzoyl Pregnancy category peroxide?Tretinoin Yes Yes CAdapalene No No CTazarotene No Yes XComparison of topical retinoids with regards to inactivated by sunlight and benzoyl peroxide and their pregnancycategories.(43,44). In one study, six patients who inadvertently became pregnant while on tazarotenehad no babies with congenital malformations (45). This difference in categorization is dueto the dual indication for tazarotene for both acne vulgaris and psoriasis. In psoriasispatients, larger amounts of tazarotene are used thus raising plasma levels of the retinoid toteratogenic potential. Only one pregnancy class can be assigned to a drug, thereforecategory “X” was designated given thus drug’s potential to be used on a large surface area(46). Therefore, female patients must undergo contraceptive counseling while ontazarotene. For women who intend to become pregnant, there is no specific recommendedwash-out period after tazarotene use (45).Adverse EffectsAlthough effective for different types of acne, topical retinoids commonly cause adverseeffects. These are generally mild in severity and usually during the start of therapy. Withinthe first month of treatment many patients experience a “retinoid dermatitis.” This mayconsist of erythema, burning, scaling, pruritus, and dryness. These effects tend to decreasewith continued use. Detailed instructions on appropriate use of retinoids can help limit anyadverse side effects and enhance tolerability (Table 3). In general, a pea-sized amountshould be applied evenly over the entire face. If any medicine is visible on the skin afterapplication too much was applied and additional irritation may ensue. Instructing patientsto apply their retinoid to dry skin can also minimize retinoid dermatitis. Patients should beadvised to wait 15 minutes after washing the face to apply a topical retinoid. Wet skinenhances the penetration of the retinoid into the dermis, thus exacerbating irritation.A gradual increase in application frequency can also help to minimize irritation. Thepatient should apply the retinoid starting every other night or every third evening for theTable 3 Patient Information About Topical RetinoidsWhen initiating treatment, apply topical retinoids every second or third day for the first couple weeks and gradually increase to once-daily applicationTretinoin must be applied at nightWait 15 minutes after washing face to apply the retinoidApply a pea-sized amount to cover the entire faceDo not use a benzoyl peroxide product at the same time of day as retinoid application (concomitant use all right with adapalene)Redness, burning, scaling, pruritus, and dryness may occur, especially during the first month of treatment. These side effects generally decrease with useA non-comedogenic moisturizer may be used to prevent drynessPhotosensitivity may occur with all retinoidsSome patients experience a flare of their acne during the first few weeks of treatmentThe above patient information regarding topical retinoid use can improve compliance and efficacy.

Acne Treatment Methodologies 279first one to two weeks of treatment. The patient can then gradually increase the frequencyto nightly use as tolerated. Tolerance is often achieved in three to four weeks. It isimportant that the topical retinoid be applied at night-time for two reasons. Firstly, patientswho use topical retinoids during the daytime notice increased sensitivity to ultraviolet(UV) light. Secondly, tretinoin is unstable when exposed to sunlight. When exposed tolight, 50% of tretinoin is degraded in two hours (47). The synthetic formulations adapalene(47) and tazarotene (48) remain chemically stable when exposed to sunlight, and may beapplied morning or evening. To combat irritation it is recommended that a non-comedogenic facial moisturizer be applied during the daytime. Some patients experience apustular acne flare during the initial weeks of retinoid treatment that subsides with use.Patients should be warned of this possibility and encouraged to continue treatment throughthe exacerbation.CLEANSERSTreatment with retinoids, and acne itself, will cause dysfunction of the skin barrier. Facialcleansers also interact with proteins and lipids on the stratum corneum, and may furtherdisrupt the skin barrier. However, acne patients need to use cleansers to control the level ofskin oils and microbial levels. It is important to utilize facial cleansers that minimallydisrupt the stratum corneum so that the barrier can be preserved. Soaps are alkalinecleansers that increase the skin’s normal pH causing a decrease in the cutaneous lipidcontent (49). Soaps that contain antibacterial agents (such as triclosan) can inhibit gram-positive cocci but increase gram-negative rods (50). The irritant effects of soaps isworsened by hard water (51). Rather than using a soap, patients should cleanse their facewith a syndet (synthetic detergent) cleanser. Rather than being alkaline, syndets have a pHclose to the skin’s pH of 5.5 (Table 4). Syndets used with hard water do not produce a scumon the skin, as do soaps. Syndets are minimally irritating, and compatible with other acnetreatment regimens (52,53). Patients using syndets report more improvement in their acnethan those using soaps. Syndets will also aid in minimizing irritation from other acnetreatments such as tretinoin (53). There are cleansers other than syndets may be more irritating but contain superioranti-acne properties. These other products, such as hydroxy acids and benzoyl peroxide,may exist as washes, and also as creams, gels, scrubs, and peels.HYDROXY ACIDSHydroxy acids are present in over-the-counter and prescription formulations (Table 5). Alpha-hydroxy acids, such as glycolic acid and lactic acid, are water-soluble, and therefore penetrateto the dermis. Glycolic and lactic acids are derived from sugar cane and sour milk,respectively. Beta-hydroxy acids, such as salicylic acid, are lipid-soluble, and penetrate intothe upper epidermis and into the pilosebaceous unit. Salicylic acid is derived from willowbark, wintergreen leaves, and sweet birch, and is also available in synthetic forms (54,55).Both alpha- and beta-hydroxy acids decrease cohesion among the keratinocytes in the stratumcorneum, causing exfoliation (56,57). Due to their ability to penetrate the pilosebaceous unit,beta-hydroxy acids such as salicylic acid have a stronger comedolytic effect than alpha-hydroxy acids (58). However, in comparison with tretinoin and isotretinoin, salicylic acid is amild comedolytic agent. Salicylic acid is available in both over-the-counter and prescriptionpreparations ranging from 0.5 to 5% (59). Over-the-counter products are listed in Table 6.

280 Fernandez et al.Table 4 CleansersBrand name pH CompositionAderm 6.44 SyndetAvecyde 3.61 SyndetAve´ne 6.94 SyndetCetaphil 7.72 SyndetDove white 7.53 SyndetDove baby 7.0 SyndetDove (liquid) 5.16 SyndetDove pink 7.23 SyndetJohnson’s baby 11.9 SoapJohnson’s baby oat 12.35 SoapLux with glycerin 12.38 SoapNivea baby creamy 12.35 SyndetaNivea bath care 12.21 SyndetaNivea bath c. Almond 12.22 SyndetaNivea bath c. Oat 12.30 SyndetaOilatum 10.26 SyndetaNatural oilatum 10.01 SyndetaZest neutral 9.85 SoapZest citrus sport 9.75 SoapZest herbal 9.97 SoapZest aqua 9.89 SoapPalmolive green 10.18 SoapPalmolive (white) 10.23 SoapPalmolive botanicals 10.38 SoapCamay classic 10.38 SoapCamay gala 10.36 SoapCamay soft 10.26 SoapRosa venus 10.65 SoappH and composition of some commercially available cleansers. The pH of each emulsion or liquid cleanser wasrecorded by using the Chemcadet pH meter (Cole-Parmer Instrument Co.).a Plus mineral oil.Source: Adapted from Ref. 60.Table 5 Properties of Hydroxy AcidsHydroxy acid Solubility Derived from Penetration Action ExfoliativeAlpha-hydroxy acids Water- Sugar cane Dermis soluble Sour milk Exfoliative & Epidermis & comedolytic Glycolic acid pilose Lactic acid baceous unitBeta-hydroxy acid Lipid-solubleSalicylic acid Willow bark, wintergreen leaves, sweet birchSolubility, derivation, penetration, and action of alpha- and beta-hydroxy acids.

Acne Treatment Methodologies 281BENZOYL PEROXIDEBenzoyl peroxide is a topical medication that has bactericidal effects to reduce P. acnes. Itis available in both over-the-counter (Table 7) and prescription formulations as a bar soap,wash, gel or lotion in varying concentrations. The stay-on formulations of benzoylperoxide will decrease P. acnes counts more so than the washes although both significantlydecrease P. acnes. The concomitant use of benzoyl peroxide with antibiotics will lessenP. acnes resistance to antibiotics and increase the bactericidal effect of the antibiotic (61).None of the topical antibiotics alone is more effective against P. acnes than benzoylperoxide (27). Benzoyl peroxide products need to be used at different times of the day thantretinoin or tazarotene. Oxidation of these retinoids, and thus decreased efficacy, can occurwhen in contact with benzoyl peroxide. A benzoyl peroxide product may be utilized in themorning with night-time application of a retinoid. Caution should be given to the patientthat benzoyl peroxide products can bleach linens and clothing. Benzoyl peroxide allergiccontact dermatitis may happen but is rare with a 1:500 incidence (62). There are several topical products that combine benzoyl peroxide with eithererythromycin or clindamycin. These combination topical products treat inflammatory acnebetter than either product alone (63,64). The shelf-life for these combination products islimited; therefore, some formulations of erythromycin, and benzoyl peroxide need to berefrigerated. Diarrhea and pseudomembranous colitis are rare but have been associatedwith topical clindamycin.OTHER TOPICAL TREATMENTSOther topical products with antimicrobial effects include azelaic acid and sodiumsulfacetamide. Azelaic acid is a naturally occuring nine-carbon dicarboxylic acid. It isavailable for the treatment of acne in a 20% cream preparation. Azelaic acid hasantimicrobial and weak anti-comedogenic effects. It reduces the production ofkeratohyalin granules in the pilosebaceous epithelium, thus normalizing ductalkeratinocyte proliferation (62). Its anti-microbial effect is inferior to that of antibioticsor benzoyl peroxide (65). Azelaic acid can also decrease pigmentation by competing withtyrosinase (66). It may therefore be helpful for acne patients with post-inflammatoryhyperpigmentation. It causes minimal erythema and does not produce the same degree ofirritation as topical retinoids (62). Additionally, azelaic acid is safe for use in pregnancy. Sulfur–sodium sulfacetamide is another well-tolerated topical antimicrobial. It isavailable as washes, bars, and creams. Sulfur presumably inhibits the growth of P. acnesby inhibiting its sustenance, para-aminobenzoic acid (PABA). The irritant effect on theskin causes keratolysis. The addition of sodium sulfacetamide lotion to sulfur has made itsuse more cosmetically acceptable.ORAL ANTIBIOTICSOral antibiotics are often administered to patients with moderate to severe acne or inpatients in whom topical therapy has failed. Patients with moderate acne with scarring orthose whose acne covers a large surface area making topical application difficult may alsobe candidates for oral antibiotics. Oral antibiotics used in acne are typically of thetetracycline or macrolide family (Table 8).TetracyclinesThe tetracyclines work by interacting with the 30S ribosomal subunit of bacteria, and thusinhibiting protein synthesis. Included in the tetracycline family are tetracycline,

282 Fernandez et al.Table 6 Over-the-Counter Salicylic Acid ProductsProduct Strength (% salicylic acid)Aveeno Clear Complexion Cleansing Bar 1%Aveeno Clear Complexion Correcting Treatment 1%Aveeno Clear Complexion Daily Cleansing Pads 0.5%Biore Pore Perfect Blemish Fighting Cleansing Cloths 0.5%Biore Pore Perfect Unclogging Scrub 2%Biore Pore Perfect Warming Anti-blackhead Cream Cleanser 2%Bye Bye Blemish Anti-acne Serum 1%Bye Bye Bleamish Anti-acne Cleanser 0.5%Clean and Clear Acne Wash Oil-free 2%Clean and Clear Advantage Acne Spot TreatmentClean and Clear Advantage Acne Cleanser 2%Clean and Clear Advantage Daily Cleansing Pads 2%Clean and Clear Blackhead Clearing Scrub 2%Clearasil 3 in 1 Acne Defense Cleanser 2%Clearasil Icewash Gel Cleanser 2%Clearasil Pore Cleansing Pads 2%Clearasil Wipes 2%Cuticura Acne Treatment Foaming Face WashEucerin Clear Skin Formular Concealer Pencil 2%Neutrogena Acne Wash Foam Cleanser 2%Neutrogena Acne Wash Cloths 2%Neutrogena Acne Wash Cream Cleanser 2%Neutrogena Blackhead Eliminating Daily Scrub 2%Neutrogena Body Clear Body Wash 2%Neutrogena Oil-free Acne Wash 2%Neutrogena Oil-free Acne Wash Cream Cleanser 2%Neutrogena Oil-controlling Cleansing Pads 0.5%Neutrogena Healthy Skin Anti-wrinkle Anti-blemish Cleanser 2%Neutrogena Advanced Solutions Acne Mark Fading PeelNeutrogena Deep Clean Cream Cleanser 2%Neutrogena Clear Pore Treatment 2%Olay Daily Facials Clarity Foaming Cleanser 2%pH Isoderm Facial Wash Clear Confidence 0.5%Stridex Face Wipes to Go 2.0%Stridex Triple Action Acne Pads 0.5%Stridex Sensitive Skin PadsSome commercially available over-the-counter salicylic acid products and the percent of salicylic acid theycontain.minocycline, and doxycycline. In addition to their antimicrobial effect, all of thetetracyclines are anti-inflammatory agents. They inhibit white blood cell chemotaxis,decrease lipase production by P. acnes, and decrease cytokine production. They also offeranti-inflammatory effects by decreasing the activity of matrix metalloproteinases(MMPs) (67). MMPs degrade several components of the extracellular matrix. Tetracycline is a first-generation tetracycline. It is often administered at 500 mgtwice daily for acne. Tetracycline should not be taken with milk as calcium blocks itsabsorption in the gut. It therefore must be taken on an empty stomach, one hour prior to ortwo hours after meals. Tetracycline may also cause gastrointestinal upset in some patients.Patients should also be warned of increased photosensitivity while on tetracycline. Other

Acne Treatment Methodologies 283Table 7 Over-the-Counter Benzoyl Peroxide ProductsProduct Strength (% benzoyl peroxide)Clean and Clear Continuous Control Acne Cleanser 10%Clean and Clear Persa-gel Maximum Strength 10%Clearasil Cream 10%Clearasil Ultra Acne Treatment Cream 10%Neutrogena Clear Pore Cleanser/Mask 3.5%Neutrogena On-the-Spot Acne Treatment Vanishing 2.5% Formula 10%Oxy Acne Wash 10%Oxy Acne Treatment Vanishing 10%Panoxyl Bar 10%Panoxyl Aqua Gel 2.5%Stridex Power Pads 10%Zapzyt Bar 10%Zapzyt Treatment GelSome commercially available over-the-counter benzoyl peroxide products and the percent of benzoyl peroxidethey contain.photosensitive side effects that may occur while on tetracycline include painful photo-onycholysis and pseudoporphyria. Tetracycline is deposited in areas of calcification. As aresult, hyperpigmentation of deciduous and permanent teeth and bone may occur. For thisreason, tetracycline should not be used in children under the age of 10 as deposition in thebone epiphyses may halt bone growth. Tetracycline is pregnancy category D since it canbe deposited in the fetal bones. Nursing mothers should not be given tetracyclines due tothe potential for drug excretion through the breast milk. Doxycycline is a second generation tetracycline administered at 100 mg twice dailyfor acne. It is better absorbed from the gastrointestinal tract than tetracycline, and can betaken with food, although maximum absorption occurs when taken 30 minutes prior to ameal. Like tetracycline, it can be deposited in areas of calcification such as the teeth andbones, and therefore cannot be used in children under the age of 10, and is pregnancycategory D. Photosensitivity is most common with doxycycline and is dose-dependent.42% of patients taking a total of 200 mg a day will develop photosensitivity (68). Doxycycline can also be administered for acne at subantimicrobial doses of 20 mgtwice a day. In this manner the doxycycline is given at a low dose so that it has only anti-inflammatory effect, and not an antimicrobial effect. Without an antimicrobial action, thereTable 8 Comparing the Oral TetracylinesAntibiotic Dosing Advantages DisadvantagesTetracycline Taken on an empty Inexpensive Gastrointestinal upsetMinocycline stomach without milk Risk of pigmentation,Doxycycline dizziness, May be taken with food Rapid onset of action autoimmune disorders May be taken with food May be used at Photosensitivity subantimicrobial dosesComparing tetracycline, minocycline, and doxycycline with regards to dosing and the unique advantages anddisadvantages of each.

284 Fernandez et al.is no opportunity for antibiotic resistance to arise. Doxycycline is the almost effective ofthe tetracyclines used at subantimicrobial doses because it is the most potent inhibitor ofMMP (69). In a study of 40 acne patients who received doxycycline 20 mg po bid for6 months, no adverse events such as nausea, vomiting, phototoxicity, or vaginitis werenoted (70). Minocycline is another second generation tetracycline given at 100 mg twice daily.Of the tetracyclines it has the best gastrointestinal absorption. It can be taken with food butis best absorbed 30 minutes prior to a meal. Compared to tetracycline and doxycycline,minocycline has more rapid clinical improvement. It also demonstrates a more persistentreduction of inflammation. In vitro, minocycline has the greatest reduction of P. acnes ofall the antibiotics used for acne (65). Minocycline’s superior effects are due to its highlipophilicity, and thus better penetration into the pilosebaceous unit. Minocycline canpotentially cause a blue-grey hyperpigmentation, vestibular disturbances, or ahypersensitivity drug reaction (70). Three types of hyperpigmentation can occur. Type Ihyperpigmentation occurs in areas of scar tissue. Type II hyperpigmentation occurs onpreviously normal skin, commonly on the anterior shins. Type III hyperpigmentation has apredilection for sun-exposed areas, and often is a diffuse hyperpigmentation. Sinceminocycline is highly lipophilic it can easily cross the blood-brain barrier. This may resultin vestibular disturbances such as dizziness, vertigo, or ataxia. Rarer side effects ofminocycline include drug-induced lupus, serum sickness, hepatic failure, and vasculitis.With the exception of serum sickness (which on average occurs 16 days after startingtherapy), these side effects often occur after more than a year of therapy (71). Benign intracranial hypertension, also known as pseudotumor cerebri, can occurwith any of the tetracycline antibiotics, and is an increase in cerebrospinal fluid. Thisincrease in intracranial pressure is seen most frequently with minocycline due to itsability to cross the blood-brain barrier. Pseudotumor cerebri can occur betweenfour weeks and 18 months after starting therapy. Patients will complain of a headachethat worsens in the evening, diplopia on lateral gaze, and nausea. Papilledema will bedemonstrated by ophthalmologic examination. A lumbar puncture can aid in diagnosis,and also be therapeutic by relieving pressure of excess cerebrospinal fluid.MacrolidesThe macrolide antibiotics can also be useful in treating acne. This family of antibioticsworks by binding irreversibly to the 50S ribosomal subunit thus inhibiting translocationduring protein synthesis. Erythromycin and clindamycin are members of the macrolidefamily that are commonly used in acne. Both are used alone or in conjunction withbenzoyl peroxide as a combination product. When given orally, erythromycin isadministered at 500 mg twice daily. Erythromycin can and should be taken with food asit commonly causes gastrointestinal upset. It is safe in pregnancy and in lactatingwomen, although erythromycin estolate should be avoided in these groups as it maycause cholestatic jaundice. Erythromycin inhibits the cytochrome P450 system thuscausing reduced clearance of theophylline, warfarin, carbamazepine, and cyclosporine(70,72). Concomitant use of these medications should be avoided.ClindamycinThe oral use of clindamycin is limited since 20–30% of patients will experience diarrhea.Oral clindamycin can also cause an overgrowth of Clostridium difficile in the gut thuscausing pseudomembranous colitis (72). Topical clindamycin is generally well tolerated,and is available by prescription in solution, gel, and foam formulations.

Acne Treatment Methodologies 285Trimethoprim/SulfamethoxazoleTrimethoprim/sulfamethoxazole is another oral antibiotic option for acne. It isadministered 160 mg/800 mg twice daily. It works by inhibiting dihydrofolate reductasethus impeding purine and pyrimidine synthesis. It has a broad spectrum of antimicrobialactivity, and therefore should be reserved as a second line agent or for patients with gram-negative folliculitis. Due to its sulfa moiety, trimethoprim/sulfamethoxazole also hasthe potential to cause a drug hypersensitivity syndrome with multi-organ involve-ment. Anemia, thrombocytopenia, and agranulocytosis are also potential side effects oftrimethoprim/sulfamethoxazole.Antibiotic CounselingIt is important to discuss and educate patients on the potential side effects of each antibioticin order to maximize patient compliance. Patients may express several concerns about oralantibiotic use. One of these concerns may be possible reduced efficacy of their oralcontraceptives. No pharmacokinetic interaction has been demonstrated between oralcontraceptive pill and antibiotics (except rifampin). Oral contraceptive failure rates while onantibiotics, including those used for treating acne, fall within the range of oral contraceptivefailure rates of patients not on antibiotics which is 1% to 3% (73). There are some individualswho will have decreased absorption of the oral contraceptive due to changes in the gut floraby antibiotics. It is impossible to predict who these patients will be. Therefore, all patientsshould be counseled regarding the small risk that their oral contraceptive may be lesseffective while taking antibiotics. Patients may also express concern regarding thepublicized cancer risk with antibiotic use. A study in 2004 showed an increased risk of breastcancer with long-term antibiotic use (74). This risk was the same if antibiotics were beingused to treat acne/rosacea or respiratory tract infections. A direct effect was notdemonstrated in this study, only an association. It is important to point out to patients thatno causal relationship between antibiotic use, and breast cancer was identified in this study. Frequently antibiotics produce favorable results but sometimes a patient does notrespond to antibiotic treatment. Several reasons exist for a poor clinical response. Theantibiotic may have been given at an inadequate dose or for an inadequate duration.A maximum response is usually seen in three to four months. The patient may have beengiven suboptimal instructions on use or had poor compliance. Patients with a high sebumexcretion rate (greater than 2.5 micrograms/cm/minute) may not respond due to dilutionof the antibiotic in the pilosebaceous unit. Antibiotics may not be helpful if the patient ismisdiagnosed with acne when the eruption truly is folliculitis due to gram negativeenterobacteria, staphylococci, or yeasts.Antibiotic ResistanceA patient may also not respond to antibiotics therapy if there is P. acnes resistance (75).Antibiotic resistance is a real problem of growing concern. The overall incidence ofP. acnes antibiotic resistance increased from about 20% in 1978 to approximately 62% in1996. Resistance of P. acnes is most common for erythromycin, clindamycin, tetracycline,doxycycline, and trimethoprim. Minocycline resistance is present in about 1% of patientstoday (76). There is no resistance to benzoyl peroxide, azeleic acid, or sulfur. Several things can be done to minimize selection, and spread of antibiotic resistantstrains of P. acnes. Antibiotics should be used judiciously, and only until control isachieved. The antibiotic should then be discontinued. If repeat treatment with antibioticsis required, the same antibiotic should be reused (unless it has lost efficacy). Patients who

286 Fernandez et al.are on oral or topical antibiotics should also use a benzoyl peroxide product to reduce thenumbers of antibiotic resistant organisms. Oral, and topical antibiotics with dissimilarproperties should not be used concomitantly, as combining these agents may cause crossresistance. Patient education is important to maximize compliance and prevent resistance.HORMONAL THERAPYHormonal therapy is another treatment option for females with acne. Hormonal therapymay be helpful in acne patients with hirsutism, irregular menstrual periods and/or othersigns of hyperandrogenism. Patients who have failed isotretinoin or oral antibiotics maystill benefit from hormonal therapy. Women with flares of acne around the time of mensesand those with excessive seborrhea may also respond well to hormonal therapy. Only oralretinoids and hormonal therapy can decrease sebum production. Anti-androgens,glucocorticoids, and oral contraceptives are all types of hormonal therapies (77).SpironolactoneThe anti-androgens include the androgen receptor blockers spironolactone, cyproteroneacetate, and flutamide. Spironolactone is an aldosterone antagonist that also blocks theandrogen receptor (72). Oral spironolactone reduces sebum excretion by 45–50%. It istaken 25–100 mg orally twice a day. Patients frequently experience breast tenderness andmenstrual irregularities with spironolactone. These side effects increase with the dosage ofspironolactone, and can be minimized by using an oral contraceptive. If a woman becomespregnant with a male fetus, spironolactone as an anti-androgen may lead to feminization ofthe male genitalia and endocrine dysfunctions (78). Spironolactone can also cause mildelevations of potassium, and should therefore be used with caution in patients with renal orcardiac disease (79,80). For patients taking ethinyl estradiol/drospirinone (Yasminw) inconjunction with spironolactone, this risk of hyperkalemia is increased.Cyproterone AcetateCyproterone acetate is a hydroxy-progesterone that blocks the binding of androgens totheir receptors. It also inhibits the synthesis of androgens in the adrenal glands and in theskin. Cyproterone acetate is not available in the United States but is available in Canadaand Europe. It is incorporated in an oral contraceptive pill at 2 mg per day with ethinylestradiol. Women with abnormal androgen metabolism can take additional 10–50 mg oncedaily during the first 10 days of their menstrual cycle (81).FlutamideFlutamide is a potent anti-androgen that is used to treat prostate cancer, and can also beuseful for acne (82). It is administered at 250 mg twice daily in combination with an oralcontraceptive. Liver function tests must be monitored in patients on flutamide as it cancause fatal hepatitis (83). Patients with adrenal hyperandrogenism may benefit froma combination of low dose glucocorticoidsteroid with an oral contraceptive. Theglucocorticoid works byblocking adrenal androgen production. Prednisone 2.5–5 mg canbe given daily at bedtime. Alternatively, dexamethasone 0.25–0.75 mg can be givennightly. Chronic glucocorticoid use may cause adrenal suppression (especiallydexamethasone), and should be used with caution (84).

Acne Treatment Methodologies 287Oral ContraceptiveOral contraceptives have several mechanisms of action in treating acne. They reduceandrogen production by both the ovaries and the adrenal glands. Oral contraceptives alsoreduce free serum testosterone by increasing sex hormone-binding globulin. Sebumproduction is decreased with oral contraceptive use, possibly due to androgen reduction orpossibly directly due to increased levels of estrogens (77). Most formulations consist of anestrogen in combination with a progestin. Progestin is needed to minimize the increased riskof endometrial cancer with unopposed estrogens. Progestins themselves have intrinsicandrogenic activity, which can worsen acne in addition to causing changes in lipidmetabolism and glucose intolerance (85). The newer generations of progestins (second andthird generations) have been formulated to have lower androgenic properties. The second-generation progestins include ethynodiol diacetate, norethindrone, and levonorgesterol.The third-generation progestins have less cross reactivity with the androgen receptor, andincrease sex hormone binding globulin. These oral contraceptives that lessen androgenicactivity include: desogestrel, norgestimate, and gestodene. Only two oral contraceptives arecurrently FDA-approved for the treatment of acne, Ortho Tri-Cyclenw (Ortho, Raritan, NJ)and Estrostepw (Parke Davis Laboratories, Detroit, MI). Ortho Tri-Cyclenw is a triphasiccontraceptive contaning ethinyl estradiol (35 micrograms) and the third-generationprogestin, norgestimate. Estrostepw contains ethinyl estradiol (graduated dose from20–35 micrograms), and the second-generation progestin, norethindrone acetate (86). Clinical improvement due to hormonal therapy will be evident as early asthree months. Hormonal therapy is especially beneficial for acne in a “beard” distribution,involving the mandible and chin. Co-management with a patient’s gynecologist is neededso that patients may be appropriately followed while on an oral contraceptive. Often times,the oral contraceptives approved for acne may not be the best choice for patientsexperiencing heavy or abnormal menses. Relatively common side effects from oralcontraceptives includes: nausea, vomiting, abnormal menses, weight gain, and breasttenderness. More detrimental but rarer side effects include: thrombophlebitis, pulmonaryembolism, and hypertension (87). The risk of these serious side effects increases inpatients who smoke cigarettes.ISOTRETINOINIsotretinoin (13-cis retinoic acid) is an oral retinoid that has been available for thetreatment of acne since 1971 in Europe, and since 1983 in the United States. The Food andDrug Administration (FDA) indication for the use of isotretinoin is severe, nodulocysticacne that has not been helped by other treatments, including antibiotics. However, patientswith other forms of acne have also benefited from isotretinoin. These patients includethose with: significant acne unresponsive to treatment including oral antibiotics, acne thatresults in significant physicial or emotional scarring, and patients with gram-negativefolliculitis, pyoderma faciale, and acne fulminans (88,89). The exact mechanism of action of isotretinoin is not known. It is believed that 13-cis-retinoic acid exerts its action by isomerization to all-trans-retinoic acid, which then interactswith the retinoid receptors (90). It is the only acne medicine available that affects all fourpathogenic factors of acne. Isotretinoin is comedolytic, reduces sebaceous gland size (up to90%), and suppresses sebum production which in turn inhibits P. acnes and its ability toelicit inflammation (91). During the course of isotretinoin therapy, the pustular lesionsgenerally clear first, and the codemos will be the last to resolve. Lesions on the face andupper arms tend to respond faster to isotretinoin than lesions on the trunk (92).

288 Fernandez et al.DosingThere is variation in the dosing of isotretinoin with daily doses ranging from 0.1 to 2 mg/kg.Typically, 0.5–2 mg/kg/day is recommended for 16–20 weeks to reach a total cumulativedose of 120–150 mg/kg. A lower starting dose may be necessary in patients with significantinflammatory acne to prevent flares in the first month of treatment. Patients at risk for initialflaring may be concomitantly given prednisone to reduce flaring and prevent exuberantgranulation tissue. Patients with pyoderma faciale should be controlled on prednisone priorto beginning isotretinoin. Studies have demonstrated that about 23% of patients using the typical dosing mayneed to repeat treatment with isotretinoin. 96% of patients who experience a relapseof their acne do so within the first three years. Of patients taking a lower regimen of0.1 mg/kg/day, 40% need a repeat course (93). Factors contributing to the need foradditional courses are lower dose regimens (0.1–0.5 mg/kg/day or cumulatively less than120 mg/kg), the presence of severe acne, being a female older than 25 years at the start oftherapy, and having a prolonged history of acne (94,95). If repeat therapy is needed, atleast two to three months should elapse between courses. An even longer interval may besensible as the effects of isotretinoin can be seen five months after discontinuation.Side EffectsSince RAR are found in many organs of the body, isotretinoin can cause numerous sideeffects (Table 9). This profile of adverse effects closely mimics those of hypervitaminosisA (96). Mucocutaneous side effects are the most common and are dose dependent. The mostfrequently encountered mucocutaneous side effects are: cheilitis, generalized xerosis, anddry mucosa. Cheilitis is so common that its absence would indicate a suboptimal dose orcause suspicion of the patient’s compliance. Dry nasal mucosa frequently results in epistaxis(97). Xerophthalmia is common with subsequent contact lens intolerance, and possibleconjunctivitis. Photophobia, decreased night vision, keratitis, and optic neuritis are lesscommon, while cataracts, and corneal opacities rarely develop. Hair thinning, and hair lossoccurs in less than 10% of patients on isotretinoin (98,99). Neuromuscular complaints are relatively common in patients taking isotretinoin.About 14% of patients will experience myalgias, and a higher percentage will experiencearthralgias and back pain. These neuromuscular complaints may coexist with a transient risein creatinine phosphokinase, and are more common in physically active patients (100,101). Nausea, vomiting, diarrhea, and abdominal pain have occurred in patients onisotretinoin but are rare. Transient mild increases in liver transaminases occur in about15% of patients. Frank hepatitis is very rare, and has been reported in adults but not inchildren on isotretinoin (102). Pseudotumor cerebri, or benign intracranial hypertension, is a rare side effect ofisotretinoin. Patients who develop this increase in intracranial pressure will complain ofheadache, blurred vision, double vision, and/or vomiting. If recognized by history, and thefinding of papilledema, a lumbar puncture can confirm the diagnosis, and be therapeutic.The likelihood of developing pseudotumor cerebri is increased with concomitanttetracycline use (103). The impact of isotretinoin on a patient’s psychological well-being has incited muchattention. From 1982 to May 2000, 37 cases of suicide, 110 cases of hospitalizeddepression, suicidal ideation, or suicide attempt, and 284 cases of nonhospitalizeddepression were reported to the FDA’s Adverse Event Reporting System (104). In onepopulation-based cohort study comparing isotretinoin users with oral antibiotic users, therelative risk for development of depression or psychosis was approximately 1.0, indicating

Acne Treatment Methodologies 289 (Continued)Table 9 Isotretinoin Side EffectsTeratogenicity Hydrocephalus Micorcephaly External ear abnormalities Microphthalmia Craniofacial dysmorphia Cardiac septal defects Thymus gland abnormalitiesMucocutaneous Chelitisa Xerosisa Skin fragilitya Palmoplantar peelinga Dry nosea Epistaxsisa Pruritusa Facial erythema/ rasha Desquamation Atrophy Granulation tissue Alopecia Brittle nails Acne fulminans Pyogenic granuloma-like lesionsOphthalmologic Xerophthalmiaa Blepharitis Papilledema Blurred vision Night blindness Corneal opacitiesGastrointestinal Nausea Anorexia Abdominal pain CirrhosisNeuromuscular/Psychiatric Headachea Fatigue Lethargy Myalgias Stillness Irritiablility Depression Suicidal ideation Psychosis Papilledema Pseudotumor cerebriRheumatologic Arthralgias DISH-like vertebral hyperostoses

290 Fernandez et al.Table 9 Isotretinoin Side Effects (Continued ) Altered bone remodeling Extraspinal tendon and ligament calcification Premature epiphyseal closure Demineralization/ osteoporosis Periosteal thickeningLaboratoryElevated triglyceridesa Elevated cholesterol Elevated liver function tests Elevated creatine phosphokinasea Denotes most common side effects.Source: Adapted from Refs. 100, 129, 130.no increased risk (105). A recent study demonstrated a decrease in depressive symptoms inpatients undergoing treatment with isotretinoin (106). Further studies are needed toresolve this issue of causality. Isotretinoin is a potent teratogen, and is rated pregnancy category X. The exactmechanism of embryopathy is unknown, but exposed infants have characteristiccraniofacial defects as well as cardiac, thymus, and central nervous system abnormalities(107). Approximately 3–4 per 1000 women on isotretinoin become pregnant. In an effort toeliminate pregnancy while on isotretinoin, the manufacturer has implemented severalregulations. There are additional consent forms for women regarding the potentialteratogenicity. Appropriate contraception must be used one month prior to and one monthfollowing a course of isotretinoin. Two negative pregnancy tests must be obtained beforestarting isotretinoin, and a negative test must be obtained each month while on therapy.Laboratory MonitoringIn addition to the laboratory tests that need to be performed to ensure that a woman is notpregnant, both men and women must get additional laboratory studies. A complete bloodcount, liver function test, and a lipid profile is checked at baseline and four weeks afterstarting isotretinoin. Elevated triglyceride levels occur in about 25–45% of patients (107).Those who have increased cholesterol during therapy often had elevated baselinecholesterol (108). Elevated liver function enzymes are also possible during isotretinoin butrarely does frank hepatitis develop. This elevation is reversible with discontinuation ofisotretinoin. Other reversible changes during isotretinoin therapy include: leukopenia,thrombocytopenia, thrombocytosis, and an elevated erythrocyte sedimentation rate.MANUAL TREATMENTSIn addition to topical and oral medications, physical modalities exist for treating acne.Comedone extraction can provide prompt cosmetic results. The keratinous debris of theopen comedo may be extracted by using the Schamberg, Unna, and Saalfield types ofcomedo extractors. The closed comedo can also be removed by extraction but must first benicked with an 18-gauge needle or an #11 blade. Extraction should not be attempted on aninflamed comedo or pustule due to the risk of scarring. Electrocautery andelectrofulguration have also been reported as effective treatment for comedones. Thesemeans are often useful for treating large comedos, also known as macrocomedos.Macrocomedos are often resistant to topical retinoids.

Acne Treatment Methodologies 291 Intralesional triamcinolone can be utilized to decrease both the size and pain ofinflammatory cysts or nodules. Triamcinolone acetonide (2–5 mg/ml) is injected into theselesions using a 30-gauge needle. The steroid should be injected until the lesion blanches.The maximum amount of steroid used per lesion should not exceed 0.1 mL. Excesstriamcinolone injected into a lesion may result in hypopigmentation, atrophy,telengiectasias, and needle tract scarring.PHOTOTHERAPYVarious forms of phototherapy are under investigation for their use in treating acne vulgaris.Up to 70% of patients report that sun exposure improves their acne (109). This reportedbenefit may be due to camouflage by UV radiation-induced erythema and pigmentation,although it is likely that the sunlight has a biologic effect on the pilosebaceous unit andP. acnes. Porphyrins are formed endogenously by P. acnes, and are also acquired byexogenous sources. Protoporphyrin IX is taken up via cell wall receptors (110), andcoproporphyrin III is the major endogenous porphyrin. Coproporphyrin III can absorb lightat the near-UV and blue-light spectrum of 415 nm (111). In vitro irradiation of P. acnes withblue light leads to photoexcitation of endogenous bacterial porphyrins, singlet oxygenproduction, and subsequent bacterial destruction (112). Although UVB can also killP. acnes in vitro, it is clinically insignificant since it has low skin penetration, and only highdoses causing sunburn have be shown to improve acne (113,114). UV radiation may haveanti-inflammatory effects by inhibiting cytokine action (115).UV RadiationStudies investigating the effect of UV radiation on acne have demonstrated a modestimprovement in only inflammatory acne. There is some effect with UVB radiation alone, andslightly more benefit with combined UVB and UVA radiation. UVA light alone is the leastbeneficial. Twice-weekly phototherapy sessions are needed for clinical improvement. Thetherapeutic utility of UV radiation in acne is superseded by its carcinogenic potential (116–120). Visible light is effective in treating both inflammatory and non-inflammatory acnelesions (121). A high-intensity, enhanced, narrow band (407–420 nm) blue-light source(ClearLight) has been FDA-approved for the treatment of moderate inflammatoryacne (122). Red light can also be used to treat acne. It is less effective at photoactivatingporphyrins than blue light, but red light can penetrate deeper into the dermis. Red light mayalso have additional anti-inflammatory properties. Combined blue and red light therapy maybe more efficacious than either alone. It can be used twice weekly, taking 15 minutes persession to treat just the face. To treat the face, chest, and back, a 45-minute session is needed.Clinical improvement is maintained for at least one month after the last treatment (121).Photodynamic TherapyPhotodynamic therapy is another phototherapy option for treating acne. Aminolevulinicacid (ALA) is applied topically one hour prior to exposure to a low-power light source (suchas a pulsed excimer laser or a halogen source). The ALA is metabolized in the pilosebaceousunits to protoporphyrin IX which is then targeted by the light. This results in the destructionof the sebaceous glands and damage to the hair follicles and epidermis (123,124).LasersLasers too are beginning to find a role in the treatment of acne. They work by emittingminimally divergent, coherent light that can be focused over a small area of tissue. Pulsed

292 Fernandez et al.dye laser (585 nm) can be used at lower fluences to treat acne. Instead of ablating bloodvessels and causing purpura, the lower fluence can stimulate procollagen production byheating dermal perivascular tissue (121). The beneficial effects of a single treatment canlast 12 weeks (125). The 1450 nm diode laser has also demonstrated significant efficacy intreating acne (126,127). This laser works by causing thermal damage to the sebaceousglands. The concurrent use of a cryogen spray device protects the epidermis (128).REFERENCES 1. Smithard A, Glazebrook C, Williams H. Acne prevalence, knowledge about acne and psuchological morbidity in mid-adolescence: a community-based study. Br J Dermatol 2001; 145:274–279. 2. Rademaker M, Garioch JJ, Simpson NB. Acne in schoolchildren: no longer a concern for dermatologists. BMJ 1989; 298:1217–1220. 3. Pearl A, Arroll B, Lello J, Birchal N. The impact of acne: a study of adolescents’ attitudes, perception and knowledge. NZ Med J 1998; 1111:269–271. 4. Atkan S, Ozmen E, Sanli B. Anxiety, depression and nature of acne vulgaris in adolescents. Int J Dermatol 2000; 39:354–357. 5. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol 1999; 41:577–580. 6. Cunliffe WJ, Gould DJ. Prevalence of facial acne vulgaris in late adolescence and in adults. BMJ 1979; 166:1109–1110. 7. Scott-Levin. Acne. Physician Drug Diagn Audit 2000. 8. Baldwin HE. The interaction between acne vulgaris and the psyche. Cutis 2002; 70:133–139. 9. Mallon E, Newton JN, Klassen A, Stewart-Brown SL, Ryan TJ, Finlay AY. The quality of life in acne: a comparison with general medical conditions using generic questionnaires. Br J Dermatol 1999; 140:672–676. 10. Cunliffe WJ. Acne and unemployment. Br J Dermatol 1986; 115:386. 11. Zaenglein AL, Thiboutot DM. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Acne Vulgaris. 1st ed. In: Dermatology, 1st ed, Vol. 1. New York: Elsevier, 2003:531–543. 12. Thiboutot D, Knaggs H, Gilliland K, Hagari S. Activity of type 1 5a-reductase is greater in the follicular infrainfundibulum compared with the epidermis. Br J Dermatol 1997; 136:166–171. 13. Thiboutot D, Knaggs H, Gilliland K, Lin G. Activity of 5-alpha-reductase and 17-beta- hydroxysteroid dehydrogenase in the infrainfundibulum of subjects with and without acne vulgaris. Dermatology 1998; 196:38–42. 14. Imperato-McGinley J, Gautier T, Cai LQ, Yee B, Epstein J, Pochi P. The androgen control of sebum production. Studies of subjects with dihydrotestosterone deficiency and complete androgen insensitivity. J Clin Endocrinol Metabol 1993; 76:524–528. 15. Downing D, Stewart M, Wertz P, Strauss J. Essential fatty acids and acne. J Am Acad Dermatol 1986; 14:221–225. 16. Guy R, Green M, Kealey T. Modeling of acne in vitro. J Invest Dermatol 1996; 106:176–182. 17. Sanders DA, Philpott MP, Nicolle FV, Kealey T. The isolation and maintenance of the human pilosebaceous unit. Br J Dermatol 1994; 131:166–176. 18. Harris HH. Sustainable rates of sebum secretion in acne patients and matched normal control subjects. J Am Acad Dermatol 1983; 8:200. 19. Kligman AM, Wheatley VR, Mills OH. Comedogenicity of human sebum. Arch Dermatol 1970; 102:267–275. 20. Pochi PE, Strauss JS. Sebaceous gland response in man to the administration of testosterone, D4- androstenedione, and dehydroisoandrosterone. J Invest Dermatol 1969; 52:32–36. 21. Thiboutot D, Gilliland K, Light J, Lookingbill D. Androgen metabolism in sebaceous glands from subjects with and without acne [see comments]. Arch Dermatol 1999; 135:1041–1045. 22. Lucky AW, Biro FM, Simbartl LA, Morrison JA, Sorg NW. Predictors of severity of acne vulgaris in young adolescent girls: results of a five-year longitudinal study [see comments]. J Pediatr 1997; 130:30–39. 23. Thiboutot D, Harris G, Iles V, Cimis G, Gilliland K, Hagari S. Activity of the type 1 5a-reductase exhibits regional differences in isolated sebaceous glands and whole skin. J Invest Dermatol 1995; 105:209–214.

Acne Treatment Methodologies 29324. Strauss J, Kligman A. Effect of cyclic progestin-estrogen therapy on sebum and acne in women. JAMA 1964; 190:815–819.25. Thiboutot D. Regulation of human sebaceous glands. Dermatol Found 2003; 37:1–12.26. Norris JFB, Cunliffe WJ. A histological and immunocytochemical study of early acne lesions. Br J Dermatol 1988; 118:651–659.27. Leyden JJ. Propionibacterium levels in patients with and without acne vulgaris. J Invest Dermatol 1975; 65:382.28. Webster G, Indrisano J, Leyden JJ. Antibody titers to propionobacterium acnes cell wall carbohydrate in nodulocystic acne patients. J Invest Dermatol 1985; 84:496–500.29. Webster GF. Complement activation in acne vulgaris. Consumption of complement by comedones. Infect Immuno 1979; 26:183.30. Puhvel SM, Hoffman IK, Reisner RM. Delayed hypersensitivity of patients with acne vulgaris to corynebacterium acnes. J Invest Dermatol 1967; 49:154–158.31. Webster G, Leyden JJ, Musson RA, Douglas SD. Susceptibility of propionobacterium acnes to killing and degradation by human neutrophils and monocytes in vitro. Infect Immuno 1985; 49:116–121.32. Vowels B, Yang S, Leyden J. Induction of proinflammatory cytokines by a soluble factor of propionibactreium acnes: implications for chronic inflammatory acne. Infect Immun 1995; 63:3158–3165.33. Kim J, Ochoa M, Krutzik S, et al. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol 2002; 169:1535–1541.34. Lee JK, Duong B, Ochoa M. Propionobacterium acnes induction of pro-inflammatory cytokines in polymorphonuclear cells occurs through toll-like receptor 2: the role of innate immune response in acne vulgaris. Abstr Soc Invest Dermatol 2002.35. Fisher GF, Talwar HS, Xiao JH. Immunological identification and functional quantitation of retinoic acid and retinoid X receptor proteins in human skin. J Biol Chem 1994; 269:20629–20635.36. Fisher FJ, Voorhees JJ. Molecular mechanisms of retinoid actions in skin. FASEB J 1996; 10:1002–1013.37. Quigley JW, Bucks DA. Reduced skin irritation with tretinoin containing polyolprepolymer- 2, a new topical tretinoin delivery system: a summary of preclinical and clinical investigations. J Am Acad Dermatol 1998; 38:S5–S10.38. Lucky AW, Cullen SI, Jarratt MT, Quigley JW. Comparative efficacy and safety of two 0.025% tretinoin gels: results from a multicenter double-blind, parallel study. J Am Acad Dermatol 1998; 38:S17–S23.39. Shalita A, Weiss J, Chalker D, et al. A comparison of the efficacy and safety of adapalene gel 0.01% and tretinoin gel 0.025% in the treatment of acne vulgaris: a multicenter trial. J Am Acad Dermatol 1996; 34.40. Webster G, Berson D, Stein LF, Fivenson DP, Tanghetti EA, Ling M. Efficacy and tolerability of once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.025% gel in the treatment of facial acne vulgaris: a randomized trial. Cutis 2001; 67:4–9.41. Leyden JJ, Tanghetti EA, Miller B, Ung M, Berson D, Lee J. Once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.1% microsponge gel for the treatment of facial acne vulgaris: a double-blind randomized trial. Cutis 2002; 69:12–19.42. Bershad S, Kranjac Singer G, Parente JE, et al. Successful treatment of acne vulgaris using a new method: results of a randomized vehicle-controlled trial of short-contact therapy with 0.1% tazarotene gel. Arch Dermatol 2002; 138:481–489.43. Shapiro L, Pastuszak A, Curto G, Koren G. Safety of first-trimester exposure to topical tretinoin: prospective cohort study [letter]. Lancet 1997; 350:1143–1144.44. Jick S, Terris BZ, Jick H. First trimester topical tretinoin and congenital disorders. Lancet 1993; 341:1181–1182.45. Tang-Liu DD, Matsumoto RM, Usansky JI. Clinical pharmacokinetics and drug metabolism of tazarotene: a novel topical treatment for acne and psoriasis. Clin Pharmacokinet 1999; 37:273–287.46. Menter A. Pharmocokinetics and safety of tazarotene. J Am Acad Dermatol 2000; 43:S31–S35.47. Martin B, Meunier C, Montels D, Watts O. Chemical stability of adapalene and tretinoin when combined with benzoyl peroxide in presence and in absence of visible light and ultraviolet radiation. Br J Dermatol 1998; 139:8–11.48. Hecker D, Worsley J, Yueh G. Interactions between tazarotene and ultraviolet light. J Am Acad Dermatol 1999; 41:927–930.

294 Fernandez et al. 49. Gfatter R, Hackl P, Braun F. Effects of soap and detergents on skin surface pH, stratum corneum hydration and fat content in infants. Dermatol 1997; 195:258–262. 50. Shehaded NH, Kligman AM. The effect of topical antibacterial agents on the bacterial flora of the axial. J Invest Dermatol 1963; 40:61–71. 51. Warren R, Ertel KD, Bartolo RG. The influence of hard water (calcium) and surfactants on irritant contact dermatitis. Contact Dermatitis 1996; 35:337–343. 52. Baranda L, Gonzalez-Amaro R, Torres-Alvarez B, Alvarez C, Ramirez V. Correlation between pH and irritant effect of cleansers marketed for dry skin. Int J Dermatol 2002; 41:494–499. 53. Subramanyan K. Role of mild cleansing in the management of patient skin. Dermatol Ther 2004; 17:26–34. 54. Draelos Z. Hydroxy acids for the treatment of aging skin. J Geriatr Dermatol 1997; 5:236. 55. Brackett W. The chemistry of salicylic acid. Cosmet Dermatol 1997; 10:5. 56. Davies MG, Marks R. Studies on the effect of salicylic acid on normal skin. Br J Dermatol 1976; 95:187–192. 57. Van Scott EJ, Yu RJ. Hyperkeratinization, corneocyte cohesion and alpha hydroxy acids. J Am Acad Dermatol 1984; 11:867–879. 58. Kligman AM. A comparative evaluation of a novel low-strength salicylic acid cream and glycolic acid products on human skin. Cosmet Dermatol 1997;11. 59. Baumann L. Cosmetic Dermatology: Principles and Practice. 1st ed. Hong Kong: McGraw- Hill, 2002. 60. Baranda L, Gonzalez-Amaro R, Torrer-Alvarez B, Alvarez C, Ramirez V. Correlation between pH and irritant effect of cleansers marketed for dry skin. Int J Dermato 2002; 41:494–499. 61. Eady E, Bojar R, Jones C, Cove J, Holland K, Cunliffe W. The effects of acne treatment with a combination of benzoyl peroxide and erythromycin on skin carriage of erythromycin- resistant propionibacteria. Br J Dermatol 1996;134. 62. Gollnick H, Schramm M. Topical drug treatment in acne. Dermatology 1998; 196:119–125. 63. Chalker DK, Shalita A, Smith JG, Swann RW. A double-blind study of the effectiveness of a 3% erythromcin and 5% benzoyl-peroxide combination in the treatment of acne vulgaris. J Am Acad Dermatol 1983; 9:933–936. 64. Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and vehicle gel: combined results of two double-blind investigations. J Am Acad Dermatol 1997; 37:590–595. 65. Leyden JJ. The evolving role of propionibacterium acnes in acne. Semin Cutan Med Surg 2001; 20:139–143 [Review] [26 refs]. 66. Nazzaro-Porro M, Passi S, Picardo M, Breathnach A, Clayton R, Zina G. Beneficial effect of 15% azelaic acid cream on acne vulgaris. Br J Dermatol 1983; 109:45–48. 67. Leyden JJ. Current issues in antimicrobial therapy for the treatment of acne. J Eur Acad Dermatol Venereol 2001; 15:51–55. 68. Layton AM, Cunliffe WJ. Phototoxic eruptions due to doxycycline—a dose related phenomenon. Clin Exp Dermatol 1993; 18:425–427. 69. Bikowski J. Subantimicrobial dose doxycycline for acne and rosacea. Skinmed 2003; 2:222–228. Jul-Aug. 70. Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol 2003; 139:459–464. 71. Elkayam O, Yaron M, Caspi D. Minocycline-induced autoimmune syndromes: an overview. Semin Arthritis Rheumatol 1999; 28:392–397. 72. Zouboulis CC, Piquero-Martin J. Update and future of systemic acne treatment. Dermatology 2003; 206:37–53. 73. Dickinson B, Altman R, Nielsen N, Sterling M. Drug interactions between oral contraceptives and antibiotics. Obstet Gynecol 2001; 98:853–860. 74. Velicer C, Heckbert S, Lampe J. Antibiotic use in relation to the risk of breast cancer. J Am Med Assoc 2004; 291:827–835. 75. Eady EA. Bacterial resistance in acne. Dermatology 1998; 196:59–66. 76. Cooper AJ. Systematic review of propionibacterium acnes resistance to systemic antibiotics. Med J Aust 1998; 169:259–261. Sep 7. 77. Thiboutot D, Chen W. Update and future of hormonal therapy in acne. Dermatology 2003; 206:56–67.

Acne Treatment Methodologies 295 78. Jaussan V, Lemarchand-Bernaud T, Gomez F. Modifications of the gonadal function in the adult rat after fetal exposure to spironolactone. Biol Reprod 1985; 32:1051–1061. 79. Shaw J. Spironolactone in dermatologic therapy. J Am Acad Dermatol 1991; 24:236–243. 80. Shaw JC. Low-dose adjunctive spironolactone in the treatment of acne in women: a retrospective analysis of 85 consecutively treated patients. J Am Acad Dermatol 2000; 43:498–502. 81. van Waygen R, van den Ende A. Experinece in the long term treatment of patients with hirsutism and/or acne with cyproterone acetate-containing preparations. Exp Clin Endocrinol Diabetes 1995; 103:241–251. 82. Dodin S, Faure N, Cedrin I, et al. Clinical efficacy and safety of low-dose flutamide alone and combined with an oral contraceptive for the treatment of idiopathic hirsutism. Clin Endocrinol 1995; 43:575–582. 83. Wysowski D, Freiman J, Tourtelot J, Horton M. Fatal and nonfatal hepatotoxicity associated with flutamide. Ann Int Med 1993; 118:860–864. 84. Vexiau P, Basoeyras M, Chaspoux C, Foin N, Allaert F. Acne in adult women: data from a national study on the relationship between type of acne and markers of clinical hyperandrogenism. Ann Dermatol Venereol 2002; 129:174–178. 85. Thiboutot D. Acne and rosacea: new and emerging therapies. Dermatol Clin 2000; 18:63–71. 86. Maloney M, Arbit D, Flack M, McLaughlin-Miley C, Sevilla C, Derman R. Use of a low-dose oral contraceptive containing norethindrone acetate and ethinyl estradiol in the treatment of moderate acne vulgaris. Clin J Women’s Health 2001; 1:124–131. 87. Beylot V, Faundes A, Alvarez F, Cochon L. Nonmenstrual adverse events during use of implantable contraceptives for women: data from clinical trials. Contraception 2002; 65:63–74. 88. Pochi PE, Shalita AR, Strauss JS, et al. Report of the consensus conference on acne classification. Washington, D.C., March 24 and 25, 1990. J Am Acad Dermatol 1991; 24:495–500. 89. Cunliffe W, van de Kerkhof P, Caputo R, et al. Roaccutane treatment guidelines: results of an international survey. Dermatology 1997; 194:351–357. 90. Tsukada M, Schroder M, Roos T, et al. 13-cis retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoic acid receptors. J Invest Dermatol 2000; 115:321–327. 91. Leyden JJ, McGinley KJ, Foglia AN. Qualitative and quantitative changes in cutaneous bacteria associated with systemic isotretinoin therapy for acne conglobata. J Invest Dermatol 1986; 86:390–393. 92. Cunliffe WJ, Layton AM. Oral isotretinoin: patient selection and management. J Dermatol Treat 1993; 4:S10–S15. 93. Strauss J, III, Rapini R, Shalita A. Isotretinoin therapy for acne: results of a multicenter dose- response study. J Am Acad Dermatol 1984; 10:490–496. 94. Layton AM, Knaggs H, Taylor H, Cuncliffe WJ. Isotretinoin for acne vulgaris—10 years later: a safe and successful treatment. Br J Dermatol 1993; 129:292–296. 95. Stainforth J, Layton A, Taylor J, Cunliffe W. Isotretinoin for the treatment of acne vulgaris: which factors predict the need for more than one course? Br J Dermatol 1993; 129:297–301. 96. Orfanos C, Zouboulis C. Oral retinoids in the treatment of seborrhea and acne. Dermatol 1998; 196:140–147. 97. Brecher AR, Orlow SJ. Oral retinoid therpay for dermatologic conditions in children and adolescents. J Am Acad Dermatol 2003; 49:171–182. 98. Hull PR, Demkiw-Bartel C. Isotretinoin use in acne: prospective evaluation of adverse events. J Cutan Med Surg 2000; 4:66–70. 99. McElwee NE, Schumacher MC, Johnson SC, et al. An observational study of isotretinoin recipients treated for acne in a health maintenance organization. Arch Dermatol 1991; 127:341–346.100. Heudes AM, Laroche L. Muscular damage during isotretinoin treatment. Ann Dermatol Venereol 1998; 125:94–97.101. Landau M, Mesterman R, Ophir J, Mevorah B, Alcalay J, Harel A. Clinical significance of markedly elevated creatinine kinase levels in patients with acne on isotretinoin. Acta Derm Venereol 2001; 81:350–352.102. Ellis CN, Krach KJ. Uses and complications of isotretinoin therapy. J Am Acad Dermatol 2001; 45:S150–S157.103. Quinn A, Singer S, Buncic J. Pediatric tetracycline-induced pseudotumor cerebri. J AAPOS 1999; 3:53–57.

296 Fernandez et al.104. Wysowski D, Pitts M, Beitz J. Depression and suicide in patients treated with isotretinoin. N Engl J Med 2001; 344:460.105. Jick S, Kremers H, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide and attempted suicide. Arch Dermatol 2000; 136:1231–1236.106. Chia C, Lane W, Chibnall J, Allen A, Siegfried E. Isotretinoin therapy and mood changes in adolescents with moderate to severe acne. Arch Dermatol 2005; 141:557–560.107. Hanson N, Leachman SA. Safety issues in isotretinoin therapy. Semin Cutan Med Surg 2001; 20:166–183.108. Barth JH, MacDonald-Hull SP, Mark J, Jones RG, Cunliffe WJ. Isotretinoin therapy for acne vulgaris: a re-evaluation of the need for measurements of plasma lipids and liver function tests. Br J Dermatol 1993; 129:704–707.109. Cunliffe WJ. Acne. London: Dunitz, 1989.110. Melo TB. Uptake of protoporphyrin and violet light photodestruction of propionibacterium acnes. Z Naturforsch 1987; 42:123–128.111. Lee WL, Shalita A, Poh-Fitzpatrick MB. Comparative studies of porhyria production in propionibacterium acnes and propionibacterium granulosum. J Bacteriol 1978; 133:811–815.112. Arakane F, Ryu A, Hayashi C. Singlet oxygen (1 delta g) generation from coproporphyrin in propionibacterium acnes on irradiation. Biochem Biophys Res Commun 1996; 223:578–582.113. Sigurdsson V, Knulst AC, van Weelden H. Phototherapyof acne vulgaris with visible light. Dermatol 1997; 194:256–260.114. Kjelstad B, Johnsson A. An action spectrum for blue and near UV inactivation of propionibacterium acnes; with emphasis on a possible porphyrin photosensitization. Photochem Photobiol 1986; 43:67–70.115. Suh DH, Kwon TE, Youn JI. Changes of comedonal cytokines and sebum secretion after UV irradiation in acne patients. Eur J Dermatol 2002; 12:139–144.116. Mills OH, Kligman AM. UV phototherapy and photocemotherapy of acne vulgaris. Arch Dermatol 1978; 114:221–223.117. Lassus A, Salo O, Forstrom L. Treatment of acne with selective UV-phototherapy (SUP): an open trial. Dermatol Monatsschr 1983; 169:376–379.118. Meffert H, Kolzsch J, Laubstein B. Phototherapy of acne vulgaris with the “TuR” UV 10 body section irradiation unit. Dermatol Monatsschr 1986; 172:9–13.119. Meffert H, Laubstein B, Kolzsch J. Phototherapy of acne vulgaris with the UVA irradiation instrument TBG 400. Dermatol Monatsschr 1986; 172:105–106.120. van Weelden H, de Gruijl FR, van der Putte SC. The carcinogenic risks of modern tanning equipment: is UV-A safer than UV-B? Arch Dermatol Res 1988; 280:300–307.121. Charakida A, Seaton E, Charakida M, Mouser P, Averginos A, Chu A. Phototherapy in the treatment of acne vulgaris. Am J Clin Dermatol 2004; 5:211–216.122. Fien S, Ballard C, Nouri K. Multiple modalities to treat acne: a review of lights, lasers, and radiofrequency. Cosmet Dermatol 2004; 17:789–793.123. Divaris DX, Kennedy JC, Pottier RH. Phototoxic damage to sebaceous glands and hair follicles of mice after systemic administration of 5-aminolevulinic acid correlates with localized protoporphyrin IX fluorescence. Am J Pathol 1990; 136:891–897.124. Ibbotson SH. Topical 5-aminolevulinic acid photodynamic therapy for the treatment of skin conditions other than non-melanoma skin cancer. Br J Dermatol 2002; 146:178.125. Seaton E, Charakida A, Mouser A. Pulsed dye laser treatment for inflammatory acne vulgaris: randomised controlled trial. Lancet 2003; 362:1347–1352.126. Paithankar D, Ross V, Saleh B, Blair M, Graham B. Acne treatment with a 1450nm wavelength laser and cryogen spray cooling. Lasers Surg Med 2002; 31:106–114.127. Friedman P, Jih M, Kimyai-Asadi A, Goldberg L. Treatment of inflammatory facial acne vulgaris with the 1450-nm diode laser: a pilot study. Dermatol Surg 2004; 30:147–151.128. Lloyd J, Mirkov M. Selective photothermolysis of the sebaceous glands for acne treatment. Lasers Surg Med 2002; 31:115–120.129. DiGiovanna JJ. Isotretinoin effects on bone. J Am Acad Dermatol 2001; 45:S176–S182.130. McLane J. Analysis of common side effects of isotretinoin. J Am Acad Dermatol 2001; 45:S188–S194.

18Topical BotanicalsTracy Cornuelle and Jan LephartResearch and Development, Nu Skin Enterprises, Provo, Utah, U.S.A.INTRODUCTIONBotanicals have been part of cosmetics and toiletries since before recorded history. Asearly as 10,000 BC scented oils and ointments were used to soften skin and mask bodyodor (1). The ancient Egyptians freshened their breath by chewing pellets made of groundtamarisk leaves (2) and made perfumes from mixtures of essential oils such as myrrh,chamomile, rose, and cedar combined in vegetable oils of olive, sesame, or almond (1).The Picts of the British Isles made blue body paint from woad (Isatis tinctoria L). Weknow this dye was used as war paint from Roman writings of the time. In ancient Persia,and across the ancient world, henna dyes were used to stain hair and faces and theEgyptians used it to paint their fingernails. Botanicals aren’t just for fragrance and color. Many plant extracts have providedimportant pharmaceutical drugs. For decades, powdered Digitalis purpurea (foxglove)leaf (Powdered Digitalis U.S.P.) has been sold as a prescription drug for congestive heartfailure. Tubocurarine, the active constituent from curare arrow poison (derived from theSouth American vine Chondrodendron tomentosum) is used as a skeletal muscle relaxantduring surgery. Morphine and codeine (from Papaver somniferum L.) are still extremelyimportant analgesics. Many important anti-cancer drugs, such as Paclitaxel (from thePacific yew tree, Taxus brevifolia) and vincristine and vinblastine (both from Madagascarperiwinkle, Catharanthus roseus, a common garden flower), originally were identifiedfrom plants. Plants have the ability to biosynthesize a stunning array of primary and secondarymetabolites. Primary metabolites include those constituents that all plants make andare necessary for plants to function. These include carbohydrates, proteins, lipids, etc.Secondary metabolites are compounds that are not generally found in every speciesof plant. Flavonoids, polyphenols, terpenoids, and alkaloids are usually classified assecondary metabolites. These compounds perform special functions in the plant suchas pollinator attractants, anti-feedants, antimicrobials, and antivirals. Plants don’t have theability to get up and move, so they depend on their biosynthetic abilities to protectthemselves and to propagate themselves. The wide variety of chemical constituents found in plants, many of them highlycomplex chemical structures, have been used as a biochemical resource by mankind. 297

298 Cornuelle and LephartPlants have been extensively screened for biological activities that are useful to man,including medical and agricultural uses. The unique and complex structures have oftenshown new types of biological activity and have been a tool for elucidating aspects of howdiseases attack our bodies or how pathogens damage crops. When a new mechanism ofaction is identified, a synthetic method for producing the compound is often pursued.The compound may be used as a template for the development of new drugs. Syntheticvariations of the chemical structure can be analyzed for improved activity, fewer sideeffects, etc. Biologically active compounds from plants have the ability to provide real healthbenefits, and perhaps real cosmetic benefits as well. Today botanicals can be found ineverything from foot cream to lipstick. Botanical extracts come in many forms. Some aredesigned to be easily incorporated into cosmetic formulations, but impart little more thana pretty name to the ingredient deck. Other extracts are prepared in such a way as tooptimize any potential benefits that the plant may impart. Some of these extracts arestandardized to ensure a known concentration of the active compound and that theconcentration of the compound will be consistent from batch to batch.SELECTING PLANT SPECIESSelection of potential plant species for cosmetic application should be based onethnobotanical knowledge or scientific research demonstrating beneficial properties.The safety of the plant and the therapeutic constituent in question also needs to beinvestigated. Once you have determined what type of benefits or claims you are lookingfor from a botanical extract and which plants could provide the desired effects, you shouldinvestigate if any of the plants in question are threatened or endangered species. TheConvention on International Trade in Endangered Species of Fauna and Flora Web site isan excellent resource for this type of information (www.cites.org). If the selected plant hasno issues in this area, is it being produced in a fashion that will permit sustained harvestingand is it available in the quantities necessary to support your needs? Wildcrafting, collecting plants from the wild for commercial uses, has been knownto devastate species, or at least a local population of plants, and has led to certain speciesbecoming threatened or endangered. Surprisingly, many plant species used in herbalmedicines and extracts are still being collected from the wild (3). Many medicinal plantsare disappearing at an alarming rate due to rapid agricultural and urban development,uncontrolled deforestation, and indiscriminate collection. Ornamental species, includingnative orchids, are under these pressures as well. According to the World ConservationUnit Red List of Threatened Plants, 12.5% (or 34,000 plant species) of vascular plantsalone are at risk of extinction (4). Even in North America plants such as ginseng(Panax quinquefolium) and goldenseal (Hydrastis canadensis) have been notably reduceddue to over-harvesting (5). Limonium wrightii H., a plant used in traditional Chinesemedicine, is no longer found growing wild in Taiwan. In order to meet commercialdemands, this plant is now farm grown (3).SOURCING PLANT MATERIALNumber of sources and reliability of sources available are important considerations whenselecting an extract or a supplier. For instance, lauric acid is used widely in soaps anddetergents. It used to be obtained mainly from Philippine coconut oil. However, the price

Topical Botanicals 299of coconut oil was highly unstable due to drought, aging plantations, typhoons, pests, anddiseases in the Philippines. One good typhoon could wipe out an entire years crop. Africanoil palm (Elaeis guineensis) is also an excellent source of lauric oils. It is grown inIndonesia and Malaysia and other parts of the tropics and is now an important commercialsource for lauric acid. Fu Ling or poria (Poria cocos) is a fungus widely used in traditional Chinesemedicine. When the SARS outbreak occurred, the demand for poria in Asia was so greatthat it was virtually impossible for western herb companies to obtain (6). Any plant cropthat comes from one specific location could potentially be unavailable or the year’s cropwiped out due to weather, natural catastrophe, war, or even epidemic. The number andreliability of sources available should be a consideration when selecting a new botanical.ACCURATE IDENTIFICATION OF PLANT SPECIESHistorically, plants have been identified by an examination by a plant taxonomist of theleaf, fruit, flower, and other plant parts necessary for proper determination (7). Precisenotes regarding the specimen’s colleting location, including latitude and longitude,village, county, province or state, and country, and a description and photos of the plantsheight, width, habit, color, fragrance, etc. in its natural habitat, may also be required.Of course, this type of information is usually not available when purchasing an extractor dried plant material from a vendor. The U.S. Pharmacopeia (8) has thin-layer chromatography (TLC) methods foridentifying certain commonly found dietary supplement herbal products, based upon theirchemical constituents. Other analytical techniques such as gas chromatography (GC) orhigh performance liquid chromatography (HPLC) could just as easily be used. DNA fingerprinting methods can also be developed for identifying plants (9). This isespecially useful to ensure that microbial strains, which seem often to be counted asbotanicals in the cosmetic world, have maintained their integrity over multiple generationsof serial transfers during the culture maintenance process.HARVESTING PLANT MATERIALThere are several things to consider when harvesting plants for extraction. Firstly, the plantmaterial harvested should come from healthy, disease-free plants. The plant material istypically air-dried in arid regions or oven-dried in humid regions (to avoid mold) toa moisture content of %10%. The plant material is then ground or milled to a smallparticle size, typically 1–10 mm. This provides a larger surface area for extraction anda more exhaustive extraction in a shorter period of time. For some types of extracts, the fresh plant material is extracted without drying. Forexample, volatile compounds (e.g., monoterpenes, sesquiterpenes) may evaporate offduring the drying process. So, the fresh plant material is often steam distilled or extractedas soon as it is harvested. Certain highly sensitive compounds may be degraded during thedrying process by heat, light, oxygen, or even enzymes within the plant material. Thesemay also be extracted shortly after harvest in order to maintain biological activity of thefinal extract. It is not uncommon for a desired constituent to be found at varying concentrations indifferent parts of the plant (Table 1). So, for instance, glaberdines, the skin lighteningconstituents from licorice, are found in higher concentration in the roots of the licorice

300 Cornuelle and LephartTable 1 Concentration of Constituents in Different Parts of the PlantPlant Constituent Leaf Root Other Reference (10)Astragalus Isoflavones 0.55 mg g/l 3.04 mg g/l (10) membra Flavonols dry wt dry wt. (11) neaceus Brachycerine 3.54 mg g/l 0.49 mg g/l (12)Astragalus dry wt dry wt. membra (13) neaceus 0.1–0.2% Not detected 0.3% dry wt. in (13) inflorescen-Psychotria dry wt in roots ces 0.045% brachyceras dry wt. in mature fruits (leaves and 2.3% w/w in green stems) rhizomes !0.1% w/wHydrastis 5-O-(40-[b-d- Not detected 1.0% w/w in stems canadensis glucopyra- nosyl]-trans- 10.6 mg/gPanax quin- feruloyl) Not detected quefolius quinic acidP. quinque Rg3 ginseno- 7.5 mg/g folius side Rg2 ginseno- 11.3 mg/g sideplant. For green tea catechins, the leaf is utilized. The beneficial constituents of SaintJohn’s Wort are highest in the flowers, although a combination of flowers and leaves areoften used. The entire aerial, or above ground portion of the plant, may be used in othercases. Other aspects to consider are that constituent concentration can vary dependingon the weather, time of year, elevation, soil conditions, fertilizer, age of plant, diseasestate, etc. (14).COSMETIC EXTRACTSExtracts that are designed specifically for cosmetic products come in many forms. Theyare usually liquid extracts in a cosmetically friendly solvent or solvent blend such as water,butylene glycol, glycerin, vegetable oil, or cosmetic ester. Some of them are standardizedto a marker compound, but many are not. Many non-standardized extracts are designedsimply to add a botanical name to your ingredient deck, but others have in vitro or clinicaldata from the vendor indicating various benefits to skin. Sometimes these tests have beencarried out by an independent lab and sometimes the vendor’s own testing facilities haveproduced the data. It is important to remember that, unlike academic journal articles, thistype of data is not peer-reviewed and outside labs do not often repeat the testing to confirmthe results. Some larger cosmetic companies will in fact do their own ingredient testing toconfirm vendor claims before they choose to use the ingredient in a personal care product. In most cases, the goal of producing an extract is to increase the potency of thebotanical by concentrating the biologically active constituents. Although it is notuncommon for one particular constituent from the plant to be predominantly responsiblefor the therapeutic benefit derived from the plant, frequently there will be a series ofclosely related compounds, or in some cases unrelated compounds, each of which

Topical Botanicals 301contributes to some degree to the beneficial properties of the plant. For oral supplements,another benefit to producing an extract is that it reduces the total quantity of plant materialthat must be ingested to achieve an efficacious dose. In the case of topical applications, asin cosmetics, where the benefit of the digestive process is not available, extraction of thebiologically active compound increases the bioavailability of the compound to the skin. Many types of extraction processes are used commercially to produce extracts. Forinstance, volatile products, such as essential oils, are often extracted by steam distillation.Lipophillic compounds, such as carotenoids, xanthophylls, and, once again, essential oilsor their constituents, are more and more often extracted by CO2 super critical fluidextraction. This process uses pressure and low heat to convert CO2 into a fluid phase, orphysical state, in which it acts as an excellent non-polar solvent. The polarity can bemodified, to some extent, by adding more polar solvents, such as ethanol, to the extraction.A major advantage to this process is that it is “green”; no harmful organic solvents arereleased into the environment. Enzymes such as cellulases can be used to break down thecell walls of the plant tissue causing the cells to expel their contents into the enzymesolution. Despite the many options, solvent extractions are probably still the most commonmethod for extracting small molecules such as the secondary metabolites of plants. The general approach for solvent extraction is “like dissolves like.” In other words,non-polar solvents will extract non-polar constituents and polar solvents will extract polarconstituents. So an extraction process needs to be based on the particular compound,or class of compounds, that provide the beneficial properties of the plant in question. For a high concentration of the target compound(s) in the final extract, the solventselection and extraction process development must be based upon optimal extraction andpurification of the desired compound. Factors such as solvent choice, extraction duration,temperature, etc. of the extraction process must all be evaluated. While applying heatduring the extraction process can reduce the required duration of the process and producea more exhaustive extraction, some compounds are heat labile. Light and oxygen can alsocause degradation of certain compounds. If the target compound is highly labile, reducingthe extraction temperature may be required. Nitrogen blanketing may decreasedegradation, or the addition of antioxidants can also help to protect some highlylabile compounds. A common extraction process would include macerating, or often refluxing, thedried, milled plant material in an alcoholic solvent or water-alcohol mixture. The benefitsof alcohol are that it is a powerful solvent capable of extracting many types of molecules, itcan preserve the extract and so eliminate the risk of microbial degradation, and alcohol isrelatively volatile and is removed fairly easily once the extraction is complete, by vacuumdistillation or evaporation. Alcohol extracts are generally very complex mixtures of constituents. Due to the factthat alcohol is a powerful solvent, it extracts a wide range of constituents from the plantmaterial. A second purification step is often performed in order to obtain a high level of thebiologically active compound in the final extract product. The alcohol may be distilled offand a second purification step applied. A simple and common approach is to performa second extraction on the dried extract using a different solvent. For example, thealcoholic extract of Centella asiatica may be dried down to a paste consistency. The pasteis then extracted with acetone and the precipitate is recovered by filtration and dried. Theprecipitate is assayed and adjusted to 40% saponins, milled and packaged as a commercialextract (15). For other types of extracts, the target compound might be recovered from thefiltrate instead of the precipitate. Ideally, a solvent will be found in which the desiredconstituent is only partially soluble. At elevated temperatures the constituent will dissolvein the solvent and any insoluble material can be filtered out. As the extract is cooled

302 Cornuelle and Lephartthe solubility of the target compound goes down and, under the right conditions, itcrystallizes out of solution. The relatively pure compound is then recovered by filtration Other commonly used purification techniques include ultrafiltration, nanofiltration,and column chromatography. Ultrafiltration and nanofiltration are excellent purificationmethods for water-based extracts. These methods use membranes to separate compoundsbased on molecular size. Column chromatography is a procedure by which solutes areseparated by differential migration properties in a system consisting of two or morephases. One phase moves continuously in a given direction and the individual compoundswithin the phase exhibit different mobilities by reason of differences in adsorption,partition, solubility, molecular size, or ionic charge density. The second phase, a stationaryphase, may act through adsorption, as in the case of adsorbents such as activated alumina,silica gel, and ion-exchange resins, or it may act by dissolving the solute thus partitioningit between the stationary and mobile phases.STANDARDIZATION OF EXTRACTSAn extract that has been purified or formulated to contain a consistent, measurablequantity of a target compound (or sometimes class of compounds) in every batch,is referred to as “standardized.” The level of the compound is guaranteed to be withina certain range or above a certain minimum in every batch or lot of the extract that youpurchase. The exact level of the compound in a particular batch should be reported on theCertificate of Analysis, which most vendors provide with the extract shipment. Commonchemical analytical methods such as HPLC, GC, titration, etc. are generally used tomeasure the content of the target compound within the extract. Although, in some cases,pharmacological bioassays are used to measure the particular type of biological activitywithin the extract, for example, enzyme activity. There are two schools of thought regarding how an extract should be standardized.Some people feel that a virtually pure compound is the most efficacious approach toformulating an effective product. Using one pure plant derived compound eliminates anyconfounding properties that a more complex extract might have. Botanical extracts cancontain extremely complex mixtures of compounds. It is possible that some compoundsin the mixture may interfere with or counteract the benefits of the target compound.For example, the polyphenol fraction of St. John’s Wort (Hypericum perforatum)has been found to have immunostimulating activity, whereas the lipophilic fraction hadimmunosuppressing properties (16). In a complex mixture, you don’t know exactly whatyou have. Complex extracts may cause difficulties formulating, problems with formulastability, or perhaps occasionally problems with safety such as allergic responses to thefinal product. The other school of thought seems to stem mainly from ethnobotanical research.Traditional herbal medicines are usually prepared as teas (aqueous infusions of the fresh ordried plant material). In some cases, different compounds within the tea contributeadditional or different therapeutic benefits. For instance, ginger (Zingiber officinale R.)contains anti-inflammatory compounds and anti-nausea compounds (17). Using a pureform of one of the anti-inflammatory compounds will not give the full range of benefitsderived from the traditional medicine. Valarian (Valeriana officinalis), used as a sedative, is another example of an herbalmedicine that appears to contain more than one type of compound responsible for thebenefits derived from it (18). The volatile oil contains major constituents, includingvalerenic acid and its derivatives, which have demonstrated sedative properties in animal

Topical Botanicals 303models. Valepotriates and their derivatives, which belong to the iridoid class of molecules,have also demonstrated in vivo sedative activity, but they are very unstable and tend tobreak down over time, making their activity difficult to assess. Valerian extracts alsocontain gamma-aminobutyric acid (GABA) and aqueous extracts contain glutamine whichmay be converted into GABA. These compounds may also contribute to valerians sedativeeffects. In this case, the herbal medicine contains three different classes of molecules, all ofwhich may to contribute to the sedative benefits of the extract. Another important consideration is whether the extract is standardized to thecorrect constituent. As can be seen from the previous examples of herbal medicinals,often the compounds responsible for the therapeutic benefits are not well understood,sometimes not known period. For many years the constituents responsible for the anti-depressant benefits of St. John’s Wort (Hypericum perforatum) were not understood.It was thought that hypericin was the primary active in the herb. Dietary supplements ofSt. John’s Wort were standardized to hypericin, and perhaps still are in some instances.Hypericin is known to be a photosensitizer (19). This property was first recognized incattle that grazed on this plant. Several instances of photosensitization in people usingSt. John’s Wort herbals have been reported (20–22). Hyperforin is now recognized as themajor antidepressant constituent of this plant. Hyperforin has been found to be a stronguptake inhibitor of serotonin, dopamine, noradrenaline, GABA, and L-glutamate (23).Although hyperforin alone is a powerful antidepressant, several other compounds in theplant also appear to contribute to the overall antidepressant benefits from the plant (24).This compound is not a photosensitizer, but it is unstable. Its instability makes itdifficult to standardize to and perhaps explains the continued use of hypericin as themarker compound.QUALITY ISSUESQuality concerns will differ depending on the particular plant or extract. The typical typesof properties that are used to determine the quality or batch to batch consistency ofa botanical ingredient would include: appearance, color, odor, botanical characteristics(for plant material), microbial count, pH, residue on evaporation or loss on drying, totalash, acid-insoluble ash, water soluble ash, heavy metal content, alcohol-solubleextractives, water-soluble extractives, foreign organic matter, solvent residue, moisturecontent, volatile oil content, pesticide residue, and of course the level of marker compoundif the extract is standardized. In some cases, a fingerprint method may be developed toensure that the plant or plant extract is what it claims to be and/or is consistent from batchto batch. This might be a DNA fingerprint, chromatography profile (e.g., TLC, HPLC orGC), or even an IR fingerprint. Generally, five to 10 characteristics are reviewed fora particular product and the assay results will be listed on the Certificate of Analysis whichshould be available for every batch of product that is purchased. Microbial contamination is especially common in dried plant material where themicrobial counts are generally very high. USP or CTFA plate count methods may beutilized to evaluate this. Irradiation is commonly used to sterilize herbaceous material.Extracts may have microbial issues depending on what solvent was used in the extractionprocess. Many organic solvents, such as ethanol and methanol, are antiseptics and so willeffectively preserve an extract. Other extracts, especially water-based ones, are typicallypreserved or sterilized. Pesticide levels can be a concern for some plant based products. The United StatesPharmacopeia (8) is a good resource for acceptable levels. A table of 30 or more pesticides

304 Cornuelle and Lephartand the maximum limit for each is shown under “General Method for Pesticide ResiduesAnalysis” in the Chemical Tests section. Any pesticides not listed are consideredunacceptable at any level. These limits were set for dietary supplements, but are a goodguideline for cosmetics as well. Some types of plants have a tendency to accumulate certain heavy metals (14). Forinstance, mugwort plants (Artemisia vulgaris L.) and coneflower roots (Echinacea spp.)are known to accumulate iron; black cherry stems (Prunus serotina E.) and buckbushstems (Symphoricarpos orbiculatus M.) accumulate lead; cassia plants (Cinnamomumaromaticum N.) and bladderwrack plants (Fucus vesiculosus L.) accumulate mercury (25).Thus, for certain plant materials or extracts heavy metal levels should be assayed andspecified on the Certificate of Analysis. Preservatives, antimicrobials, and/or antioxidants, may be added to extracts andshould be identified by the extract manufacturer upon request. Analytical methods such asHPLC may also be applied to identify preservatives within an extract. Ash quantity is oftenused as a quality specification for extracts. Excessive quantities of ash may indicate thepresence of buffers (sometimes used during extraction process to adjust the polarity ofthe solvent) or drying agents such as silica dioxide.SAFETY AND TOXICOLOGYJust because an ingredient is plant-derived doesn’t mean it is safe. Just ask Socrates!Poisons such as strychnine come from plants (Strychnos nux-vomica L. and otherStrychnos spp.). And potent allergens, such as the heptadecylcatechols from poison oak(Toxicodendron diversilobum) and pentadecylcatedchols from poison ivy (T. radicans)are also plant derived (26). Many plant extracts are considered safe because they are made from ingredients thatare Generally Recognized as Safe (GRAS) (27). Toxicology testing is important for otherextracts. Highly purified plant constituents, even if they come from plants that are GRAS,may need testing due the increased concentration of the particular constituent. Someingredients are safe at low levels but cause problems at higher levels. Some of the types oftesting that are commonly used to test the safety of cosmetic extracts include repeat insultpatch testing (RIPT), cumulative irritation, in vitro mutagenicity (i.e., Ames test), in vitrocell culture methods for assessing potential ocular and/or dermal irritation (e.g., Bovineocular assay, Irritectione, Eyetexe, Skintexe, etc.), and photosensitization. This may notbe adequate in all cases. A noteworthy example is sanguinarine, an alkaloid extracted from Bloodroot(Sanguinaria canadendid ). Viadent used sanguinarine as an antiplaque ingredient in theirtoothpaste and mouthwash. Despite significant toxicology and clinical testingdemonstrating the safety of this compound (28–37), a study was conducted by researchersat Ohio State University (38), which showed a strong correlation between the developmentof oral leukoplakia (potentially cancerous mouth lesions) and the use of oral productscontaining sanguinarine. Several follow-up studies (39–42) have confirmed thiscorrelation. Surprisingly, other studies appear to indicate that sanguinarine may actuallyhave potential as an anti-cancer agent (43–45). This demonstrates how complicated andconfusing these safety and toxicology issues can be. Long-term safety can only bedemonstrated by long-term use. When Colgate-Palmolive purchased the brand, theyremoved the sanguinarine.

Topical Botanicals 305CONCLUSIONSPlant-derived compounds have the ability to deliver real benefits. Considerations inchoosing a plant product should include an investigation of the status of the species(is it endangered or threatened), whether sustainable harvesting practices are being used,and whether there is a reliable source with the quantities needed. Many extraction andpurification methods are used commercially depending on the desired qualities of the endproduct. As with all cosmetic ingredients, standard quality assurance techniques should befollowed to ensure the quality and consistency of the product or extract. The safety andtoxicology of the material should be investigated to eliminate or reduce the risk of harmto consumers.REFERENCES 1. Cohen M, 1999. Cosmetics and Perfumes, Egypt, 10,000 BCE. (Accessed June 2005, at www. smith.edu/hsc/museum/ancient_inventions/hsc01b.htm). 2. Narada T. Ancient Cosmetics & Fragrance. (Accessed June 2005, at www.cyonic-nemeton. com/cosmetics.htm). 3. Nalawade SM, Sagare AP, Lee C, et al. Studies on tissue culture of Chinese medicinal plant resources in Taiwan and their sustainable utilization. Bot Bull Acad Sin 2003; 44:79–98. 4. Brackett D. Red flag for plants:. World Conserv 1998; 2:10. 5. Chamberlain J, Bush R, Hammett AL. Non-timber forest products. Forest Prod J 1998; 48:10–19. 6. Personal communication from Jon Anderson, Ph.D., Vice President of Technology, Actives International, L.L.C., 81 Orchard Street, Ramsey, NJ 07446. 7. Balick MJ. Good botanical practices. In: Eskinazi D, Blumenthal M, Farnsworth N, Riggins CW, eds. Botanical Medicine: Efficacy, Quality Assurance, and Regulation. New York: Mary Ann Liebert, 1999:121–125. 8. USP NF 2004. The United States Pharmacopeia 27th Edition. The National Formulary 22nd Edition. MD: United States Pharmacopeial Convention, Inc., 2003. 9. Weising K, Nybom H, Wolff K, Kahl G. DNA fingerprinting in plants: principles, methods, and applications. 2nd ed. FL: CRC Press, 2005.10. Matkowski A, Wozniak D, Lamer-Zarawska E, et al. Flavonoids and phenol carboxylic acids in the oriental medicinal plant Astragalus membranaceus acclimated in Poland. Z Naturforsch 2003; 58:602–604.11. Gregianini TS, Porto DD, Do Nascimento NC, et al. Environmental and ontogenetic control of accumulation of brachycerine, a bioactive indole alkaloid from Psychotria brachyceras. J Chem Ecol 2004; 30:2023–2036.12. McNamara CE, Perry NB, Follett JM, et al. A new glucosyl feruloyl quinic acid as a potential marker for roots and rhizomes of goldenseal. Hydrastis canadensis. J Nat Prod 2004; 67:1818–1822.13. Popovich DG, Kitts DD. Generation of ginsenosides Rg3 and Rh2 from North American ginseng. Phytochemistry 2004; 65:337–344.14. Accessed 2005 at, http://www.springer.de.15. Personal communication from Lakshmi Prakash, Ph.D., Sabinsa Corporation, 121 Ethel Road West, Unit #6 Piscataway, NJ 08854.16. Final report on the safety assessment of Hypericum perforatum extract and Hypericum perforatum oil. Int J Toxicol 2001; 20:31–39.17. Monograph—Zingiber officinale (Ginger). Alter Med Rev 2003; 8:331–335.18. Questions and answers about valerian for insomnia and other sleep disorders. (Accessed June 2005, at http://ods.od.nih.gov).

306 Cornuelle and Lephart19. Gillett JM. The St. John’s-worts of Canada (Guttiferae): Publications in Botany. Ottowa: National Museum of Canada, 1981.20. Bernd A, Simon S, Ramirez Bosca A, et al. Phototoxic effects of Hypericum extract in cultures of human keratinocytes compared with those of psoralen. Photochem Photobio 1999; 69:218–221.21. Bove GM. Acute neuropathy after exposure to sun in a patient treated with St. John’s Wort. Lancet 1998; 352:1121–1122.22. Gulick RM, McAuliffe V, Holden-Wiltse J, et al. Phase I studies of hypericin, the active compound in St. John’s Wort, as an antiretroviral agent in HIV-infected adults. AIDS Clinical Trials Group Protocols 150 and 258. Ann Intern Med 1999; 130:510–514.23. Chatterjee SS, Bhattacharya SK, Wonnemann M, et al. Hyperforin as a possible antidepressant component of hypericum extracts. Life Sci 1998; 63:499–510.24. Simmen U, Burkard W, Gerger K, et al. Extracts and constituents of hypericum perforatum inhibit the binding of various ligands to recombinant receptors expressed with the semliki forest virus system. J Recept Signal Transduct Res 1999; 19:59–74.25. Accessed June 2005, at http://geocities.com/ResearchTriangle/2888/plants.html?2005.26. Accessed June 2005, at http://wayneswor.palomar.edu/ww0802.htm.27. United States Food and Drug Administration, Federal Food, Drug, and Cosmetic Act, Food Additives Amendment, sections 201(s) and 409, enacted in 1958.28. Frankos VH, Brusick DJ, Johnson EM, et al. Safety of Sanguinaria extract as used in commercial toothpaste and oral rinse products. J Can Dent Assoc 1990; 56:41–47.29. Kuftinec MM, Mueller-Joseph LJ, Kopczyk RA. Sanguinaria toothpast and oral rinse regiment clinical efficacy in short- and long-term trials. J Can Dent Assoc 1990; 56:31–33.30. Laster LL, Lobene RR. New perspectives on Sanguinaria clinicals: individual toothpaste and oral rinse testing. J Can Dent Assoc 1990; 56:19–30.31. Hannah JJ, Johnson JD, Kuftinec MM. Long-term clinical evaluation of toothpaste and oral rinse containing sanguinaria extract in controlling plaque, gingival inflammation, and sulcular bleeding during orthodontic treatment. Am J Orthod Dentofacial Orthop 1989; 96:199–207.32. Mallatt ME, Beiswanger BB, Drook CA, et al. Clinical effect of a sanguinaria dentifrice on plaque and gingivitis in adults. J Periodontol 1989; 60:91–95.33. Keller KA, Meyer DL. Reproductive and developmental toxicological evaluation of sanguinaria extract. J Clin Dent 1989; 1:59–66.34. Mauriello SM, Bader JD. Six-month effects of a sanguinarine dentifrice on plaque and gingivitis. J Periodontol 1988; 59:238–243.35. Parsons LG, Thomas LG, Southard GL, et al. Effect of sanguinaria extract on established plaque and gingivitis when supragingivally delivered as a manual rinse or under pressure in an oral irrigator. J Clin Periodontol. 1987; 14:381–385.36. Schwartz HG. Safety profile of sanguinarine and sanguinaria extract. Compend Contin Educ Dent 1986; Suppl 7 :S212–S217.37. Kosina P, Walterova D, Ulrichova J, et al. Sanguinarine and chelerythrine: assessment of safety on pigs in ninety days feeding experiment. Food Chem Toxicol 2004; 42:85–91.38. Damm DD, Curran A, White DK, et al. Leukoplakia of the maxillary vestibule—an association with Viadent? Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999; 87:61–66.39. Anderson KM, Stoner GD, Fields HW, et al. Immunohistochemical assessment of Viadent- associated leukoplakia. Oral Oncol 2005; 41:200–207.40. Mascarenhas AK, Allen CM, Moeschberger ML. The association between Viadent use and oral leukoplakia—results of a matched case-control study. J Public Health Dent 2002; 62:158–162.41. Mascarenhas AK, Allen CM, Loudon J. The association between viadent use and oral leukoplakia. Epidemiology 2001; 12:741–743.42. Allen CL, Loudon J, Mascarenhas AK. Sanguinaria-related leukoplakia: epidemiologic and clinicopathologic features of a recently described entity. Gen Dent 2001; 49:608–614.

Topical Botanicals 30743. Adhami VM, Aziz MH, Reagan-Shaw SR, et al. Sanguinarine causes cell cycle blockade and apoptosis of human prostate carcinoma cells via modulation of cyclin kinase inhibitor-cyclin- cyclin-dependent kinase machinery. Mol Cancer Ther 2004; 3:933–940.44. Adhami VM, Aziz MH, Mukhtar H, et al. Activation of prodeath Bcl-2 family proteins and mitochondrial apoptosis pathway by sanguinarine in immortalized human HaCaT keratino- cytes. Clin Cancer Res 2003; 9:3176–3182.45. Ahmad N, Gupta S, Husain MM, et al. Differential antiproliferative and apoptotic response of sanguinarine for cancer cells versus normal cells. Clin Cancer Res 2000; 6:1524–1528.

19Herbs in Cosmeceuticals:Are They Safe and Effective?Carl ThornfeldtEpisciences, Inc., Boise, and CT Derm, Fruitland, Idaho, and Oregon Health SciencesUniversity, Portland, Oregon, U.S.A.BACKGROUNDBotanicals used for medicinal, flavoring, or fragrances are known as herbs (1,2). Theguiding principle of herbal medicine is the naturally occurring mixture of active compoundsin plants is more effective and safer than individual molecules and man-made combinationsof synthetic molecules. The natural composition is the comminuted, powdered, or galenicextracts of the whole or specific anatomic parts of the plant. Botanical medicinals arefocused more on treatment of signs and symptoms of disease while improving total “bodycondition” than reversing the disease etiology. The foundation of modern pharmacologic medicine is rooted in ethnobotanicaltraditions utilizing indigenous flora. Over 200 indigenous medicinals were listed in thefirst U.S. Pharmacopeia in 1820 including podophyllin resin, white willow bark,wintergreen, and juniper tar, which are still used today (1). Several botanical treatments for cutaneous diseases have stood the test of time fortheir effectiveness as documented by modern scientific evidence. Podophyllotoxin isa prescription purified podophyllin resin, a galenic extract of Mayapple (Podophyllumpeltatum). Capsaicin is a nonprescription therapy for pruritis and pain extracted fromCayenne peppers (Capsicum species). Henna (Lawsonia inermis) is a hair dye used bypeople sensitized to other commercial coloring agents (3). Botanical sales in 2004 exceeded $4 and one-third billion, growing by one-third overonly six years. Noni/Morinda was the largest selling botanical in 2004 with sales of nearly$220 million. Now about 70 different herbs are formulated into cosmeceuticals. Botanicalproduct growth has flourished to now consume 25% of all health- and lifestyle-relateddollars (4). Thus dermatologists must have a working knowledge of botanicals, especiallythe most common ones, to provide optimal preventive medical care. Herbal medicine plays a vital role in current healthcare by: (i) providing alternativesto prescription medications, (ii) enhancing therapeutic effects of other prescriptives, (iii)protecting against adverse reactions to allopathic therapy, and (iv) providing treatment fordiseases which there is no current prescription therapy or only poorly effective or high-risktherapy. Herbal and other alternative medical strategies are utilized by over half of thepopulation and especially by those suffering chronic diseases such as psoriasis and those 309

310 Thornfeldtwith less hope for cure such as human immunodeficiency virus (HIV) and terminal diseases(5,6). Extensive public use of complementary and alternative medicine resulted in theNational Institute of Health establishing the Office of Alternative Medicine in the UnitedStates in 1995 (1). Unfortunately, two major myths taint herbal medicine. Most patients believe themyth that there are no side effects because herbal medicine uses “natural substances.” Infact, experienced Chinese practioners are concerned about the well-known side effects ofhepatotoxicity and contact dermatitis with oral and topical Chinese herbal medicinal andpreparations, respectively (7). Many allopathic physicians believe the myth that double-blinded, placebo-controlled studies do not exist for ancient and herbal medicines. Yet, there have beenmany such studies conducted throughout Asia and India including studies investigatingmechanisms of action of the medicinal botanicals (7). The understanding of the function, metabolism, and interaction of these herbalmedicines is often lacking. The specific scientific issues include documenting: (i)complete characterization of the multiple active compounds in each plant source, (ii)activity and synergistic or additive interaction of each of these compounds and theirmetabolites, (iii) interaction of these active components with food, nutrients, nutritionalsupplements, and other medicines, and (iv) how the potential toxicity of specificcompounds is blunted (2). For example, there are the castor bean in the source of ricin, oneof the most poisonous compounds known to man, and azelaic acid, a nontoxic prescriptiondermatological medicine.PROCESSING BOTANICALSBotanicals must undergo a significant amount of processing prior to incorporation into acosmeceutical which usually significantly affects the biologic activity of the herb. Themost important factor for biologic activity is the source of the plant material because eachplant part may contain hundreds of different chemicals, ions and molecules. Growingconditions including soil composition, amount of available water, climate variations, plantstress, and harvesting conditions such as time from harvest to transport, care of plantmaterials during shipping, storage conditions prior to manufacture, and preparation of theherb and final product as well as mixing with other herbs are other factors that maysubstantially alter solubility, stability, biologic availability, pharmacokinetics, pharma-cologic activity, and toxicity. Galenic extracts are made from leaves, roots, fruits, berries, stems, twigs, barks, andflowers by crushing, grinding, comminuting, boiling, distilling, pressing, drying, orexposing to solvents. Usually, the plant material is heated or processed to obtain essentialoils or other distillates that can be easily added to a cosmetic formulation; however, thisprocessing may destroy or adversely modify some of the physiologically active molecules.The results are oil, wax, juice, tincture, decoction, tea, infusion, and/or powders which arethen formulated into topical applications including solutions, gels, lotions, creams,ointments, and pastes. Some of these preparations are further applied as fomentation,compress, or poultice (2,8). These terms are defined in Table 1 (9). The concentration of the herb, its extract, and the active molecules affect therapeuticactivity. Usually in cosmeceuticals the medicinal botanicals are added in very small, sub-therapeutic amounts for the marketing story. Most synthetic pharmaceuticals, utilizea very low concentration to provide the desired effect. Few herbs are that potent, thushigher doses (O1%) are needed. Herbal efficacy is challenged by the trans-stratumcorneum delivery of mucocutaneous surfaces which is usually difficult due to the

Herbs in Cosmeceuticals 311Table 1 Definitions Preventing and/or relieving inflammation Arrests secretions, contracts tissue, and controls bleedingAntiphlogistic Whole plant or portion broken into multiple piecesAstringent Liquid extract produced by simmering the plant part in water for overComminutedDecoction 20 minutes Sweetened alcohol extractElixir Concentrated oil from the whole plant, usually volatile, and fragrantEssential oil Liquid extract soaked clothFomentation Crude plant remediesGalenic Botanical used for medicine, flavoring, or fragranceHerb Liquid extracts combined in hot waterInfusion Botanicals that swell with exposure to water for soothing applicationMucilage Liquid extract combined with powdered herb applied directly toPoultice lesions while mass is moistRubefacient Substance that causes cutaneous erythema by counter-irritant effectsTea Dried whole or parts of plant simmered in hot water usuallyTincture 5–10 minutes Alcoholic solution of whole or portion of plant or extractherb’s concentration and multiple active compounds with different solubility, polarity, andtherapeutic concentration as well as reactivity of different mucocutaneous receptors. These complex biologic science and formulation issues indicate the only validationof herbal activity in a cosmeceutical formulation is a human clinical trial conducted bya reputable third-party researcher. Without such studies, health care providers and thepublic are being asked to trust in products based on voodoo science.REGULATORY CLIMATEMedicinal botanicals used in cosmeceuticals are considered food additives or dietarysupplements by the United States Food and Drug Administration (FDA) which declaredthem as safe. The herbs are allowed to be marketed to consumers directly without obtainingdrug status or restricted by FDA’s over-the-counter monograph requirements. Thus, nostandards of herbal potency, concentration in the marketed product, safety, nor efficacystudies exist. The German Regulatory Authority for herbs is the “Commission E.” It is the bestexpert consensus for weighing the quality of clinical evidence and systemic and topicalsafety to identify reasonably effective uses of over 300 botanicals (3). The Physician’s Desk Reference for Herbal Medicines, 3rd ed. (2004), by ThomsonPDR, Montvale, NJ, published an exhaustive literature review conducted by the respectedPhytoPharm U.S. Institute of Phytopharmaceuticals for about 400 more herbs with regardto their use and adverse reactions (3).ADVERSE REACTIONSA news magazine in 2001 revealed over 2900 adverse events requiring medical care whichwere attributed to herbs the previous year. In addition, 104 deaths were attributedprimarily to ephedra, St. John’s Wort, gingko, and ginseng (10). In 2003 the FDA removed

312 ThornfeldtEphedra and Ma Huang (Ephedra sinica) from the market due to 155 deaths directlyattributed to it (11).The most common adverse cutaneous reactions to herbal products include allergicand/or irritant contact dermatitis. Cross-sensitivity to the most sensitizing botanicals is notuncommon. For example, 12 of 106 dermatitis patients had positive patch test to tea tree oil(TTO) and all these had positive reactions to one or more of 12 other natural compoundsincluding lavender (Lavandula angustifolia) (12). Severe cutaneous reactions includingangioedema/urticaria, exfoliative erythroderma, linear IgA bullous dermatosis, lupuserythematosus, malignancies, pemphigus, Steven’s Johnson syndrome, Sweet’s syndrome,ulcerative stomatitis, and vasculitis have all been reported. Ten additional herbs haveinduced fatal reactions including aristolochia, arnica, cayenne, comfrey, henna, kava kava,mistletoe, rue, senna, and yohimbine. Other severe reactions include anaphylaxis, coma,rhabdomyolysis, and shock (3,13). Herbs known to pose dermatologic surgery dangersinclude St. John’s Wort, gingko, ginseng, garlic, echinacea, kava kava, and valerian (14).See mucocutaneous and severe complications in Table 2.Even simple plants contain multiple reactive and interactive compounds, but naturalmedicine advocates and media frequently do not warn the public of the importance ofinteractions between different herbs and with over-the-counter and prescription drugs.Moreover, 70% of patients fail to disclose their use of herbal products preoperatively.Interactions with medical consequences probably are under-reported (14). There aremany herb/food, herb/drug, and herb/herb interactions as in combinations of caution inTable 3 (3).The medicinal botanicals of proven and potential dermatologic significance arelisted by therapeutic uses in Table 4 (3). Multple herbs are effective for several differentindications. Herbal medicines may be divided into several groups. Clinically validatedones have published human-controlled clinical trials. These herbs are among the mostcommonly used by the public and alternative medicine practitioners and would beexpected to be the most commonly used in cosmeceuticals. Green and black tea, soy,pomegranate, and date have published human clinical trials for signs of photoaging as theonly active. Avocado and black cohosh are included with two other actives in differenttopical formulations treating photoaging. Other herbs with published human studiestreating dermatologic conditions with topical formulations include almond, allantoin andcomfrey, aloe, anise, bitter orange, black nightshade, black seed, camptotheca, cayenne,curcumin, date palm, echinacea, german chamomile, horse chestnut, lemon balm, neem,oat, onion, oregon grape, pomegranate, St. John’s wort, tea tree, oolong tea, and westernmedicinal herbal mixtures. Borage, evening primrose, gotu kola, grape seed, ginko biloba,horse chestnut, black tea, and Chinese herbal mixtures have been documented to treatdermatologic conditions when administered orally.The second group consists of herbs used in current cosmeceuticals with a scientificrationale supported only by animal, in vivo or in vitro studies, and/or proven efficacy inhuman systemic disease but without clinical data with topical application. These includeapple, arnica, cactus pear, eucommia, ginseng, hibiscus, jojoba, licorice, milk thistle,myrtle, olive oil, papaya, prickly pear, rosemary, sandalwood, sarsaparilla, saw palmetto,spearmint, peppermint, wheat germ, and white birch.The third group consists of herbs approved for therapy of a cutaneous conditionby the German Commission E which are currently or potentially will be incorporated intocosmeceuticals. These include agrimony, bittersweet nightshade, butcher’s broom, cajuput,chaste tree, English plantain, fenugreek, flax, heartsease, horsetail, jambolan, lavender,marigold, oak, oat, pansy flower, Peruvian balsam, pineapple, poplar, sage, sesame seed,shepherd’s purse, sweet clover, walnut, and white nettle. (text continued on page 328)

Table 2 Mucocutaneous and Serious Complications Herbs in CosmeceuticalsAcne Chaste Tree (Vitex agnus-castus)Alopecia St. John’s Wort (Hypericum perforatum)Anaphylaxis Caraway (Carum carvi), Cayenne (Capsicum annuum), Echinacea (Echinacea angustifolia), Flax linseed (LinumBurningCarcinogenic usitatissimum), German Chamomile (Matricaria recutita), Garlic (Allium sativum), Horse Chestnut (Aesculus hippocastanum), Mistletoe (Phoradendron species), Willow Bark (Salix alba)Contact Blistering Cowhage (Mucuna pruniens) Alkanet (Alkanna tinctoria), Aloe (Aloe barbadensis; Aloe capensis: Aloe vera), Alpine Ragwort (SenecioConjunctivitis nemorensis), Areca Nut (Areca catechu), Basil (Ocimum basilicum), Bergamot (Citrus aurantium), CascaraCutaneous, Nonspecific Sagrada (Rhamnus purshiana), Coca (Erythroxylum coca), Colt’s Foot (Tussilago farfara), Comfrey (Symphytum officinale), Cypress Spurge (Euphorbia cyparissias), Dusty Miller (Senecio aureus), Forget-me-not (Myosotis arvensis), Golden Ragwort (Senecio aureus), Groundsel (Senecio vulgaris), Hemp Agrimony (Eupatorium cannabinum), Jalap (Ipomoea purga), Madder (Rubia tinctorum), Morning Glory (Ipomoea hederacea), Petasites (Petasites hybridus), Ragwort (Senecio jacobaea), Red Clover (Trifolium pratense), Rue (Ruta species), Sassafras (Sassafras albidum), Senna (Cassia species) American Liverwort (Hepatica nobailis), Arnica (Arnica montana), Bergamot (Citrus aurantium), Bitter Orange (Citrus aurantium), Black Mustard (Brassica nigra), Bulbous Buttercup (Ranunculus bulbosus), Buttercup (Ranunculus acris), Cashew (Anacardium occidentale), Cayenne (Capsicum annuum), Clematis (Clematis recta), Cypress Spurge (Euphorbia cyparissias), Garlic (Allium sativum), Gingko (Ginko biloba), Globe Flower (Trollius europaeus), Henna (Lawsonia inermis), Juniper (Juniperus species), Marsh Marigold (Caltha palustris), Mezereon (Daphne mezereum), Pasque Flower (Pulsatilla pratensis), Poison Ivy, Oak, Sumac (Rhus toxicodendron) Poisonous Buttercup (Ranunculus sceleratus), Rue (Ruta species), Savin Tops (Juniperus sabina), Senna (Cassia species), Tea Tree (Melaleuca alternifolia [IgA linear dermatosis]), Traveller’s Joy (Clematis vitalba), White Bryony (Bryonia alba), Wood Anemone (Anemone nemorosa) Black Mustard (Brassica nigra), Cypress Spurge (Euphorbia cyparissias), German Chamomile (Matricaria recutita), Goa Powder (Andira araroba), Psyllium (Plantago ovata), Psyllium Seed (Plantago afra) American Hellebore (Veratrum viride), American Liverwort (Hepatica nobilis), Arnica (Arnica montana), Artichoke (Cynara scolymus), Asarum (Asarum europaeum), Birch (Betula species), Black Bryony (Tamus communis), Blessed Thistle (Cincus benedictus), Boneset (Eupatorium perfoliatum), Bulbous Buttercup (Ranunculus bulbosus), Burdock (Arctium lappa), Buttercup (Ranunculus acris), Camphor Tree (Cinnamomum camphora), (Continued) 313

Table 2 Mucocutaneous and Serious Complications (Continued) 314 ThornfeldtCutaneous Yellowing Cashew (Anacardium occidentale), Castor Oil Plant (Ricinus communis), Chaste Tree (Vitex agnus-castus),Death Chaulmoogra (Hydnocarpus species), Chicory (Cichorium intybus), Chinese Cinnamon (CinnamomumDermatitis aromaticum), Chinese Olive (Canarium species), Cinnamon (Cinnamomum verum), Clematis (Clematis recta), Clove (Syzygium aromaticum), Cowhage (Mucuna pruriens), Croton Seeds (Croton tiglium), Cypress SpurgeDermatitis, Allergic Contact (Euphorbia cyparissias), Elecampane (Inula helenium), English Ivy (Hedera helix), English Lavender (LavandulaDermatitis, Contact Irritant angustifolia), Feverfew (Tanacetum parthenium), Ginkgo (Ginko biloba), Globe Flower (Trollius europaeus), Goa Powder (Andira araroba), Guaiac (Guaiacum officinale), Hemp Agrimony (Eupatorium cannabinum), Hops (Humulus lupulus), Hydrangea (Hydrangea arborescens), Indian Squill (Urginea indica), Jack-in-the-Pulpit (Arisaema atrorubens), Lesser Celandine (Ranunculus ficaria), Marsh Marigold (Caltha palustris), Mayapple (Podophyllum peltatum), Mugwort (Artemisia vulgaris), Nasturtium (Tropaeolum majus), Nerve Root (Cypripedium calceolus), Night-Blooming Cereus (Selenicereus grandiflorus), Orris (Iris species), Ox-eye Daisy (Chrysanthemum leucanthemum), Pasque Flower (Pulsatilla pratensis), Peppermint (Menthe piperita), Pipsissewa (Chimaphila umbellate), Poisonous Buttercup (Ranunculus sceleratus), Poplar (Populus species), Poppyseed (Papaver somniferum), Savin Tops (Juniperus sabina), Saw Palmetto (Serenoa repens), Scotch Pine (Pinus species), Soapwort (Saponaria officinalis), Spikenard (Aralia racemosa), Spurge (Euphorbia resinifera), Squill (Urginea maritima), Stavesacre (Delphinium staphisagria), Stillingia (Stillingia sylvatica), Tansy (Tanacetum vulgare), Tea Tree (Melaleuca alternifolia), Traveller’s Joy (Clematis vitalba), White Bryony (Bryonia alba), White Mustard (Sinapis alba) Kava Kava (Piper methysticum) Aristolochia (Aristolochia species), Arnica (Arnica montana), Cayenne (Capsicum annuum), Comfrey (Symphytum officinale), Henna (Lawsonia inermis), Kava Kava (Piper methysticum), Mistletoe (Phoradendron species), Rue (Ruta species), Senna (Cassia species), Yohimbine (Pausinystalia yohimbe) Bergamot (Citrus aurantium), Bitter Orange (Citrus aurantium) Bloodroot (Sanguinaria canadensis), Camphor Tree (Cinnamomum camphora) Caraway (Carum carvi), Cayenne (Capsicum annuum), Garlic (Allium sativum), German Chamomile (Matricaria recutita), Ginger (Zingiber officinale), Gingko (Ginko biloba), Hawthorn (Crataegus species), Henna (Lawsonia inermis), Horse Chestnut (Aesculus hippocastanum), Juniper (Juniperus species), Kava Kava (Piper methysticum), Lavender (Lavandula), Licorice (Glycyrrhiza glabra), Onion (Allium cepa) Peppermint (Mentha piperita), Quinine (Cinchona pubescens) Rue (Ruta species), Squill (Urginea maritima), Stavesacre (Delphinium staphisagria) Tea Tree (Melaleuca alternifolia), Turmeric (Curcuma domestica/longa), Yarrow (Achillea millefolium), Yohimbine (Pausinystalia yohimbe) Black Mustard (Brassica nigra), German Chamomile (Matricaria recutita), Parsley (Petroselinum crispum), Poison Ivy, Oak, Sumac (Rhus toxicodendron), Rosemary (Rosmarinus officinalis), Tea Tree (Melaleuca alternifolia) Boxwood (Buxus sempervirens), Cajuput (Melaleuca leucadendra), Copaiba Balsam (Copaifera langsdorffi), Feverfew (Tanacetum parthenium), Lesser Celandine (Ranundulus ficaria), Nutmeg (Myristica fragrans)

Dermopathy—Pellagra-like Kava Kava (Piper methysticum) Herbs in CosmeceuticalsDyspigmentation, Hair Trailing Arbutus (Epigae repens)Dyspigmentation, Skin Bergamot (Citrus aurantium), Bitter Orange (Citrus aurantium), Cayenne (Capsicum species), Henna (LawsoniaDyspigmentation, TeethEdematous inermis), Trailing Arbutus (Epigae repens) Cayenne (Capsicum annuum)Erythematous Aloe (Aloe barbadensis: Aloe capensis: Aloe vera), Asa Foetida (Ferula foetida)—lips, Bitter Orange (CitrusErythema Multiforme aurantium), Buckthorn (Rhamnus catharticus), Butterbur (Petasites hybridus), Cascara Sagrada (RhamnusErythema Nodosum purshiana), Chinese Rhubarb (Rheum palmatum), Cypress Spurge (Euphorbia cyparissias)—eyelid, ErgotErythroderma, Exfoliative (Claviceps purpurea)—local, Flax Linseed (Linum usitatissimum)—eyelid, Frangula (Rhamnus frangula), GinsengFasciculation (Panax species), Henna (Lawsonia inermis), Juniper (Juniperus species), Licorice (Glycyrrhiza glabra), MezereonGlossodynia (Daphne mezereum), Mistletoe (Phoradenfron species)—lip, Pagoda Tree (Sophora japonica)—face, Phelloden- dron (Phelldendron species), Rue (Ruta species), Senna (Cassia species)Halitosis Bergamot (Citrus aurantium), Bitter Orange (Citrus aurantium), Butterbur (Petasites hybridus), CashewHigh Morbidity (Anacardium occidentale), Flax Linseed (Linum usitatissimum), Gingko (Ginko biloba), Henbane (HyoscyamusHypesthesia niger), Henna (Lawsonia inermis), Horse Chestnut (Aesculus hippocastanum)—facial, Juniper (Juniperus species), Mandrake (Mandragora officinarum), Mezereon (Daphne mezereum), Mistletoe (Phoradendron species), PoisonHypohidrosis Ivy (Rhus toxicodendron), Rue (Ruta species), Stavesacre (Delphinium staphisagria), Yohimbe Bark (Pausinystalia yohimbe) Henna (Lawsonia inermis), Tea Tree (Melaleuca alternifolia) 315 Echinacea (Echinacea angustifolia), Mistletoe (Phoradendron species) St. John’s Wort (Hypericum perforatum), Yohimbine (Pausinystalia yohimbe) Horse Chestnut (Aesculus hippocastanum), Poppyseed (Papaver somniferum), Wormseed (Artemisia cina) Asarum (Asarum europaeum), Black Hellebore (Helleborus niger), Celandine (Chelidonium majus), Croton Seeds (Croton tiglium), Cypress Spurge (Euphorbia cyparissias), Monkshood (Aconitum napellus), Mountain Laurel (Kalmia latifolia), Night-Blooming Cereus (Selenicereus grandifloras), Peppermint (Mentha piperita) Garlic (Allium sativum) Blue Cohosh (Caulophyllum thalictroides)—shock, Gingko (Ginko biloba)—coma, Licorice (Glycyrrhiza glabra)— rhabdomyolysis Cowage (Mucuna pruriens), Croton Seeds (Croton tiglium), Cypress Spurge (Euphorbia cyparissias), Garlic (Allium sativum), Ginseng (Panax species), Monkshood (Aconitum napellus), Peppermint (Menta piperita)—anal, Tea Tree (Melaleuca alternifolia), Tree of Heaven (Ailanthus altissima) Henbane (Hyoscyamus niger) (Continued)

Table 2 Mucocutaneous and Serious Complications (Continued) 316 ThornfeldtInfection, Predisposition White Bryony (Bryonia alba)Jaundice Bishop’s Weed (Ammi visnaga), Black Cohosh (Cimicifuga racemosa), Germander (Teucrium chamaedrys)Keloid Henna (Lawsonia inermis)Keratosis Bloodroot (Sanguinaria canadensis)Lichenoid Henna (Lawsonia inermis), Peppermint (Mentha piperita)Leukoplakia Bloodroot (Sanguinaria canadensis)Lupus Erythematosis Yohimbine (Pausinystalia yohimbe)Mastitis / Mastodynia / Gynecomastia Black Cohosh (Cimicifuga racemosa), Dong Quai (Angelica sinensis), Ginseng (Panax species)Mucositis / Stomatitis American Liverwort (Hepatica nobilis), Arum (Arum maculatum), Bitter Apple (Citrullus colocynthis), BulbousParesthesia Buttercup (Ranunculus bulbosus), Buttercup (Ranunculus acris), Clematis (Clematis recta), Elecampane (InulaPemphigus helenium), Gingko (Ginko biloba), Globe Flower (Trollius europaeus), Green Hellebore (Helleborous viridis),Photoreactions Hedge-Hyssop (Gratiola officinalis), Horse Chestnut (Aesculus hippocastanum), Horseradish (Armoracia rusticana), Marsh Marigold (Caltha palistris), Mezereon (Daphne mezereum), Orris (Iris species), PeppermintPruritis (Mentha piperita), Poisonous Buttercup (Ranunculus sceleratus), Poke (Phytolacca americana), Spurge (Euphorbia resinifera), Traveller’s Joy (Clematis vitalba), White Bryony (Bryonia alba)Psoriasis Echinacea (Echinacea angustifolia), St. John’s Wort (Hypericum perforatum), Mountain Laurel (Kalmia latifolia) Garlic (Allium sativum) Angelica (Angelica archangelica), Bergamot (Citrus aurantium), Bishop’s Weed (Ammi visnaga), Bitter Orange (Citrus aurantium), Burning Bush (Dictamnus albus), Celery (Apium graveolens), Contrayerva (Dorstenia contrayerva), Dill (Anethum graveolens), Dong Quai (Angelica sinensis), Haronga (Haronga madagascariensis), Henna (Lawsonia inermis), Hogweed (Heracleum spondylium), Kava Kava (Piper methysticum), Lovage (Levisticum officinale), Masterwort (Peucedanum ostruthium), Parsley (Petroselinum crispum), Parsnip (Pastinaca sativa), Pimpinella (Pimpinella major), Rue (Ruta graveolens), St. John’s Wort (Hypericum perforatum), Tolu Balsam (Myroxylon balsamum), Wafer Ash (Ptelea trifoliate), Yarrow (Achillea millefolium) Arnica (Arnica montana), Black Cohosh (Cimicifuga racemosa), Chaste Tree (Vitex agnus-castus), Cowhage (Mucuna pruriens), Cypress Spurge (Euphorbia cyparissias), Dan-Shen (Salvia miltiorrhiza), Ergot (Claviceps purpurea), Feverfew (Tanacetum parthenium), Gingko (Ginko biloba), Ginseng (Panax species), Henna (Lawsonia inermis), Horse Chestnut (Aesculus hippocastanum), Kava Kava (Piper metaysticum), Mistletoe (Phoradendron species), Night Blooming Cereus (Selenicereus grandiflorus), Poppyseed (Papaver somniferum), Quinine (Cinchona pubescens), Sandalwood (Santalum album), Senna (Cassia species), Stavesacre (Delphinium staphisagria), St. John’s Wort (Hypericum perforatum), Tea Tree (Melaleuca alternifolia) Henna (Lawsonia inermis)

Purpura / Hemorrhage / Bleeding Garlic (Allium sativum), Ginger (Zingiber officinale), Gingko (Ginko biloba), Ginseng (Panax species), Horse Herbs in Cosmeceuticals Chestnut (Aesculus hippocastanum), Phellodendron (Phellodendron species), Saw Palmetto (Serenoa repens),Pustular St. John’s Wort (Hypericum perforatum), Tolu Balsam (Myroxylon balsamum)Sialorrhea Bitter Orange (Citrus aurantium), Black Bryony (Tamus communis), Chaste Tree (Vitex agnus-castus), Goa PowderStomatitis, Ulcerative (Andira araroba)Sweet’s SyndromeToxic Epidermal Necrolysis / Necrosis / Areca Nut (Areca catechu), Black Hellebore (Helleborus niger), Daffodil (Narcissus pseudonarcissus), Echinacea (Echinacea angustifolia), Jaborandi (Pilocarpus microphyllus), Kousso (Hagenia abyssinica), Mezereon (Daphne Ulcers mezereum), Mountain Laurel (Kalmia latifolia), Quebracho (Aspidosperma quebrachoblanco), StavesacreUrticaria / Angioedema (Delphinium staphisagria)Vasculitis / Petechiae Feverfew (Tanacetum parthenium), Mezereon (Daphne mezereum), Tolu Balsam (Myroxylon balsamum)Xerostomia Arnica (Arnica montana), Cayenne (Capsicum species)Xerosis Arnica (Arnica montana), Black Mustard (Brassica nigra), Cayenne (Capsicum annuum), European Mistletoe (Viscum album), Ginseng (Panax species), Mezereon (Daphne mezereum), Savin Tops (Juniperus sabina), White Bryony (Bryonia alba) American Pawpaw (Asimina triloba), Black Bryony (Tamus communis), Caraway (Carum carvi), Chaste Tree (Vitex agnus-castus), Echinacea (Echinacea angustifolia), European Mistletoe (Viscum album), Feverfew (Tanacetum parthenium), Garlic (Allium sativum), Henna (Lawsonia inermis), Milk Thistle (Silybum marianum), Psyllium (Planatgo ovata), Psyllium Seed (Plantago afra), Stinging Nettle (Urtica dioica), Tolu Balsam (Myroxylon balsamum), Yarrow (Achillea millefolium) Black Cohosh (Cimicifuga racemosa), Gingko (Ginko biloba) Chaste Tree (Vitex agnus-castus), Henbane (Hyoscyamus niger), Mandrake (Mandragora officinarum), St. John’s Wort (Hypericum perforatum), Yellow Jessamine (Gelsemium sempervirens) Kava Kava (Piper methysticum) 317

Table 3 Combination Cautions of Discussed Herbs 318 ThornfeldtAloe Antiarrhythmics (aloe-induced hypokalemia may affect cardiac rhythm), digitalis glycosides (increases effect), corticosteroids, thiazide diuretics, and licorice (increased potassium loss)ArnicaCayenne Anticoagulant, antiplatelet, heparin, salicylates, thrombolytic drugs, and warfarin (increased effect)Chaste Tree Same as above Amantadine, dopamine D1 antagonists, levodopa, pergolide mesylate, pramipexole, and ropinirole (enhanceCurcuminEchinacea Angustifolia dopaminergic adverse effects). Dopamine D2 antagonists (decreased effectiveness)Evening Primrose Anticoagulant, antiplatelet, heparin, thrombolytic drugs (increase effect) Corticosteroids, immunosuppressants (interferes with effectiveness)Fenugreek Anticonvulsants including phenothiazines (may lower seizure threshold and decrease effectiveness) anticoagulant,FlaxGerman Chamomile antiplatelet, heparin, and thrombolytic drugs (decrease effectiveness)Gingko Hypoglycemic drugs (may have an additive hypoglycemic effect) Absorption of other drugs may be delayed when taken simultaneouslyGinseng Alcohol, benzodiazepines (may increase sedative effect), anticoagulants, and warfarin (increase effect) MAO inhibitors (potentiate effect), anticonvulsants (precipitate seizures), insulin (alters need), anticoagulant,Green TeaHorse Chestnut antiplatelet, heparin, thrombolytic, and NSAID drugs (increase effect), nicardipine (reduce hypotensive effect),Licorice nifedipine, and papaverine (increase effect), SSRI (precipitate hypomania), thiazide diuretics (increase blood pressure) Hypoglycemic drugs (increases effect), loop diuretics (increases diuretic resistance), MAO inhibitors (combination increases chance for headache, tremors, mania), insulin (reduces effect), estrogen (increases effect), albendazole (alters effectiveness), anticoagulants (decreases INR), nifedipine (increase effect), opiates (decrease effect) Alkaline drugs (decrease absorption) Anticoagulant drugs (additive effect) Aloe, buckthorn, antiarrhythmics, digitalis glycoside, laxatives (increase hypokalemia, increase toxicity), glucocorticoids (potentiates), loop, and thiazide diuretics (additive hypokalemia), anticoagulant, antiplatelet, heparin, thrombolytic drugs, (increase effect), antihypentensives (decrease effect), antidiabetic insulin (reduce effect), MAO inhibitors (increase toxicity), potassium (decrease), testosterone (reduce), oral contraceptive (increase toxicity)

Milk Thistle (Silymarin) Haloperidol phenothiazines (decrease lipid peroxidation), phentolamine mesylate, yohimbine (antagonize effect) Herbs in CosmeceuticalsOak Alkaline drugs, alkaloids (absorption reduced)Papaya Anticoagulant drugs (additive effect)Peppermint CYP450 (increases substrate level)Pineapple Anticoagulant, thrombolytic drugs (increase bleeding), tetracycline (increase blood, urine level)Rue Hypoglycemic drugs (additive effect)Saw Palmetto Alpha-adrenergic blockers (additive effect), androgens (antagonizes), iron (complexes increasing toxicity), warfarinSt. John’s Wort (increase effect)Soy Increased effectiveness: antidiabeticWhite Willow Reduced effectiveness: amioradone, anticoagulants, barbiturates, benzodiaze-pines, beta blockers, caffeine, calcium channel blockers, clozapine, chlorzoxazone, cyclophosphamide, cyclosporine, digoxin, etoposide, imatinib mesylate, indinavir, irinotecan, iron, methadone, nonnucleoside reverse transcriptase inhibitors, paclitexal, phenytoin, protease inhibitors, reserpine, sirilimus, statins, tacrolimus, tamoxifen, theophylline Increased toxicity: acetretin (birth defects), aminolevulinic acid, tetracycline, sulfonamide, thiazides (photosensi- tivity), buspirone, MAOI, nefazodone, nortryptiline, SSRI, trazadone, tricyclic antidepressants, venlafaxine (increase serotonin syndrome[hypertension, hyperthesmia, myoclonus, mental alterations, coma]), loperamide, gingko, opiates (sedation), oral contraceptives (breakthrough bleeding), tyramine, sympathomimetics Alters effect: carbamazepine Iron (reduced absorption), levothyroxine (decrease effect), tamoxifen (decrease effect), warfarin (reduce effect) Alcohol, barbiturates (enhance toxicity), antiplatelet, NSAID, salicylates (additive effect), carbonic anhydrase inhibitors (potentiate effect) 319

Table 4 Therapeutic Uses a Bittersweet Nightshade (Solanum dulcamara), Duckweed (Lemna minor), Eucalyptus (Eucalyptus globulus), German 320 ThornfeldtAcne Chamomile (Matricaria recutita), Heartsease (Viola tricolor), Tea Tree (Melaleuca alternifolia)Alopecia Arnica (Arnica montana), Black Bryony (Tamus communis), Boxwood (Buxus sempervirens), Cashew (AnacardiumAlopecia Areata occidentale), Horsetail (Equisetum arvense), Maidenhair (Adiantum capillus-veneris), Nasturtium (Tropaeolum majus),Aphthous Stomatitis Oriental Arborvitae (Thuja orientalis), Stavesacre (Delphinium staphisagria)Bites Birch (Betula species), Burr Marigold (Bidens tripartita)Bitter taste Common Stonecrop (Sedum acre), Water Dock (Rumex aquaticus)Bleeding Behen (Moringa oleifera), Bistort (Persicaria bistorta), Black Cohosh (Cimicifuga racemosa), Calotropis (CalotropisBruises / Contusion procera), Cane-Reed (Costus speciosa), Cotton (Gossypium hirsutum), Echinacea (Echinacea angustifolia), Great Burnet (Sanguisorba officinalis), Matico (Piper elongatum), Picrorhiza (Picrorhiza kurroa), Plantain (Musa paradisiaca), PurpleBurns Gromwell (Lithospermum erytrorhizon), Quassia (Picrasma excelsa), Rauwolfia (Rauwolfia serpentine), Red SandalwoodCandidiasis (Pterocarpus santalinus), Scarlet Pimpernel (Anagallis arvensis), Tea Tree (Melaleuca alternifolia), Turmeric (CurcumaCarcinoma, squamous cell domestica/longa), Wormseed Oil (Chenopodium ambrosioides) Chinese thoroughwax (Bupleurum chinese) prevention of palliaiton Agrimony (Agrimonia eupatoria), Brooklime (Veronica beccabunga), Cane Reed (Costus speciosa), Catechu (Acacia catechu), Elephant Ears (Bergenia crassifolia), Eucalyptus (Eucalyptus globules), European Mistletoe (Viscum album), Groundsel (Senecio vulgaris), Henbane (Hyoscyamus niger), Horsetail (Equisetum arvense), Lesser Celandine (Ranunculus ficaria), Matico (Piper elongatum), New Jersey Tea (Ceanothus americanus), Periwinkle (Vinca minor), Purple Loosestrife (Lythrum salicaria), Sage (Salvia officinalis), Scotch Broom (Cytisus scoparius), Shepherd’s Purse (Capsella bursa- pastoris) Basil (Ocimum basilium), Beth Root (Trillium erectum), Bittersweet Nightshade (Solanum nigrum), Black Bryony (Tamus communis), Black Currant (Ribes nigrum), Black Nightshade (Solanum nigrum), Cajuput (Melaleuca leucadendra), Calotropis (Calotropis procera), Comfrey (Symphytum officinale), Cane-Reed (Costus speciosa) German Ipecac (Cynanchum vincetoxicum), Horse Chestnut (Aesculus hippocastanum), Onion (Allium cepa), Rue (Ruta graveolens), Smartweed (Persicaria hydropiper), Solomon’s Seal (Polygonatum multiflorum), Spikenard (Aralia racemosa), Tansy (Tanacetum vulgare), Tolu Balsam (Myroxylon balsamum), Turmeric (Curcuma domestica/longa), Vervain (Verbena officinalis), Wild Daisy (Bellis perennis), White Fir (Abies alba) Hibiscus (Hibiscus sabdariffa), Tea Tree (Melaleuca alternifolia) Cornflower (Centaurea cyanus) Green and White Tea Catechins (Camellia sinensis), Congorosa (Maytenus ilicifolia), Spurge (Euphorbia resinifera)

Cheilitis, actinic Areca Nut (Areca catechu), Condurango (Marsdenia condurango) Herbs in CosmeceuticalsDermatitis Behen (Moringa oleifera), Bilberry (Vaccinium myrtillus), Birch (Betula species), Bittersweet Nightshade (SolanumFissure, Anal dulcamara), Borage Oil (Borage officinalis), Boxwood (Buxus sempervirens), Carline Thistle (Carlina acaulis), CeladineFurunculosis / Abcess (Chelidonium majus), Evening Primrose Oil (Oenthera biennis), Heartsease (Viola tricolor), Henna (Lawsonia inermis), Licorice (Glycyrrhiza glabra), Marigold (Calendula officinalis), Mezereon (Daphne mezereum), Mountain Grape (MahoniaHalitosis aquifolium), Oats (Avena sativa), Peanut (Arachis hypogaea), Quillaja (Quillaja saponaria), Stinging Nettle (Urtica dioica),Hyperhidrosis / Excessive Teazle (Dipsacus silvertris), Winter’s Bark (Drimys winteri) Aloe (A. barbadensis, A. capensis, A. vera), Buckthorn (Rhamnus catharticus), Cascara Sagrada (Rhamnus purshiana), Lacrimation Chinese Rhubarb (Rheum palmatum), European Peony (Paeonia officinalis), Field Scabious (Knautia arvensis), Frangula (Rhamnus fragula), Manna (Fraxinus ornus)Hyperpigmentation American White Pond Lily (Nymphaea odorata), Ammmoniac Gum (Dorema ammoniacum), Arnica (Arnica montana),Hyposalivation Behen (Moringa oleifera), Bistort (Persicaria bistorta), Bittersweet Nightshade (Solanum dulcamara), Black NightshadeIchthyosis / Hyperkeratosis (Solanum nigrum), Bog Bean (Menyanthes trifoliata), Burdock (Arctium lappa), Calotropis (Calotropis procera), Castor OilInfection, Herpes Plant (Ricinus communis), Chaulmoogra (Hydnocarpus species), Corydalis (Corydalis cava), Croton Seeds (Croton tiglium), Digitalis (Digitalis purpurea), Dogwood (Cornus florida), Echinacea (Echinacea angustifolia), German Chamomile (Matricaria recutita), Great Burnet (Sanguisorba officinalis), Ground Ivy (Glechoma hederacea), Hibiscus 321 (Hibiscus sabdariffa), Larch (Larix decidua), Licorice (Glycyrrhiza glabra), Marshmallow (Althaea officinalis), Myrrh (Commiphora molmol), Onion (Allium cepa), Plumbago (Plumbago zeylanica), Psyllium (Plantago ovata), Red-Rooted Sage (Salvia miltiorrhiza) Solomon’s Seal (Polygonatum multiflorum), Vervain (Verbena officinalis), White Lily (Lilium candidum), White Nettle (Lamium album), Wild Indigo (Baptisia tinctoria) Clove (Syzygium aromaticum), Coriander (Coriandrum sativum), Juniper (Juniperus communis) Arjun Tree (Terminalia arjuna), Asiatic Dogwood (Cornus officinalis), Belladonna (Atropa belladonna), Coral Root (Corallorhiza odontorhiza), Japanese Atractylodes (Atractylodes japonica), Knotweed (Polygonum aviculare), Lycium Bark (Lycium chinense), Oak Gall (Quercus infectoria), Rehmannia (Rehmannia glutinosa), Rice (Oryza sativa), Rose (Rosa centifolia), Safflower (Carthamus tinctorius), Sage (Salvia officinalis), Sarsaparilla (Smilax species), Schisandra (Schisandra chinensis), Soybean (Glycine soja), Walnut (Juglans regia) Wild Carrot (Daucus carota), Wormwood (Artemisia absinthium) Lemonwood (Schisandra sphenanthera) Burdock (Arctium lappa), Cashew (Amacardium occidentale), Cypress Spurge (Euphorbia cyparissias), English Ivy (Hedera helix), Garlic (Allium sativum), Peanut (Arachis hypogaea) Goldenseal (Hydrastis canadensis), Hibiscus (Hibiscus sabdariffa), Mezereon (Daphne mezereum), Mountain Laurel (Kalmia katifolia), Scarlet Pimpernel (Anagallis arvensis), Thuja (Thuja occidentalis) (Continued)

Table 4 Therapeutic Uses (Continued) 322 ThornfeldtInfection, Viral Astragalus (Astragalus species), Behen (Moringa oleifera), Black Cohosh (Cimicifuga racemosa), Cat’s Claw (Unicaria tomentosa), Coriander (Coriandrum sativum), Duckweed (Lemna minor), Echinacea (Echinacea angustifolia), EucalyptusInfections, Fungal (Eucalyptus globules), Pasque Flower (Pulsatilla pratensis)Infections, Bacterial / Aloe (Aloe barbadensis; Aloe capensis; Aloe vera), Beet (Beta vulgaris), Henna (Lawsonia inermis), Onion (Allium cepa), Cellulitis / Erysipelas / Mountain Laurel (Kalmia latifolia), Poke (Phytolacca americana), Turmeric (Curcuma domestica/longa) Impetigo / Scarlatina Anemarrhena (Anemarrhena asphodeloides), American Pawpaw (Asimina triloba), Black Nightshade (Solanum nigrum),Inflammation Burning Bush (Dictamnus albus), Cashew (Anacardium occidentale), Coconut Palm (Cocos nucifera), Corydalis (Corydalis cava), Duckweed (Lemna minor), Elecampane (Inula helenium), English Ivy (Hedera helix), Eucalyptus (Eucalyptus globules), Goa Powder (Andira araroba), Ground Ivy (Glechoma hederacea), Heartsease (Viola tricolor), Jack-in-the-Pulpit (Arisaema atrorubens), Kamala (Mallotus philippinensis), Linden (Tilia species), Oak Gall (Qeurcus infectoria), Oats (Avena sativa), Pasque Flower (Pulsatilla pratensis), Pitcher Plant (Sarracenia purpurea), Psyllium (Plantago ovata), Purple Gromwell (Lithospermum erytrorhizon), Tea Tree (Melaleuca alternifolia), Teazle (Dipsacus silvestris), Thuja (Thuja occidentalis), Turmeric (Curcuma domestica/longa), Virola (Virola theiodora), Wild Indigo (Baptisia tinctoria) Agrimony (Agrimonia eupatoria), Arnica (Arnica montana), Bear’s Garlic (Allium ursinum), Behen (Moringa oleifera), Bittersweet Nightshade (Solanum dulcamara), Black Nightshade (Solanum nigrum), Bladderwort (Utricularia vulgaris), Boxwood (Buxus sempervirens), Broad Bean (Vicia faba), Burning Bush (Dictamnus albus), Cashew (Anacardium occidentale), Castor Oil Plant (Ricinus communis), Chaulmoogra (Hydnocarpus species), Chickweed (Stellaria media), Chicory (Cichorium intybus), Club Moss (Lycopodium clavatum), Common Stonecrop (Sedum acre), Congorosa (Maytenus ilicifolia), Cornflower (Centaurea cyanus), Dandelion (Taraxacum officinale), English Ivy (Dedera helix), English Plantain (Plantago lanceolata), European Elder (Sambucus nigra), European Water Hemlock (Cicuta virosa), Evening Primrose (Oenothera biennis), Fenugreek (Trigonella foenum-graecum), Field Scabious (Knautia arvensis), Flax (Linum usitatissimum), Fumitory (Fumaria officinalis), German Chamomile (Matricaria recutita), Haronga (Haronga madagascariensis), Heartsease (Viola tricolor), Henna (Lawsonia inermis), Herb Robert (Geranium robertianum), Hibiscus (Hibiscus sabdariffa), Horse Chesnut (Aesculus hippocastanum), Houseleek (Sempervivum tectorum), Indian Nettle (Acalypha indica), Jambolan (Syzygium cumini), Japanese Mint (Mentha arvensis piperascens), Labrador Tea (Ledum latifolium), Lady’s Mantle (Alchemilla vulgaris), Lycium bark (Lycium chinense), Marigold (Calendula officinalis), Marshmallow (Althaea officinalis), Mezereon (Daphne mezereum), Moneywart (Lysimachia nummularia), Monkshood (Aconitum napellus), Mullein (Verbascum densiflorum), Oak (Quercus robar), Oak Gall (Quercus infectoria), Oats (Avena sativa), Olive (Olea europaea), Pasque Flower (Pulsatilla pratensis), Peanut

Keloid / Hypertrophic (Arachis hypogaea), Periwinkle (Vinca minor), Purple Gromwell (Lithospermum erytrorhizon), Purple Loosestrife (Lythrum Herbs in CosmeceuticalsLeprosy salicaria), Quinine (Circhona pubescens), Red Clover (Trifolium pratense), Rosemary (Rosmarinus officinalis), Rue (Ruta graveolens), Saw Palmetto (Serenoa repens), Scotch Pine (Oinus species), Soapwart (Saponaria officinalis), SpurgeMastitis / Mastodynia (Euphorbia resinifera), St. John’s Wort (Hypericum perforatum), Tolu Balsam (Myroxylon balsamum), Turmeric (CurcumaMiliaria domestica/longa), Walnut (Juglans regia), White Lily (Lilium candidum), White Nettle (Lamium album), Witch HazelMucocutaneous pain (Hamamelis virginiana), Wormseed Oil (Chenopodium ambrosioides)Mucocutaneous Pruritus Henbane (Hyoscyamus niger), Onion (Allium cepa) Betel Nut (Piper betle), Black Nightshade (Solanum nigrum), Calotropis (Calotropis procera), Cashew (AnacardiumPhotodermatosisPruritis, Anii occidentale), Chaulmoogra (Hydnocarpus species), Coriander (Coriandrum sativum), Cumin (Cuminum cyminum), Giant Milkweed (Calotropis gigantea), Gotu Kolu (Centella asiatica), Henna (Lawsonia inermis), Hwema Bark (Corynanthe pachyceras), Jasmine (Jasminum officinale), Kamala (Mallotus philippinensis), Lemongrass (Cymbopogon citrates), Lily- 323 of-the-Valley (Convallaria majalis), Luffa (Luffa aegyptica), Neem (Antelaea azadirachta), Northern Prickly Ash (Zanthoxylum americanum), Storax (Liquidambar orientalis), Turmeric (Curcuma domestica/longa) Adrue (Cyperus articulatus), Bugleweed (Lycopus virginicus), Chaste Tree (Vitex agnus-castus), Dandelion (Taraxacum officinale), Pipsissewa (Chimaphalia umbellata) Speedwell (Veronica officinalis) Black Currant (Ribes nigrum), Bladderwrack (Fucus vesiculosus), Comfrey (Symphytum officinale), Echinacea (Echinacea angustifolia), Houseleek (Sempervivum tectorum), Indian Nettle (Acalyphia indica), Marshmallow (Althaea officinalis), Onion (Allium cepa), Poplar (Populus species), Quince (Cydonia oblongata), Reed Herb (Phragmites communis), Rue (Ruta graveolens), Tobacco (Nicotiana tabacum), White Fir (Abies alba), Wild Indigo (Baptisia tinctoria), Wild Thyme (Thymus serpyllum), Wormwood (Artemisia absinthium) Butcher’s Broom (Ruscus aculeatus), Buckwheat (Fagopyrum esculentum), Cabbage (Brassica oleracea), Cashew (Anacardium occidentale), Chaulmoogra (Hydnocarpus species), Club Moss (Lycopodium clavatum), Evening Primrose (Oenothera biennis), Fumitory (Fumaria officinalis), Golden Shower Tree (Cassia fistula), Gotu Kola (Centella asiatica), Heartsease (Viola tricolor), Houseleek (Sempervivum tectorum), Jasmine (Jasminum officinale), Knotweed (Polygonum aviculare), Plantain (Musa paradisiaca), Poison Ivy (Rhus toxicodendron), Sarsaparilla (Smilax species), Scarlet Pimpernel (Anagallis arvensis), Scotch Pines (Pinus species), Speedwell (Veronica officinalis), Storax (Liquidambar orientalis), Sweet Gale (Myrica gale), Thyme (Thymus vulgaris), Turmeric (Curcuma domestica longa) Vervain (Verbena officinalis), Wheat (Triticum aestivum), Wild Thyme (Thymus serpyllum) Wild Carrot (Daucus carota) Field Scabious (Knautia arvensis), Mullein (Verbascum densiflorum) (Continued)

Table 4 Therapeutic Uses (Continued) 324 ThornfeldtPsoriasis Agrimony (Agrimonia eupatoria), Black Nightshade (Solanum nigrum), Burdock (Arctium lappa), Cashew (Anacardium occidentale), Chaulmoogra (Hydnocarpus species), Goa Powder (Andira araroba), Hogweed (Heracleum sphondylium),Radiation Dermatitis Mountain Grape (Mahonia aquifolium), Mountain Laurel (Kalmia latifolia), Olive (Olea europea), Pasque FlowerScabies / Pediculosis (Pulsatilla pratensis), Red Clover (Trifolium pratense), Sarsaparilla (Smilax species), Sunflower (Helianthus annuus)Scrofulosis Sea Buckthorn (Hippophae¨ rhamnoides)Seborrhea Angelica (Andelica archangelica), Black Catnip (Phyllanthus amarus), Black Pepper (Piper nigrum), Bog Bean (MenyanthesSjogren’s SyndromeSkin Care trifoliata), Burning Bush (Dictamnus albus), Carambola (Averrhoa carambola), Celandine (Chelidonium majus),Snakebite Chaulmoogra (Hydnocarpus species), Field Scabious (Knautia arvensis), Fish Berry (Anamirta cocculus), Gotu Kola (Centella asiatica), Grape (Vitis vinifera), Ground Ivy (Glechoma hederacea), Henna (Lawsonia inermis), Lycium BerriesStomatitis / Gingivitis (Lycium barbarum), Morning Glory (Ipomoea hederacea), Oleander (Nerium oleander), Picrorhiza (Picrorhiza kurroa), Plantain (Musa paradisiaca), Plumbago (Plumbago zeylanica), Poisonous Buttercup (Ranunculus sceleratus), Pyrethrum (Chrysanthemum cinerariifolium), Quassia (Picrasma exselsa), Safflower (Carthamus tinctorius), Smartweed (Perisicaria hydropiper), Stavesacre (Delphinium staphisagria) Bistort (Persicaria bistorta), Coriander (Coriandrum sativum), English Ivy (Hedera helix), Ground Ivy (Glechoma hederacea), Oregano (Origanum vulgare), Stavesacre (Delphinium staphisagria) Stavesacre (Delphinium staphisagria) Borage Oil (Borago officinalis), Evening Primrose Oil (Oenthera biennis) Almond (Prunus dulcis), Avocado (Persea americana), Jojoba (Simmondsia chinesis), Peanut (Arachis hypogaea), Sorb Apple (Sorbus domestica) Calotropis (Calotropis procera), Cane Reed (Costus speciosa), Cashew (Anacardium occidentale), Contrayerva (Dorstenia contrayerva), Cotton (Gossypium hirsutum), Echinacea (Echinacea angustifolia), German Ipecac (Cynanchum vincetoxicum), Muskmallow (Abelmoschus moschatus), Rauwolfia (Rauwolfia serpentine), Red Sandalwood (Pterocarpus santalinus), Scotch Broom (Cytisus scoparius) Acacia (Acacia arabica), Agrimony (Agrimonia eupatoria), Amaranth (Amaranthus hypochondriacus), American Pawpaw (Asimina triloba), Anise (Pimpinella anisum), Arnica (Arnica montana), Basil (Ocimum basilicum), Bilberry (Vaccinium myrtillus), Black Currant (Ribes nigrum), Black Pepper (Piper nigrum), Blackberry (Rubas fruticosus), Bladderwort (Utricularia vulgaris), Bugle (Ajuga reptans), Catechu (Acacia catechu), Cayenne (Capsicum annuum), Cinquefoil (Potentilla erecta), Cleavers (Galium aparine), Clove (Syzygium aromaticum), Coffee (Coffea arabica), Colt’s Foot (Tussilago farfara), Comfrey (Symphytun officinale), Echinacea Purpurea (Echinacea purpurea), English Chamomile (Chamaemelum nobile), English Plantain (Plantago lanceolata), Eucalyptus (Eucalyptus globulus),

European Five-Finger Grass (Potentilla reptans), European Golden Rod (Solidago virgaurea), Gambir (Uncaria species), Herbs in Cosmeceuticals German Chamomile (Matricaria recutita), Herb Robert (Geranium robertianum), Hollyhock (Alcea rosea), High MallowStyes (Malva sylvestris), Houseleek (Sempervivum tectorum), Iceland Moss (Cetraria islandica), Jack-in-the-Pulpit (ArisaemaSyphilis / T. Pallidum atrorubens), Jambolan (Syzygium cumini), Japanese Mint (Mentha arvensis piperascens), Knotweed (Polygonum aviculare), Lady’s Mantle (Alchemilla vulgaris), Larch (Larix decidua), Lesser Galangal (Alpina officinarum), Marigold Infections (Calendula officinalis), Marshmallow (Althaea officinalis), Myrrh (Commiphora molmol), Oak (Quercus robar), Oak Gall (Quercus infectoria), Onion (Allium cepa), Peppermint (Mentha piperita), Pimpinella (Pimpinella major), PotentillaUlcers, Skin / Decubitus, Leg, (Potentilla anserina), Rhatany (Krameria triandra), Rose (Rosa centifolia), Rue (Ruta graveolens), Sage (Salvia officinalis), Vascular Scotch Pine (Pinus species), Self-Heal (Prunella vulgaris), Sloe (Prunus spinosa), Speedwell (Veronica officinalis), Spruce (Picea species), Strawberry (Fragaria vesca), Sweet Violet (Viola odorata), Tamarind (Tamarindus indica), Tea Tree (Melaleuca alternifolia), Thyme (Thymus vulgaris), Tomato (Lycopersicon esculeutum), Tropical Almond (Terminalis chebula), Turmeric (Curcuma domestica/longa), Usnea (Usnea species), White Nettle (Lamium album), Wild Indigo (Baptisia tinctoria), Willow Herb (Epilobium angustifolium) Eyebright (Euphrasia officinalis) Brazilian Pepper Tree (Schinus terebinthifolius), Calotropis (Calotropis procera), Dill (Anethum graveolens), Giant Milkweed (Calotropis gigantea), Gotu Kola (Centella asiatica), Guaiac (Guaiacum officinale), Indian-Hemp (Apocynum cannabinum), Kava Kava (Piper methysticum), New Jersey Tea (Ceanothus americanus), Poke (Phytolacca americana), Sassafras (Sassafras albidum), Stillingia (Stillingia sylvatica) American Adder’s Tongue (Erythronium americanum), Ash (Fraxinus excelsior), Bilberry (Vaccinium myrtillus), Bittersweet Nightshade (Solanum dulcamara), Black Nightshade (Solanum nigrum), Burdock (Arctium lappa), Calotropis (Calotropis procera), Cashew (Anacardium occidentale), Castor Oil Plant (Ricinus communis), Catechu (Acacia catechu), Cleavers (Galium aparine), Clematis (Clematis recta), Congorosa (Maytenus ilicifolia), Digitalis (Digitalis purpurea), Echinacea (Echinacea angustifolia), English Adder’s Tongue (Ophioglossum vulgatum), English Ivy (Hedera helix), Field Scabious (Knautia arvensis), Frostwort (Helianthemum canadense), Ground Ivy (Glechoma hederacea), Henna (Lawsonia inermis), Indian Nettle (Acaltpha indica), Lady’s Mantle (Alchemilla vulgaris), Linden (Tilia species), Marigold (Calendula officinalis), Martagon (Lilium martagon), Myrrh (Commiphora molmol), Ox-Eye Daisy (Chrysanthemum leucanthemum), Periwinkle (Vinca minor), Petasites (Petasites hybridus), Quinine (Cinchona pubescens), Southern Bayberry (Myrica cerifera), Scurvy Grass (Cochlearia officinalis), Storax (Liquidambar orientalis), Tea Tree (Melaleuca alternifolia), Tolu Balsam (Myroxylon balsamum), Turmeric (Curcuma domestica/longa), Wild Indigo (Baptisia tinctoria), Yellow Lupin (Lupinus leteus) (Continued) 325

Table 4 Therapeutic Uses (Continued) 326 ThornfeldtVenous Insufficiency / Ammoniac Gum (Dorema ammoniacum), Beth Root (Trillium erectum), Buckwheat (Fagopyrum esculentum), Butcher’s Varicosities / Venous Stasis / Broom (Ruscus aculeatus), Clematis (Clematis recta), Club Moss (Lycopodium clavatum), Echinacea (Echinacea Lymphedema angustifolia), Figwort (Scrophularia nodosa), Garlic (Allium sativum), Gotu Kola (Centella asiatica), Grape (Vitis vinifera), Great Burnet (Sanguisorba officinalis), Horse Chestnut (Aesculus hippocastanum), Lemon Verbena (Aloysia triphylla),Warts / Condyloma acuminata Marigold (Calendula officinalis), Pimpinella (Pimpinella major), Purple Loosestrife (Lythrum salicaria), Rue (Ruta graveolens), Smartweed (Persicaria hydropiper), Sweet Clover (Melilotus officinalis), Sweet Woodruff (Galium odoratum),Wound Care Witch Hazel (Hamamelis virginiana), Yarrow (Achillea millefolium) Behen (Moringa oleifera), Bittersweet Nightshade (Solanum dulcamara), Broad Bean (Vicia faba), Calotropis (Calotropis procera), Cashew (Anacardium occidentale), Celandine (Chelidonium majus), Common Stonecrop (Sedum acre), Cypress Spurge (Euphoria cyparissias), Garlic (Allium sativum), Giant Milkweed (Calotropis gigantean), Houseleek (Sempervivum tectorum), Indian-Hemp (Apocynum cannabinum), Mayapple (Podophyllum peltatum), Oats (Avena sativa), Onion (Allium cepa), Savin Tops (Juniperus sabina), Scarlet Pimpernel (Anagallis arvensis), Spurge (Euphorbia resinifera), Sundew (Drosera ramentacea) Agrimony (Agrimonia eupatoria), Alkanet (Alkanna tinctoria), American White Pond Lily (Nymphaea odorata), Ammoniac Gum (Dorema ammoniacum), Ash (Fraxinus excelsior), Basil (Ocimum basilicum), Behen (Moringa oleifera), Beth Root (Trillium erectum), Birthwort (Aristolochia clematitis), Bistort (Persicaria bistorta), Black Catnip (Phyllanthus amarus), Black Currant (Ribes nigrum), Black Nightshade (Solanum nigrum), Bladderwort (Utricularia vulgaris), Blessed Thistle (Cnicus benedictus), Brazillian Pepper Tree (Schinus terebinthifolius), Broad Bean (Vicia faba), Bugle (Ajuga reptans), Burning Bush (Dictamnus albus), Cajuput (Melaleuca leucadendra), Carline Thistle (Carlina acaulis), Cascara Sagrada (Rhamnus purshiana), Cat’s Claw (Unicaria tomentosa), Catechu (Acacia catechu), Chickweed (Stellaria media), Cinnamon (Cinnamomum verum), Cinquefoil (Potenilla erecta), Clematis (Clematis recta), Club Moss (Lycopodium clavatum), Coconut Palm (Cocos nucifera), Coffee (Coffea arabica), Cola (Cola acuminata), Common Kidney Vetch (Anthyllis vulneraria), Common Stonecrop (Sedum acre), Congorosa (Maytenus ilicifolia), Corydalis (Corydalis cava), Costus (Saussurea costus), Date Palm (Phoenix dactylifera), Digitalis (Digitalis purpurea), Dogwood (Cornus florida), Echinacea (Echinacea angustifolia and purpurea), Elm Bark (Ulmus minor), English Ivy (Hedera helix), English Plantain (Plantago lanceolata), English Lavendar (Lavandula angustifolia), Eucalyptus (Eucalyptus globulus), European Goldenrod (Solidago virgaurea), Fenugreek (Trigonella foenum-graecum), Feverfew (Tanacetum parthenium), Galbanum (Ferula gummosa), German Chamomile (Matricaria recutita), Goldenseal (Hydrastis canadensis), Gotu Kola (Centella asiatica), Goutweed (Aegopodium podagraria), Great Burnet (Sanguisorba officinalis), Ground Ivy (Glechoma hederacea), Heather (Calluna vulgaris), Henna (Lawsonia inermis), High Mallow (Malva sylvestris), Horehound (Marrubium vulgare), Horsetail (Equisetum arvense), Hound’s Tongue (Cynoglossum officinale), Houseleek (Sempervivum tectorum),

Iceland Moss (Cetraria islandica), Indian Nettle (Acalypha indica), Jambolan (Syzygium cumini), Jujube (Zyzyphus jujube), Herbs in Cosmeceuticals Lady’s Bedstraw (Galium verum), Lesser Celandine (Ranunculus ficaria), Licorice (Glycyrrhiza glabra), LoosestrifeXerosis (Lysimachia vulgaris), Lungwort (Pulmonaria officinalis), Male Fern (Dryopteris fili-max), Marigold (Calendula officinalis), Marsh Marigold (Caltha palustris), Marshmallow (Althaea officinalis), Moneywort (Lysimachia nummularia), Monkshood (Aconitum napellus), Mouse Ear (Pilosella officinarum), Mullein (Verbascum densiflorum), Myrrh (Commiphora molmol), Nasturtium (Tropaelum majus), Oak Gall (Quercus infectoria), Onion (Allium cepa), Ox-Eye Daisy (Chrysanthemum leucanthemum), Petasites (Pentasites hybridus), Peruvian Balsam (Myroxylon balsamum), Pimpinella (Pimpinella major), Pineapple (Ananas comosus), Poplar (Populus species), Poley (Teucrium polium), Quinine (Cinchona pubescens), Rauwolfia (Rawolfia serpentina), Rose (Rosa centifolia), Rosemary (Rosemary officinalis), Safflower (Carthamus tinctorius), Scarlet Pimpernel (Anagallis arvensis), Sea Buckthorn (Hippophae¨ rhamnoides), Shepherd’s Purse (Capsella bursa-pastoris), Slippery Elm (Ulmus rubra), Smartweed (Persicaria hydropiper), Speedwell (Veronica officinalis), Spikenard (Aralia racemosa), Squill (Urginea maritima), St. John’s Wort (Hypericum perforatum), Storax (Liquidambar orientalis), Sunflower (Helianthus annuus), Tansy (Tanacetum vulgare), Teazle (Dipsacus silvestris), Thyme (Thymus vulgaris), Tolu Balsam (Myroxylon balsamum), Traveller’s Joy (Clematis vitalba), Tropical Almond (Terminalia chebula), Turmeric (Curcuma domestica/longa), Vervain (Verbena officinalis), Virola (Virola theiodora), Water Dock (Rumex aquaticus), Water Germander (Teucrium scordium), White Fir (Abies alba), White Lily (Lilium candidum), White Nettle (Lamium album), White Willow (Salix nigra), Wild Daisy (Bellis perennis), Wild Indigo (Baptisia tinctoria), Willow Herb (Epilobium angustifolium), Witch Hazel (Hamamelis virginiana), Wood Sage (Teucrium scorodonia), Woodsorrel (Oxalis acetosella), Wormwood (Artemisia absinthium), Woundwort (Stachys palustris), Yarrow (Achillea millefolium), Yellow Toadflax (Linaria vulgaris), Zedoary (Curcuma zedoaria) Marigold (Calendula officinalis), Mountain Grape (Mahonia aquifolium)a These herbs are approved by the German Commission E. for this indication. 327

328 ThornfeldtSPECIFIC HERBSAllantoin and Comfrey (Symphytum officinale)Comfrey is approved by the Commission E to treat blunt injuries due to the activity oftriterpene saponins, tannins, and silicic acid as well as allantoin (3). Allantoin has been extracted from the comfrey root and leaves but is nowcommercially manufactured. Allantoin is an antipholgistic, antioxidant, and soothingkeratolytic that has antitrichomonal effect and induces cell proliferation. It is listed in theFDA over-the-counter monograph as a safe and effective skin protectant at 0.1% to 2.0%(15). Allantoin- and/or comfrey-based products are used to treat wounds, ulcers, burns,dermatitis, psoriasis, impetigo, and acne. When formulated with surfactant andbenzalkonium chloride it is an effective hand sanitizer and onychomycosis therapy (3). Comfrey contains hepatotoxic pyrriolizidine alkaloids which have resulted in deathswith oral consumption. It is carcinogenic and contraindicated in pregnancy and lactation (3). Allantoin formulated with onion (Allium cepa) extract in a proprietary topicalformulation improved the signs and symptoms of scars and keloids (16,17). No photo-aging clinical trials using topical allantoin and/or comfrey have been published.Aloe (Aloe barbadensis, A. capensis, A. vera)Aloe is used in asian medicine for therapy of fungal and other infections, infestations,tumors, and other skin diseases. The aloe substance released from comminuted leavescontains mucopolysaccharides, glucommamman including beta-mannan, allantoin,anthracenes such as aloin and emodin, alkylchromone including aletinic acid, andcholine salicylate, flavonoids, amino acids, hydroxyquinine glycosides, carboxy-peptidases, and minerals (3). The hydroxyanthraquinone emodin inhibits neuroecto-dermal tumors such as Merkel cell carcinoma (18). Acetylated mannans and lectinsappear to have immunomodulatory effects. Aloe is antibacterial to Staphylococcusaureus, Helicobacter pylori, and dermatophyte fungus. It is viricidal to herpes simplexand varicella zoster and is clinically effective in treating genital herpes. This herb inhibitsthromboxane vasconstriction. Aloe inhibits photoimmunosuppression of UVB andinhibits cyclooxygenase for anti-inflammatory effects. It also increases collagenbiosynthesis and degradation in granulation tissue (3). The antineoplasia effect isimproved with melatonin and ascorbic acid. Aloe vera applied topically is acceptedtherapy for radiation and stasis dermatitis and ulcers, frostbite, burns, fungal andbacterial infections, cold sores, pruritis, pain, psoriasis, and contact irritant dermatitis.The latter two were documented in blinded studies (19,20). No photoaging clinical studies using topical aloe vera have been published despiteits use as one of the two most common extracts in skin care formulations. The health risksof aloe are cutaneous eruptions and mutagenicity. It is contraindicted in pregnancy andlactation (3,18).Anise (Pimpinella anisum)Commission E has approved this herb for mucocutaneous inflammation. The galenicformulations consist of 30% fatty oil, 20% proteins, 4% volatile oils of which 94% isanethole, caffeic acids such as chlorogenic acid, and flavonoids. This herb hasantibacterial, antiviral, antiphlogistic, insect repellant, and estrogenic functionalities.Anise is administered as oil or infusion. It has very rarely produced sensitization (3).

Herbs in Cosmeceuticals 329 A recent blinded clinical trial in 119 children with scabies documented efficacy of92% cure, identical to the mix of prescriptives used as the control. The anise formulationalso included coconut oil and ylang ylang, an essential aromatic oil (21).Avocado (Persea americana)The oil from this food heals wounds, treats sclerosis and has long been used in products forskin aging. The oil primarily consists of monosaturated lipids (22).Bitter Orange (Citrus aurantium)Although this herb has no dermatologic indications in Asian, homeopathic or CommissionE, it has been evaluated in clinical trials for cutaneous disease and has been added tomultiple cosmeceuticals. The active compounds include flavonoids, triterpenoid bitterprinciples (limonoids), furocoumarins, methyl anthranilate, and volatile oils includinglimonene, nerol, and linalool. Bitter orange may cause sensitization, phototoxicity, andhyperpigmentation. It is administered as a tonic, tea, tincture, or galenic drops (3). A blinded, three-arm trial of 65 patients suffering from tinea corporis wasconducted. One arm used a poultice of 100% of this herb applied once daily forthree weeks while another arm used 25% emulsion three times daily for four weeks andboth were compared to imidizole twice daily for four weeks. At two weeks, 93% of the100% bitter orange poultice were clinically cured and 80% were cured with the emulsionof this herb while none were cured with the imidizole (23).Black Cohosh (Cimicifuga racemosa)This North American herb is primarily prescribed to reduce menopause symptoms. It is alsoknown as an insect repellant, to treat acne and warts and improve skin appearance. This herbcontains salicylic acid, tannins, long-chain fatty acids, glycosides and phytoestrogens (22).Black Nightshade (Solanum nigrum)This herb is used in Asian medicine for abcess, furuncle, erysipelas, leprosy, psoriasis,wound, ulcer, and hemorrhoid but is not approved by Commission E for any indication.The active compounds include steroid alkaloid glycosides, alkaloids such as solasonine,and steroid saponins including tigogenin. The major clinical effect is anesthetic/analgesic,but recent studies focus on the anti-infective effects. The nightshades have no reportedhealth hazards. They are administered as liquid extract or tinctures (22). Two blinded comparative studies tested this herb and Solanum chrysotrichum todocument clinical antifungal efficacy. The first compared Solanum nigrum to nystatin in 100patients suffering from vaginal candidiasis. This herbal product cured the same number ofpatients in 25 days with treatment twice daily as nyststin did in 15 days (24). The other studyconsisted of the 28 patients suffering from tinea pedis who were treated twice daily forfour weeks. The test products were 2% micronazole and 5% Solanum chrysotrichum eachapplied to one foot. The herb cure rate was 45% vs. no cure for micronazole (25).Black Seed (Nigella sativa)This herb has traditionally been a hemorrhoid, skin condition, and cancer treatment and hasan immune stimulant effect. Its active compounds include nigellone and thymoquinone.Black seed has antioxidant, antiphlogistic, antibacterial, and antihelminthic effects (22).

330 Thornfeldt Four clinical studies documented efficacy of this herb for treatment of atopicdermatitis and asthma when administered orally. The score of subjective symptomotologyin each study decreased with a p!0.05 significantly (26).Cayenne (Capsicum species)This spicy pepper extract uniquely depletes substance P of the peripheral C nerves. It isapproved by the FDA for treatment of pruritis and pain. The active compounds areprimarily amides of vanillylamine with fatty acids known as capsaicinoids. Other activecompounds include anti-inflammatory carotenoids such as capsantain, flavonoidsincluding apiin, steroid saponins, and volatile oils. Capsaicin rarely has inducedanaphylaxis, death, and ulceration. Burning during the first few applications is common(2). It is now available as nonprescription products (3). Two other human trials documented significant resolution of visible psoriatic lesionswith six weeks of use four times daily (27,28). Other clinical studies document efficacy forchilblains, post herpetic neuralgia, and pruritis (3).Camptotheca acuminata DecneThis herb is one of the few Chinese herbal products with a single botanical appliedtopically reported in the English medical literature. Many combinations of Chinese herbsadministered as teas have documented effectiveness for dermatitis and psoriasis. Topicallyapplied Camptotheca acuminata Decne was equally effective as 1% hydrocortisone intreating psoriasis but suffered a 12% incidence of allergic contact dermatitis (29). Chinese medicine herbs must be used cautiously because in Taiwan 40% wereadulterated with corticosteroids, nonsteroidal anti-inflammatories, and/or central nervoussystem medicines. Over 50% of the Chinese herbal medicines have two or more of thesesynthetics (30).Curcumin Derived from Turmeric (Curcuma domestica/longa)This herb is not approved for dermatologic conditions but is used in Asian medicine forcutaneous inflammation, bruising, bites, pruritis, wounds, fungal infections, and ulcers. Itsactive compounds include volatile oils, such as tumerone, which provides the uniquearoma, 4% curcuminoids, heptanoids, and 30–40% starch. This extract provides theyellow color and much of the flavor for curry in foods (3). These molecules provideantioxidant, antitumor, antimicrobial, antifertility, anti-inflammatory, and insect repellenteffects. Curcumin may color cosmeceuticals claiming to be free of artificial ingredients.Tetrahydrocurcumin is an off-white color that protects cosmeceutical formulations withantioxidant effect that appears superior to tocopherol. Curcumin is contraindicated inpregnancy due to abortifacient effect. Clinical studies demonstrating any impact upon parameters of photoaging arelacking. A paste containing curcumin and neem (Antelaea azadirachta) clinically cured97% of 814 children afflicted with scabies within 15 days (31).Date Palm (Phoenix dactylifera)This food stuff is an Asian medicine therapy for inflamed wounds. The active compoundsinclude 50% sugars such as saccharose, 10% fatty oils, leukoanthocyanidins,phytohormones, and piperidine derivatives including pipecolic acid. It has no reportedhealth hazards (3).

Herbs in Cosmeceuticals 331 A placebo-controlled trial with 5% date versus placebo in 10 patients was applied tothe eye lid twice daily for five weeks. Statistically significant reduction in wrinkle surface(27.6%) and wrinkle depth was achieved. Six of the participants said visual improvementoccurred (32).Echinacea (Echinacea angustifolia, E. purpurea, E. pallida)This medicinal botanical has the largest domestic sales volume. It is among the mostuseful herbs for dermatologic treatment and prevention of skin diseases. E. angustifoliawas originally used by the Sioux Native Americans for the treatment of snake bites andwar wounds because if its antiseptic and analgesic properties (2). Echinacea is known tothe public because of its clinically documented immunostimulating effects in treating andaborting respiratory viral infections (3). All three Echinacea species stimulate immunity,protect collagen, and have antioxidant activity. They are also cytotoxic to multiplebacteria and viruses, E. purpurea is approved by Commission E for treatment of mucosalinflammation, wounds, burns, and to prevent infection. It is formulated in severalcosmeceuticals. E. angustifolia is approved for viral therapy and prophylaxis. Unproventherapies include abcesses, ulcers, and measles. An E. purpurea formulation did noteffectively treat recurrent genital herpes simplex (33). Of all three species the two most active compounds in the above ground plant includethe immunostimulating polysaccharides, echinacin, and inulin. Echinicin has an anti-inflammatory effect similar to corticosteroids but maintains collagen and ground substanceintegrity. It also stimulates wound healing. Inulin is a potent stimulator of the alternativecomplement pathyway, viral neutralization, bacterial destruction, and leukocytechemotaxis. Other active compounds in Echinacea include caffeic and ferulic acidderivatives such as chlorogenic acid, echinoside, flavonoids including rutin, pyrrolizidanealkaloids, alkamides, polyenes, and volatile oils. The roots additionally containimmunostimulating glycoproteins that function like interferon (IFN). E. purpurea alsocontains pyrrolizidane alkaloids and glycoproteins which are lacking in E. pallida and E.angustifolia. In vitro studies suggest this herb protects against cutaneous ultraviolet lightdamage (2). Echinacea species adversely effect fertility and pregnancy. They must not becombined with immunosuppressants. Echinacea is administered as comminuted herb forjuice, decoction, tea, and tincture (3).Garlic (Allium sativa)Homeopathy employs garlic for mucosal inflammation. The biologic activity is primarilydue to alkylcysteine sulfoxides, particularly alliins which are converted to allicin thendried resulting in oligosulfides and ajoene. These thiosulfinates are the major activecomponents. Others include fructosans and saponins. Garlic is a proven oral and topicalbroad spectrum antimicrobial against gram-positive and gram-negatives with potencycomparable to many antibiotics (3). The anti-yeast activity is comparable to nystatin andantifungal activity compares to seven other medicines including gentian violet. Garlic hasantiviral activity against influenza B and herpes hominis I (11). This herb inhibitscarcinogeneisis and cancer cell growth. Garlic tablets stimulate natural killer T cells tofight cancer, viral, and certain bacteria as well as enhance glutathione in cells. Ajoeneinhibits clotting and bleeding times and platelet aggregation yet enhances fibirinolysisby inhibiting thromboxane, adenosine diphosphate, and collagen release. Garlic is alsoa major source of vitamins A, B-1, and C. Virtually odorless garlic based products arebeing marketed (3).

332 Thornfeldt The adverse reactions due to topical garlic are contact irritant and allergic dermatitisand the distinctive halitosis (13). Avoid garlic while breastfeeding. Orally administeredgarlic increases bleeding during surgery especially if administered with other anticoagulants.It is administered in capsules, tablets, powder, and oil. A 0.4% ajoene cream successfullycleared all 34 patients of tinea pedis with 14 days of therapy (34).German Chamomile (Matricaria recutita)Matricaria recutita functions as an anti-allergic, antimicrobial, anti-inflammatory,antioxidant analgesic approved by Commission E for inflammatory mucocutaneousdiseases, wound, and burn therapy. The major components of German chamomile includethe primary anti-inflammatory agents: alpha-bisabolol, chamazulene, levomenol, andmatricine. Other active compounds include bisaboloxides, farnesenes, choline, glycosides,flavonoids such as apigenin, rutin, tannins, hydroxycoumarins such umbelliferone,mucilages, saccharides, fatty acids, and salicylates (3,35). Chamazulene inhibits leukotriene B4 synthesis via inhibition of lipoxygenase andcyclo-oxygenase, lipid peroxidation, leukocyte infiltration, and histamine release.Levomenol is an anti-inflammatory hydrating agent that diminishes the signs ofphotodamage and reduces pruritis. Apigenin inhibits adhesion molecules. Bisabololpromotes granulation tissue (35). Clinical studies showed topical chamomile cream was superior to 0.5%hydrocortisone in treating dermatitis and sunburn and statistically significantly decreasedwound area and healing time (29). In another trial, it was not as effective as 0.25%hydrocortisone in treating dermatitis. This herb is administered as oil for infusion, tea,ointment, gel, wash, gargle, or capsule. Chamomile is a compositae that has a significant risk of contact sensitization,conjunctivitis, angioedema, and anaphylaxis. It also has an additive anticoagulant effect towarfarin (3).Gingko (Ginko biloba)The efficacy of this herb for human dementia and peripheral occlusive arterial diseasetherapy are well documented. The mechanisms of action include antioxidant, stimulatingfibroblasts, prevent lipid peroxidation, stabilize membranes, reduce neutrophil infiltration,and protect against ischemia. The major active compounds include proanthocyanidinswhich comprise 8–12%, biflavonoids such as gingkgetin, flavonoids including kaempferol,and trilactonic diterpenes such as ginkolide and sesquiterpene bilabolids (36,37). The major health hazard encompasses spontaneous hemorrhage including intracra-nial. Others include adverse effects on oocytes and cutaneous allergic reactions. Gingko isadministered as liquid extract for infusion and powder for tablets and capsules (3). One double-blind, placebo-controlled study documented reduction in the frequency ofattacks of Raynaud’s disease with ingestion (38). Another double-blind, placebo controlledtrial with 40 mg thrice daily halted vitiligo progression in 20 of 47 patients and producedmarked improvement in 10 (39).Grape Seed (Vitis vinifera) / Pycnogenol / OPCsThe pharmacologic activity of grape seed extract (GS) along with French maritime pinebark(Pinus pinaster) extract primarily resides in the potent antioxidant proanthocyanidins. Theseare the two richest natural sources and most commercially viable. Other rich natural sourcesinclude green and black tea, red wine, red apple, red cabbage, black currant, sangre de drago,bilberry, blackberry, blueberry, strawberry, black cherry, cranberry, peanut skins, almonds,

Herbs in Cosmeceuticals 333cocoa, parsley, onions, legumes, hawthorn, and witch hazel bark (3,22). The standardizedpinebark extract is patent protected Pycnogenal (PYC), which has been the generic term forproanthocyanidins. These polyphenolic bioflavonoids are also known as procyanidins,procyandiol oligomers, leukoanthocyanidins, condensed tannins, and oligomeric proantho-cyanidins (OPCs). OPCs consist of dimers of catechins and oligomers of epicatechin andcatechin and their gallic acid esters. These compounds are scavengers of both reactiveoxygen and nitrogen species. GS also includes other therapeutic compounds includingflavonoids such as kaempferol and quercetin glucosides, stilbenes such as resveratrol andviniferins, fruit acids, tocopherols, essential fatty acids, and phenylacrylic acids such ascaffeoyl and feruloylsuccinic acid. Resveratol is a potent antioxidant which inhibitsangiogenesis and carcinogenesis, is antiviral against herpes, and has phytoestrogen activity.PYC also contains monomeric epicatechin and catechin (3,22,40). GS applied topically improved cutaneous photoprotection to UVB, inhibitshistamine synthesis, promotes wound healing, reduces apoptosis induced by chemother-apy, reduces vascular engorgement, is cytotoxic to adenocarcinoma, and inhibitsstreptococcus. GS protects DNA against oxidation more effectively than vitamins Cand E and stabilizes collagen and elastin by inhibiting MMPs. It treats chronic venousinsufficiency (CVI) and postoperative edema in clinical studies. All these functions ofGS strongly suggest is should improve photoaged skin and protect against furtherdamage. GS has been used for centuries in Asia to treat a variety of cutaneous conditions(3,22,40). PYC increases nitric oxide levels, stimulates T and B cell function, inhibits nuclearreceptor transcription factors nuclear factor-kappa B (NF-kappa B) and AP-1 and theadhesion molecule ICAM-1 as well as IFN-gamma. It recycles both vitamins C and E.Topically applied PYC reduces sunburn, immunosupression, and tumor formation by UVlight while raising the minimal erythema dose in mice (22,29). PYC administered orallyreduced the area of severity of melasma within 30 days and the signs and symptoms ofCVI by 60 days (29). A topical formulation consisting of grape seed, jojoba, lavender, rosemary, andthyme was to treat alopecia areata. After seven months of daily use, statistically significantimprovement in hair re-growth occurred (44% vs. 15% for placebo) (41). It has been usedin anti-aging creams for several years (22). No controlled clinical studies evaluating theseherbs for treatment of photoaging have been published.Horse Chestnut (Aesculus hippocastanum)This herb is approved by German Commission E for CVI, lupus and ulcer therapy. Inhomeopathy horse chestnut treats hemorrhoids. The mechanisms of action includeinhibition of elastase and hyaluronase primarily by aesin, a triterpene saponin which hasanti-exudative effects by decreasing capillary permeability, inhibits leukocyte activation,and induces vasoncontriction. The active compounds in seeds of this herb contain 50%polysaccharides and oligosaccharides, other triterpene saponins, fatty oils, sterols andflavonoids including quercetin and OPCs (3,22). Leg circumference, heaviness, and pain were statistically significantly reduced inmultiple CVI trials with oral therapy. Topically applied horse chestnut reduced the symptomsof CVI in one trial and hemorrhoids in another (42). Photoaging clinical studies are lacking. The health risks of horse chestnut include hepatotoxicity, renal toxicity, urticaria,anaphylaxis, and mucocutaneous irritant and allergic dermatitis. It may also interact withsalicylates and warfarin. This herb is administered as tea, tincture for infusion, gel, orointments (3,22).

334 ThornfeldtLemon Balm (Melissa officinalis)This herb has antibacterial, antiviral, antioxidant, and anti-hormonal effects. The activecompounds include volatile oils such as citronellal, glycosides, caffeic acids such asrosmaric acid, triperpene acids including ursolic acid, and flavonoids such as cynaro-side. Lemon balm has one reported case of contact irritation. It is administered as powder,tea, and infusion (22). A 1% cream applied five times a day in 116 patients in a double-blinded trial forHerpes Simplex documented complete clearing by day 8 in 96%. Lesion size and healingtime were statistically significantly superior to placebo (43).Milk Thistle (Silybum marianum)The extract of this herb is silymarin which consists of three flavonoids: silybin (about75%), silydianin, and silychristine. Silymarin has potent antioxidant, antiphlogistic,antiangiogenic, and antitumor activities. A 92% reduction in UVB-induced murine skintumors was produced with topical silymarin (44). Topical silybin decreased the formationof pyrimidine dimers and UVB-induced apotosis was enhanced in mice (45). It also inhibitscyclooxygenase-2 (46). Other active molecules in milk thistle include fatty oil whichaccounts for 20–30% flavonoids including apigenin and quercetin, steroids such as beta-sitosterol, fumaric acid, and polyynes. This herb is administered as a comminuted drug forliquid extracts and tinctures for infusion. No allergic reactions have been reported (3).Neem (Antelaea azadirachta)This medicinal botanical is used in Asian medicine to treat inflammatory diseases,infestations, wounds and leprosy. It has documented anti-inflammatory, antihelminthic,antipyretic, antiphlogistic, and insecticide activity due to its triterpenes, tannins, andvolatile oils. Neem is administered as a decoction, tincture or ointment. It was formulatedin a paste with curcumin to treat 814 children with scabies. A 97% cure rate was achievedwithin 15 days (22,29,31).Onion (Allium cepa)This herb is approved for mucosal inflammation therapy and to reduce the tendencytoward infection. In Asian medicine it treats wounds fungal, bacterial, and helminthicinfections. The active compounds include alliins (alkylcysteine sulphoxides), poly-saccharides, saccharose, flavonoids, and steroid saponins. In addition to anti-inflammatoryeffects, this herb inhibits gram-negative bacteria and thrombocytes and has anti-allergiceffects. Onion rarely produces contact irritant reactions. This herb effectively modulates scars and keloid formation in two human trials whenformulated with allantoin (16,17). In a study for treatment of patchy alopecia areata of23 patients, re-growth of terminal coarse hairs started after two weeks of treatment withcrude onion juice. At six weeks, the hair re-growth was observed in 20 patients. The tap-water-treated control group experienced hair re-growth in only two patients at eight weeksof treatment (p!0.0001) versus the onion juice group (47).Oregon Grape (Mahonia aquifolium)This herb is traditionally used for psoriasis therapy and disinfectant. The active moleculesare isoquinoline alkaloids such as berberine and oxyacanthine which are antibacterial,

Herbs in Cosmeceuticals 335antihelmintic, and immunostimulating. It can induce pruritis, contact irritant and allergicdermatitis. This herb is administered in powder, cream, and ointment (22). Two psoriasis clinical studies have been reported. The open study documentedimprovement in psoriasis symptoms and quality of life (48). The blinded study foundoregon grape ointment to be superior to placebo in less than half of the patients (49).Pomegranate (Punica granatum)This herb was used in ancient Egypt for inflammation of the skin, mucosa, and joints. Punicagranatum may contain a more potent antioxidant mixture than grapeseed, Pycnogenol,blueberry, cranberry red wine, or green tea. The major constituents are tannins (25–28%),including punicalagin, polyphenols such as ellagic acid, ascorbic acid, niacin, potassium,piperidine alkaloids and phytoestrogens. Pomegranate functions as an astringent that alsoinhibits NF-kappa B. It has documented antimicrobial activity for gram-negative bacteria,saccharomyces fungus, parasites, and viruses (22). Topical and oral administration of thisherb induced photoprotection to UVB in a human clinical trial (50). Topically applied, pomegranate can induce contact urticaria/angiodema andconjuctivitis. It is administered as a decoction (3,22).Soy (Glycine soja)This antioxidant, antiproliferative, antiangiogenic phytoestrogenic extract is used to treathyperhidrosis in Asian medicine (22). Epidemiologic studies indicating much lowermalignancy and cardiac disease rates in people eating a diet high in soy resulted in thoroughinvestigations revealing multiple medicinal uses. The major components of soy arephospholipids (45–60%) such as phosphatidyl choline and essential fatty oils (30–35%).The minor components include the most active compounds such as isoflavones, saponins,essential amino acids, phytosterols, calcium, potassium, iron, and the proteases soybeantrypsin inhibitor and Bowman-Burke inhibitor. The most potent isoflavones are thephytoestrogens genistein and daidzein. Topical estrogens have been shown to increase skinthickness and promote collagen synthesis; thus, soy phytoestrogen stimulatation of humanfibroblast collagen synthesis is expected. Genistein, the most potent antioxidant, inhibitslipid peroxidation and chemical- and UVB-induced carcinogenesis. The two proteaseinhibitors lighten pigmented lesions and reduce unwanted facial and body hair in humanclinical trials (3,51,52). Soy products have rarely caused dermatitis and pruritis as well as asthma andgastrointestinal symptoms (3,22).St. John’s Wort (Hypericum perforatum)This widely used herb is popular due to its sedative, anxiolytic, and antidepressantaction. St. John’s Wort is approved for wound healing, burns, and cutaneousinflammation. Asian medicine employs it for dermatitis topical therapy. This herb hasantistaphylococcal, anti-inflammatory, antineoplastic, antioxidant activity yet stimulateswound healing and T lymphocytes. The active compounds include flavonoids such asquercetin, catechins, oligomeric procyanidines, xanthones, anthracenes includinghypericin, and caffeic acids such as chlorogenic acid. This herb is administered bypowders, liquid, tincture, and tea (3). St. John’s Wort induces multiple health hazardsincluding dangerous ones such as mutagenicity to oocytes. It interacts with many majorsystemic drugs including beta-blockers, anticoagulants, calcium channel blockers,

336 Thornfeldtimmunosuppressives, anti-hypertensives, antibiotics, contraceptives, statins, SSRI,analgesics, and photosensitizers (13,22). Human clinical trials from Russia support its wound healing effectiveness (2). In a21-patient, blinded, clinical trial of mild to moderate atopic dermatitis the improvement ofthe intensity of the eczematous lesions by 1.5% hypericum-cream was significantlysuperior to the vehicle at all clinical visits (p !0.05) (53).Tea Tree (Melaleuca alternifolia)This essential oil has become one of the most commonly used nonprescription remediesfor mucocutaneous disorders. TTO active compounds include terpinenes such as cineole.The monoterpene terpinen is the major sensitizing compound in TTO which has becomeone of the most common contact allergens. The terpene alcohols such as terpin in -4-ol arethe major constituents comprising 40% of TTO. They reduce histamine induced edemaand wheal volume in type I hypersensitivity reactions. TTO does not have antioxidantactivity nor does it suppress neutrophil superoxide. Its wide antimicrobial spectrumincludes Propionobacterium acnes, Escherichia coli, Staphylococcus aureus, Herpessimplex, Candida albicans, Trichophyton dermatophytes and Sarcoptes scabeii (3,54,55). Multiple double-blinded clinical trials document that TTO effectively treats acneand fungal/yeast infections. TTO failed to effectively treat atopic dermatitis and CVI(3,22,55). TTO is cytolytic to epithelial cells and fibroblasts so it should not be used for burns.Photodamaged TTO is a stronger sensitizer and has induced erythema multiforme withtopical application. Thus, the use of TTO in cosmeceuticals for sun exposed tissue is notscientifically sound (55).Teas—Black, Green, Oolong, and White (Camellia sinensis)All true teas are derived from Camellia sinensis. Black tea is the most processed(fermented) with white tea recently supplanting green tea as the least processed; oolong ispartially fermented. Green tea contains 8–12% polyphenols and 2–4% caffeine(10-80 mg/cup). White tea is a more potent antioxidant and more effective than greentea in inhibiting bacterial dysplastic mutations (3,22,56). Green tea decreases melanomacells in tissue culture and squamous cell carcinoma cell formation with topical and oraladministration in mice. It also increases keratinocyte cell differentiation improving woundhealing. This tea inhibits Streptococcus species and Escherichia coli. It also inhibitsbradykinin and prostaglandins in animals (57). Black tea has a much lower content ofcatechins than green tea, but a higher content of other flavonoids such as kaempferol andtheaflavin. The largest catechin and most active antioxidant in any tea is epigallocatechingallate (EGCG). Green tea has the highest concentration of EGCG (3). Topical green tea provided photoprotection beginning at 24 hours and lasting48–72 hours. It reduced the number of sunburn cells by 66% when applied 30 minutesprior to UVB. When applied at 1–10% concentrations, a dose response inhibition ofUV-induced erythema occurred (58). This extract prevented psoralen UVA photo-damage with pre- and post-treatment by reducing erythema, hyperplasia, andhyperkeratosis (59,60). Green tea is used to soothe sunburn, reduce baggy eyelids,reduce gingivitis and produce hemostasis and prevent UV induced carcinogenesisincluding oral leukoplekis (2,22). Black tea extracts applied pre- and post-ultravioletlight challenge decreased signs of cutaneous photodamage, carcinogenesis, andinflammation in human and mouse skin (22). Oral administration of black and oolong

Herbs in Cosmeceuticals 337teas, like green tea, suppressed both type I and IV allergic reactions in the skin (61).Oral oolong tea effectively treated atopic dermatitis (62). A recent double-blinded trial of 51 patients treated for 12 weeks with topical greentea extract containing 5.5–8.5% EGCG did not reduce the number of actinic keratoses onforearms compared to placebo (63). The major adverse reactions are gastrointestinal upset, constipation, irritability, andvery rare hepatotoxicity, delirium, and seizures. Caution should be used during pregnancyand lactation with excessive consumption (O3 cups or 300 mg per day) (22).Western Herbal MixThis consists of grape seed, jojoba, lavender, rosemary, and thyme. It was massaged intothe scalp of 86 patients suffering from alopecia areata. After seven months of daily usestatistically significant improvement in hair re-growth occurred (44% western herbal mixvs. 15%) for placebo (64).Witch Hazel (Hamamelis virginiana)The bark and leaf of this herb yield galenic formulations with 5–12% tannins, catechinsincluding EGCG, OPCs, flavonoids such as quercitrin, and volatile oils. Astringent,antiphlogistic, and hemostatic effects result from these potent active compounds. Witchhazel is approved by Commission E and in homeopathy for mucocutaneous inflammation,wound, burn, venous insufficiency, and hemorrhoid therapy. Contact irritant dermatitisis rarely reported. Hepatotoxicity possibly occurs with chronic ingestion. It is administeredin various topical formulations via extract of comminuted drugs, steam distillate,decoction or tea, gels, and ointments (3). Witch hazel is formulated into acne and vein cosmeceuticals. Clinical studiesdocument this herb is less effective than 1% hydrocortisone in reducing UV-inducederythema (65). In 36 atopic dermatitis patients, witch hazel significantly reducedinflammation and pruritis (66).Scientifically Rational HerbsThere are a number of well-known, commonly used medicinal botanicals incorporatedinto many cosmeceuticals that have not been studied in any dermatologic human trials buthave demonstrated biologic effects in nondermatologic diseases, in vitro, in vivo, oranimal models. The lack of FDA regulation allows companies to formulate these herbsinto skin care products and market them. Cosmeceuticals that lack human clinical data,contain herbs with only in vitro scientific data, contain subtherapeutic concentrations, lackdocumented delivery systems for the herbal molecules, and lack proof of chemicalstability of the formulation should be viewed with great skepticism by clinicians.Apple (Malus domestica)Extracts of this foodstuff has been used for years in cosmeceuticals for fruit acidsparticularly malic, ascorbic acid, and pectin. Other active compounds include tannins suchas quercetin and caffeic acids such as quinic acid. Procyanidin B-2 is a protein kinase Cinhibiting tannin recently demonstrated to promote hair cell growth and anagen inductionin vitro (67).

338 ThornfeldtArnica (Arnica montana)Arnica, of the compositae family, is approved for treating inflammation of cutaneous andmuscosal surfaces and blunt injury and reducing the risk of developing infection. This herbfunctions as an analgesic, antidandruff, antiseptic, anti-inflammatory, and antiphlogistic butis an immunostimulant. The major active compounds include sesquiterpene lactone estersincluding helenalin, flavonoids, including flavonol glycosides, polyynes, volatile oils suchas thymol, free fatty acids, caffeic acids such as chlorogenic acid, and hydroxycumarines. Extract, tincture, and powder of arnica are administered topically as infusion,poultice, gel, plaster, oil, and ointment. The health hazards are primarily contact allergicand irritant dermatitis, but erosions and necrosis occur rarely (3). One death and one caseof Sweet’s syndrome have been reported. The literary giant Johann Wolfgang von Goetheingested arnica tea to relieve angina in the 19th century (29). It is controversial regardingits safety with oral administration although it is used in cosmetic surgery (unpublished).One author suggests it should not be administered orally and another states the FDAconsiders arnica to be unsafe (13,22).Cactus Pear (Opuntia ficus-indica)This herb decreases oxidative damage to lipids and improves antioxidant status in healthyhumans after oral supplementation. Vitamin C at a comparable dosage orally also enhancesoverall antioxidant defense but does not significantly decrease body oxidative stress (68).Eucommia Ulmoides Oliver (EUOL)This Chinese herb contains geniposidic acid which statistically significantly increasedstratum corneum turnover in aging mice (69).Ginseng (Eleutherococcous senticosus, Panax ginseng,P. quinquefolius)The most potent species is Siberian ginseng which is Eleutherococcus senticosus. Panaxginseng is also from the Orient while Panax quinquefolius grows in America. This is awidely used oral herb that has recently entered cosmeceutical products withoutdermatologic studies or historical use in mucocutaneous disorders. The major active ingredients of Panax ginseng are triterpene and steroid saponinsknown as ginsenosides, polysaccharides, aglycones, and polyynes. Eleutherococcus alsocontains steroid glycosides, hydroxycoumarins, phenylacrylic acids, and lignans (3).These actives all contribute to antioxidant, anti-inflammatory, anti-platelet, antitumor, andantiviral effects. Protein synthesis is also enhanced. The efficacy of oral ginsengs againstsystemic viruses is documented. Red ginseng applied topically appeared to inhibitchemically induced skin tumors in mice (29). Ginseng is contraindicated in pregnancy, lactation, cardiac disease, and diabetes.Unfortunately 25% of 133 patients using ginseng for two years developed skin reactions.These also indicate ginseng abuse syndrome. Topical application to the face has inducedpostmenopausal vaginal bleeding. This herb increases effects of antidiabetic and anti-coagulant drugs, estrogen, and MAO inhibitors. It is administered as a powder for infusion (3).Hibiscus (Hibiscus sabdariffa)This is an Asian medicine for cutaneous inflammation and edema, carbuncle, scalding, andherpes zoster therapy. The active compounds include fruit acids (15–30%),

Herbs in Cosmeceuticals 339anthocyanidins, flavonoids, and mucilages. It is administered as tea. Hibiscus has noreported health hazards (3).Jojoba (Simmondsia chinensis)The galenic formulations of this herb are used in many products as an antioxidantthickener and to exfoliate skin for treatment of acne, psoriasis, sunburn, chapped skin, hairrestorer and wounds although it is not approved for any cutaneous indication. The waxesters consist of 20–22 carbon atom length fatty acids arranged in waxy globules, alcohols,and 14% erucic acid. Health hazards include rare contact dermatitis and systemictoxicity (3,22).Licorice (Glycyrrhiza glabra and G. uralensis)The extracts of this herb are incorporated into cosmeceuticals to improve skin brightnessbut are used in Asian medicine for wounds and carbuncle therapy. The active componentsconsist of triterpene saponins such as glycyrrhizin (3–15%), flavonoids includinglicoricidin, isoflavones such as glabridin, hydroxycoumarins including glycycoumarin,cumestans such as glycynol, sterols such as beta-sitosterol, and volatile oils includingeugenol. Glycyrrhizin inhibit replication of varicella zoster, hepatitis B, cytomegalovirus,and HIV and stimulates IFN production. It is also anti-estrogenic, antistaphylococcal,antiprotozoal, anti-fungal, anti-yeast, antioxidant, anti-inflammatory, antiplatelet, anti-thrombin, anti-cancer and sebostatic effects. Glabridin is anti-inflammatory, antioxidant,and inhibits tyrosinase reducing UVB-induced erythema and pigmentation (3). Licorice is administered by comminuted drug, powder, juice, decoction, and tea forinfusions. This herb is contraindicated in pregnancy, lactation, hepato-, and renal toxicityand cardiac disease. It may induce rhabdomyolysis, pseudoaldosteronism, andhypokalemic alkylosis. Licorice interacts adversely with anti-arrythmic, antihypertensive,anticoagulant, and antidiabetic drugs, contraceptives, diuretics, laxatives, MAO inhibitors,and corticosteroid drugs (13,22).Myrtle (Myrtus communis)Cosmeceuticals incorporate this herb to calm the skin. The active compounds includemonoterpenes and sesquiterpenes such as cineol and pinene. Tannins, acylphloruglucinols,and volatile oils are present. Antibacterial, fungicidal, and antiseptic effects result from theactive molecules. It is administered as infusion. This herb is contraindicated in childrenand infants due to potential of including glottal spasm when used on the face. It should alsobe avoided in pregnancy and lactation (3).Noni (Morinda citrifolia)In 2003 and 2004 Noni was the largest selling single herb in the U.S. It has no reliablepublished clinical research. Noni’s unproven uses are for many systemic diseasesincluding diabetes, infections, fever, arthritis and wounds. The active ingredients are iridoids including asperulosid. Topically, it is anemoltient used to reduce signs of skin aging. The active ingredients are iridoids includingasperulosid, retinol, ascorbic acid, ursolic and linoleic acids (3,22).

340 ThornfeldtOlive (Olea europaea)The ancient Greeks had many uses for this plant and its by products. Olive oil hastraditionally been used to treat burns, dermatitis, psoriasis, rosacea, and xerosis. The majorcomponents include 56–83% oleic acid, 8–20% palmitic acid, and 4–20% linoleic acid.Steroids including B-sitosterol and tocopherols are present. Extra virgin oil also hasa significant amount of polar polyphenols which provide antioxidant effect and contributeto the anti-inflammatory function of olive oil. When applied to murine skin followingUVB exposure, significantly fewer tumors developed. This herb is a weak irritant. Anincreasing number of cosmeceuticals incorporate olive oil into the formulation (70,71).Papaya (Carica papaya)This foodstuff enhances resolution of bruises and wounds. It is also used forcosmeceuticals to modify the appearance of scars. The juice from the unripened fruit isprimarily papain, a mixture of proteinases, lipases, and phosphatases that additionallyhave anti-ulcerative, antimicrobial, and antihelminthic effects. This herb also containspolyketide alkaloids such as carpane, glucosinolates, saponins, and ficin. Papaya galenicextracts interact with warfarin, induce bleeding, and contact reactions. It is contraindicatedin pregnancy. It has no reported health hazards (3).Prickly Pear (Opuntia streptacantha)The juice of this medicinal botanical soothes cutaneous wounds, burns, and dermatitis due toits mucilages consisting of mucopolysaccharides, sucrose, lignans, and fruit acids. It also is anantiviral against herpes simplex and HIV. This herb is administered as a powder or galenicfor a variety of topical formulations. Prickly pear has no reported health hazards (22).Pumpkin (Cucurbita pepo)The German Commission E approved this herb for prostate therapy. Folk medicine usespumpkin for helminthic infections. Pumpkin seeds comprise fatty oils (about 50% of totalweight) including linoleic acid (55% of fatty oils) and oleic acid (25%). This extract is alsorich in gamma-tocopherol, carotenoids including lutein, sterols, and the amino acidcurcurbitin which is antihelminthic active (22). Pumpkin seed is antiphlogistic,antioxidant, and antihelminthic. This herb has no reliable published studies for anytopical preparations or dermatologic disease (3,22). There are no photoaging studies despite its use in cosmeceutical chemical peels andother products for nearly a decade. The reported adverse reactions include gastrointestinal distress.Rosemary (Rosmarinus officinalis)This medicinal botanical soothes mucocutaneous tissue leading to its formulation intocosmeceuticals. It also has antimicrobial, antiviral, and antioxidant effects. Rosemaryapplied topically inhibited chemically induced murine epithelial tumors. The activecomponents include flavonoids, triterpenes such as ursolic acid, diterpenes includingcarnosolic acid, and volatile oils in addition to caffeic and rosmarinic acids. This herb is contraindicated in pregnancy and has a mild risk of sensitization (3).

Herbs in Cosmeceuticals 341Sandalwood (Santalum album)This herb is an Asian therapy for heatstroke and sunstroke and for urethral inflammation inhomeopathy. Preliminary data suggests it may be chemopreventive for cutaneousmalignancy (57). The antiseptic and therapeutic effects result from tannins, resins, andvolatile oils. Sandalwood is administered as oil. It has minimal potential for sensitization.It is contraindicated in pregnancy (3).Sarsaparilla (Smilax medica)This herb is a homeopathic remedy for pruritic and inflammatory cutaneous diseasesincluding psoriasis, leprosy and syphilis. The active molecules include steroid saponinssuch as sarsasapogenin, phytosterols including beta-sitosterol, and quercetin. Thispreferred flavoring agent of the Old West is also an antiseptic and antipruritic. Sarsaparillacan induce asthma and renal failure. It is administered as a powder, decoction, and liquidextract (3,22).Saw Palmetto (Serenoa repens)This medicinal botanical has documented anti-androgenic, anti-estrogenic, anti-inflammatory, and anti-exudative effects. An unproven use is eczema therapy. Its majorcomponents are sitosterols and their glucosides, flavonoids, free fatty acids, andpolysaccharides. Multiple blinded human trails document effectiveness in treatingprostate disease. This compound has been introduced in at least two cosmeceuticals forphotoaging and three for hair growth because of its documented inhibition of 5-alphareductase. It is contraindicated in pregnancy and lactation and interacts with warfarin. Thisherb is administered in galenic formulations from comminuted herb (3).Sesame (Sesamum orientale)This herb is used in folk medicine to treat crusts and as a massage oil. The active ingredientsare nearly completely fatty oils including linoleic and loeic acid (35-50% each), palmiticacid (10%), lignans, and sterols (3). The lignan sesamine is immunosuppressive in vitro. No clinical studies have beenpublished. It has limited risk of sensitization.Spearmint (Mentha spicata)The distinctive aroma is due to carvone which comprises 40–80% of the extracts of thisherb. Other active compounds include caffeic acids such as rosmaric acid, flavonoidsincluding thymonin, and volatile oils. These molecules provide spearmint withantimicrobial and insecticide activity (72). This herb applied topically produced a statistically significant decrease in oxidativedamage and tumor promotion as it decreased thymidine uptake. It is used formucocutaneous inflammation, arthritis, neurogenic pain, urticaria and pruritis (22).Wheat Germ (Triticum aestivum)The oil of this medicinal botanical is used in cosmeceuticals to dissolve dirt and makeupand as a skin protectant. The active components include 60–75% triacylglycerols, 50–65%

342 Thornfeldtlinoleic acid, 15–22% oleic acid, 7–18% palmitic acid, and 9–14% phospholipids. Wheatgerm oil also contains other active compounds including glycolipids, sterol esters,tocopherol, tocotrienols, and carotenoids. It has minimal risk of sensitization. This oil isadministered orally or topically (3).White Birch (Betulae folium)This herb is included in cosmeceuticals to decrease fine lines because of its relatively highconcentration of ascorbic acid, OPCs, and flavonoids including hyperoside and quercetin.Other actives include caffeic acids, such as chlorogenic acid, D-glucosides, monoterpeneglucosides, and sesquiterpene oxides. This herb is used to treat hair loss and dandruff.White birch is administered as comminuted herb for tea and topicals. There are no reportsof sensitization but use with caution in people with renal failure (3).German Commission E Approved HerbsHerbs approved by the German Commission E for treatment of mucocutaneous indicationsnot previously discussed are listed alphabetically below. Familiarity with these medicinalbotanicals is important because these herbs should be among the most likely candidates forincorporation into future cosmeceuticals. Several have very recently been formulated intonovel cosmeceuticals due to the confidence in their known biologic activity, mechanismsof action, and relative safety. Human clinical trials are needed to document any cutaneousefficacy with these formulations just as in the previous group of botanicals.Agrimony (Agrimonia eupatoria)This herb is approved for treatment of inflammation of cutaneous and mucosal tissues.Asian medicine uses it for hemostyptic effects. Agrimony acts as an astringent due to theactive compounds being catechin tannins. This herb is administered by decoction forpoultice. There are no reported health risks with agrimony (3).Bittersweet Nightshade (Solanum dulcamara)This herb is approved to treat warts, acne, dermatitis, and furuncles. It is homeopathy forskin infection. The active compounds include steroid alkaloid glycosides and steroidsaponins. The glycosides account for the stimulation of phagocytosis, hemolytic,cytotoxic, antiviral, anticholinergic, anesthetic, and desensitizing effect. The saponinspromote resorption of the glycosides. Bittersweet nightshade is administered as decoctionand tea for compress and rinse. This medicinal botanical is contraindicated in pregnancyand lactation (3).Butcher’s Broom (Ruscus aculeatus)This medicinal botanical is approved to treat venous conditions including venousinsufficiency and hemorroids. The therapeutic activity is due to increasing venous tonewhile reversing inflammation. The major active compounds include steroid saponinsruscine and ruscoside which comprise 5% of the extract by weight. The other group ofactive compounds include benzofuranes including euparone. These extracts are orallyadministered as capsules with only rare gastrointestional adverse reactions reported (3).

Herbs in Cosmeceuticals 343Cajuput (Melaleuca leucadendra)This herb is approved to treat wounds and burns and reverse a tendency toward infection.The antimicrobial and rubefacient effects are produced by cineol, terpineol, and othersesquiterpenes and phenones. Cajuput is administered as oil but must not be applied to theface of infants or children due to potential glottalspasm or bronchospasm. Contact allergicreactions rarely occur. This herb must not be ingested (3).Chaste Tree (Vitex agnus-castus)Known as Vitex, this medicinal botanical is approved for treating premenstrual acne withoral administration. The active compounds include flavonoids such as casticin, glycosides,fatty, and volatile oils. It suppresses follicle-stimulating and luteinizing hormone levels toincrease progesterone and reduce estrogen levels. The main adverse effects aregastrointestinal tract distress and allergic eruptions (29).English Plantain (Plantago lanceolata)The extracts of this herb are approved to treat cutaneous and mucosal inflammation. Theactive compounds include mucilages such as glucomannans, monoterpenes includingaucubin, flavonoids such as apigenine glucoside, caffeic acids including chlorogenic acid,hydroxycoumarins such as aesculetin, silicic acid, tannins, and saponins. Therapeuticeffects include acceleration of hemostasis and enhanced epithelialization and arebactericidal. Monoterpenes and saponins account for most of these effects. There are nohealth hazards reported with English plantain. It is administered as a liquid extract, juice,or tea for lozenge or infusion (3).Fenugreek (Trigonella foenum-graecum)This herb is approved to treat inflammatory cutaneous diseases. It acts as soothingemollient via its major active compounds mucilages including mannogalactans whichaccount for 25–45% of the extract. Proteins comprise another 25–30% of the extract, whilesteroid saponins including trigofoenosides and foenugracein account for about 15%.Trigonelline, sterols, volatile oils, and flavonoids such as orientin and vitexin are the otheractive compounds. Topical sensitization is rare. Fenugreek must not be administeredduring pregnancy (3).Flax (Linum usitatissimum)This medicinal botanical is approved to treat inflammatory cutaneous disorders. Asianmedicine employs flax to treat superficial infections. This herb functions as a soothinganti-inflammatory emollient due to the linolenic, linoleic, and oleic acids which combinedcomprise 30–45% of the extract weight. Proteins account for another 20–27% of theextract while mucilages comprise about 10%. Antioxidant, antimycotic, and estrogeniceffects result from lignans, whose most abundant source is flax. Cyanogenic glycosidesand phenylpropanes are the other active compounds in this extract. The adverse cutaneous reactions have only been reported to linseed, the oil extractedfrom flax. They include irritation, erythema, eyelid edema, and one case of an anaphylaxis(3,13,22). Flax is administered as a cracked or ground seed, powder, linseed oil, ora poultice.

344 ThornfeldtHeartsease (Viola tricolor)Heartsease is approved for treatment of cutaneous inflammation and sehorrheic dermatitisin infants. Homeopathy employs it for eczema therapy. The active compounds function assoothing anti-inflammatory emollients. Mucilages account for 10% of the extract byweight. Other actives include tannins, salicylic acid (0.3%) and other phenolics, flavonoidsincluding rutin, saponins, and vitexin, and hydroxycoumarins such as umbelliferone. Thisherb has no reported health hazards. Heartsease is administered by powder, decoction or tea for infusion, bath additive,ointment, and shampoo (3).Horsetail (Equisetum arvense)This herb is approved for treatment of wounds and burns. The major active compound isthe astringent silicic acid which comprises 5.0–7.7% of the extract by weight. Flavonoidssuch as apigenin glucoside contribute to the astringent effect. Other actives are caffeicacids including chlorogenic acid and pyridine alkaloids such as nicotine. Horsetail shouldnot be used in patients with cardiac or renal compromise even topically (13). The liquidextract is administered as a decoction or tea for infusion or compress (3).Jambolan (Syzygium cumini)The extract of the bark of Jambolan is approved for treatment of cutaneous and mucosalinflammatory diseases but the seed extract is not. It has similar use in Asian medicine. Thetherapeutic effect is as an astringent primarily due to the tannins such as ellagic acid. Otheractive compounds include sterols such as beta-sitosterol, triterpenes including eugenin, andflavonoids such as myricetin and kaempferol. There are no reported health hazards withJambolan. It is administered as a powder or decoction for a gargle, infusion, or compress (22).Lavender (Lavandula angustifolia, L. officinalis)Lavandula officinalis was used by the ancient Greeks for its fragrant essential oil. Englishlavender (Lavandula angustifolia) is approved for balneotherapy for circulatory disorders.Tannins comprise 13% of this extract by weight. Other active compounds include volatileoils of which linalool and linoyl acetate comprise 90%, and hydroxycoumarins such asumbelliferone, caffeic acids including rosmaric acid, flavonoids, and triterpenoids are theactive molecules. Lavender oil inhibits mast cell degranulation and has antimicrobial andantiphlogistic effects (73). Lavender has weak sensitization potential but cross reacts rarely with TTO (13). It isadministered as a liquid extract for tea, infusion, poultice, bath additive, or other topicalformulations (3).Marigold (Calendula officinalis)The flower of this medicinal botanical is approved to treat wounds, burns, and mucosalinflammation. The above ground parts of the Marigold plant are not approved for therapy.This herb is homeopathy for frostbite, burns, and poorly healing wounds. The therapeuticmechanisms include antimicrobial activity to Staphylococcus aureus, Klebsiellapneumoniae, Candida species, and HIV. Acceleration of granulation tissue, angiogenesis,and epithelialization of wounds are additional therapeutic effects. Faradiol is a terpenealcohol extracted from Marigold with anti-inflammatory effect equivalent to indomethacin

Herbs in Cosmeceuticals 345in two animal studies. The major active compounds include polysaccharides such asarabinogalactans which comprise 15% of the extract by weight and triterpene saponinglycosides which comprise 2-10%. Other active compounds include flavonoids such asquercetin glycoside, hydroxycoumarins including scopoletin, volatile oils such as cadinol,and carotinoids including lutein and zeaxanthine. A very low risk of sensitization (0.2%) is the only health hazard. Marigold flower isadministered as a liquid extract, powder, tincture, tea, or decoction for infusion, oil, gel,ointment, solution, and shampoo (3).Oak (Quercus robar)This herb is approved for treatment of cutaneous and mucosal inflammatory disorders dueto its astringent, antiviral, antihelminthic, and antiphlogistic effects. All of the therapeuticactivity resides in the multiple tannins which account for 12–16% of the extract by weight.The catechin tannins include monomeric and dimeric catechins, oligomeric proanthocya-nidin, and leucocyanidins (3). The only health hazard occurs with whole body baths for “widespread open” woundsor dermatitis if the patient has cardiac insufficiency stages III and IV and hypertomiastage IV. Oak is administered as powder or tea as a bath additive (22).Oat (Avena sativa)Oat straw is approved for treatment of cutaneous inflammation, pruritis, varicella andwarts. The oat herb and fruit are not approved for therapy. The active compounds includeoligosaccharides and polysaccharides including beta-glucan, silicic acid, steroid saponinssuch as avencoside, amino acids such as avenic acid, and flavonoids including vitexin,apigenin and tocotrienols. The anti-inflammatory effect results from several of theseactives. Beta-glucan inhibits prostaglandin biosythesis yet stimulates cell-mediatedimmunity which provides antiviral and antitumor functionality. There are no reported health hazards with oat straw. It is administered as decoction,tea, or tincture for bath additive and other topicals (3,22).Peruvian Balsam (Myroxylon balsamum)This resinous herb is from scorched tree trunks while Tolu balsam is a resin from incisedtree trunks of the same plant. Peruvian balsam is approved for treatment of wounds, burns,and hemorrhoids while Tolu balsam treats mucosal inflammation by homeopathy. Balsams treat wounds as an antiseptic and promoting granulation. Peruvian balsamis also antiparasitic especially for scabies due to benzyl benzoate and benzyl cinnomoatewhich combined comprise 50–75% by weight. Resins consisting of cinnamic esterpolymers comprise another 20–30%. Volatile oils such as nerolidol are other activecompound extracted from this herb. There are significant mucocutaneous reactions toboth balsams including allergic contact dermatitis, contact urticaria, oral ulcers, purpura,angioedema, photosensitivity, and phototoxicity. Renal failure with widespread topicaluse has been reported (3,22).Pineapple (Ananas comosus)This foodstuff is also approved for therapy of wounds and burns. The activity is due to amixture of five cysteine proteinases known as bromelain. These enzymes stimulate wound

346 Thornfeldthealing by providing fibrinolytic and proteolytic activity while inhibiting thrombocyteaggregation. Bromolain also has anti-inflammatory and antineoplastic effects. The healthhazards of pineapple consist of contact allergic and irritant reactions. Pineapple extract isadministered as tablets or granules or in compounded topical formulations (3).Poplar (Populus species)Poplar leaf buds, but not the bark, and leaves, are approved to treat wounds, burns, andhemorrhoids due to the antiphlogistic, antibacterial, analgesic, and wound healing effects.The active compounds are primarily salicylic acid glycosides and esters such as salicin andpopulin. Flavonoids including propolis and chrysin, zinc lignans, and the volatile oilcaryophyllene are the other active compounds. This herb is contraindicated in hypersensitivity to salicylates, peruvian balsam, andpropolis. The cutaneous health hazards consist of allergic and irritant contact dermatitis.Poplar leaf buds are administered as topical semisolid extracts (3).Sage (Salvia officinalis)This flavoring and medicinal botanical is approved to treat excessive perspiration, burns,and wounds. Its most frequent use in homeopathy is also for excessive perspiration. Theactive compounds are caffeic acids such as chlorogenic acid, triterpenes including ursolicacid, diterpenes such as carnosolic acid, volatile oils including thujone and camphor andflavonoids such as apigenin- and luteolin-7-glucosides. These active compounds provideastringent, secretolytic, antiperspirant, fungistatic, virostatic, and bactericidal effects. This herb is contraindicated in pregnancy but has no other health hazards. It isadministered via juice, tincture, and distillate for infusion, gargle, rinse, compress, andpoultice (3).Shepherd’s Purse (Capsella bursa-pastoris)This herb is approved for treatment of burns and wounds. It is homeopathy for mucosalbleeding. The active compounds consist of caffeic acids such as chlorogenic acid,flavonoids including rutin, glucosinolates, sinigrin, and cardioactive steroids. Shepherd’spurse is contraindicated in pregnancy and used with caution in widespread cutaneouslesions. It is administered by tea for infusion (3).Sweet Clover (Melilotus officinalis)Hemorrhoids, venous conditions including insufficiency, and blunt injuries are approvedindications for this herb. It has antiphlogistic, anti-exudative, and anti-edematous effectswhile it improves venous reflux, lymphatic kinetics, and wound healing. The activecompounds include free coumarins including melilotol, hydroxycoumarins such asumbelliferone, flavonoids including kaempferol glycosides, triterpene saponins such asmelilotigenin, and volatile oils (3). Oral administration may lead to hepatoxicity. No cutaneous sensitization orirritation has been reported, but red clover (Trifolium pratense) is a mutagen (13). Sweetclover is administered as a comminuted herb for galenic formulation for infusion, poultice,ointment, suppository, and herbal sachet (3).

Herbs in Cosmeceuticals 347Walnut (Juglans regia)This foodstuff is approved for treatment of excessive perspiration and cutaneousinflammation, including abcesses, acne, dermatitis and ulcers. Asian medicine employs itas an antihelminthic and aphrodisiac. The active compounds include tannins such asgalloylglucose, flavonoids such as hyperoside, and the naphthalene juglone whichaccounts for the staining effect. The therapeutic effects with include astringent,antibacterial, antiviral and fungistatic (3). Juglone is mutagenic inducing leukoplakia and tongue carcinoma (3,22). No otherhealth hazards are reported. Walnut is administered by decoction for infusion.White Nettle (Lamium album)Treatment for cutaneous and mucosal inflammation is among the approved indications forthis herb. It is used in Asian medicine to treat carbuncles and inflamed wounds. Whitenettle functions as an astringent and emollient due to the active mucilages, flavonoidsincluding kaempferol glycosides, caffeic acids such as chlorogenic acid, triterpenesaponins, and monoterpenes including lamalbide. There are no reported health hazards. This herb is administered by tea for infusion,bath additive, poultice, compress, and rinse (3).SUMMARYThere are multiple herbs currently incorporated into cosmeceuticals with valid scientificrationale and supported with human clinical studies or have documented biologic activityby in vitro, in vivo, or animal studies. Cosmeceuticals containing these herbs maycurrently be or potentially will be valuable contributions to dermatology and skin care ifclinical efficacy can be confirmed by controlled human clinical trials conducted by third-party researchers with the finished marketed product. The cosmeceutical only hasscientific integrity if the herbal components are stable, of therapeutic concentrations, andcan be adequately delivered across human stratum correum.ACKNOWLEDGMENTSI greatly appreciate the assistance of Sheena Beavers, David Talford PA-C, CharityBurkheimer, and Elisha Andrews in this manuscript.REFERENCES 1. Winston D, Dattner AM. The American system of medicine. In: Parish LC, ed. Complementary medicine: part II. Philadephia, PA: Clinics in Dermatol Elsevier, Inc., 1999:53–56. 2. Yarnell E, Absacal K, Hooper CG. Clinical Botanical Medicine. Larchmont, NY: Mary Ann Liebert, Inc., 2002:223–242. 3. LaGow B. In: Thomson PDR, ed. PDR for Herbal Medicines. 3rd ed. New Jersey: Montvale, 2004. See pages. 9, 36–38, 41–45, 81–83, 88–91, 104, 105, 140, 141, 145, 146, 174–178, 186–188, 254, 267–274, 285–290, 318, 319,328–332, 344–359, 368–387, 408–414, 424, 425, 435, 445–448, 450, 451, 467, 468, 476, 502, 503, 510–519, 545–548, 566–570, 585, 586, 588, 589, 597–602, 604–608, 614–616, 639, 640, 652–654, 689–691, 698–700, 702–705, 707–710, 730, 731, 747–759, 767– 787, 806–808, 817–821, 826–828, 843–846, 861, 862, 867, 868, 874, 875, 887–889. 4. Geveran W, Jr. World Almanac 2005. New York: Holtzbrinck Publishers, 2005; 99.

348 Thornfeldt 5. Fleischer AB, Feldman SR, Rapp SR, et al. Alternative therapies commonly used within a population of patients with psoriasis. Cutis 1996; 58:16–20. 6. Anderson WH. Patient use and assessment of conventional and alternative therapies for HIV infection and AIDS. AIDS 1993; 74:561–564. 7. Koo J, Arain S. Traditional Chinese medicine in dermatology. Clin Dermatol Complement Med 1999; 17:21–27. Part Two. 8. Gaeddert A. Healing Skin Disorders. Berkley, CA: North Atlantic Books, 2003:39. 9. Spraycar M. 26th ed. Stedman’s Medical Dictionary. Baltimore, MD: Williams & Wilkins, 1995. See pages 107, 159, 371, 700, 1133, 1560.10. Spake A. Natural Hazards. U.S. News and World Reports, February, 2002; 21:43–49.11. Auerbach PS. In: Wilderness Medicine. 4th ed., 2001:1170–1173. See also pages. 1177.12. Jancin B. Cross-sensitivity in tea tree oil allergy. Skin and Allergy News, March 2002;38.13. Litt JZ. Litt’s Drug Eruption Reference Manual. London and New York: Taylor & Francis, 2004:430–453.14. Zoler MC. Eight herbal medications pose potenial derm surgery dangers. Skin and Allergy News. April 2003;17–18.15. Food and Drug Administration, Division of Over-The-Counter Drug Products. Skin protectant over the counter final monograph. Fed Regist 2003; 68:333–362. June 4.16. Goldman E. Onion extract a good adjunct to keloid shave. Skin and Allergy News 1999; 30:3.17. Clark LF, Baker B, Trahan C, et al. A prospective double blinded study of Mederma skin care versus placebo for traumatic scar reduction. Cosmet Dermatol 1999; 12:19–26.18. McKeown E. Aloe vera. Cosmet Toilet 1987; 102:64–65.19. Syed TA, Ahmad SA, Holt AH, et al. Management of psoriasis with aloe vera extract in a hydrophilic cream: a placebo controlled double-blind study. Trop Med Int Health 1996; 1:505–509.20. West DP, Zhu YF. Evaluation of aloe vera gel gloves in the treatment of dry skin associated with occupational exposure. Am J Infect Control 2003;40–42.21. Mumcuoglu KY, Miller J, Zamir C. The in vivo pediculicidal efficacy of a natural remedy. Isr Med Assoc J 2002; 4:790–793.22. Jellin JM, Gregory P, Batz F, et al. 8th ed. Pharmacist’s Letter/Prescriber’s Letter. Natural Medicines Comprehensive Database. Stockton, CA: Therapeutic Research Facility, 2000. See pages. 25, 54, 63, 76, 93, 165, 170, 520, 522, 620–627, 634–690, 684, 685, 719, 736, 737, 797, 798, 806–808, 891, 892, 915, 930–932, 947, 948, 972, 973, 987, 988, 1015–1017, 1039, 1040, 1042, 1112, 1113, 1155–1161, 1165, 1166, 1219, 1220.23. Ramadan W, Mourad B, Ibrahim S, Sonbol F. Oil of bitter orange: new topical antifungal agent. Int J Dermatol 1996; 35:448–449.24. Giron LM, Aguilar GA, Caccres A, Arroyo GL. Anticandidal activity of plants used for the treatment of vaginitis in Guatemala and clinical trial of a Solanum nigrum preparatlon. J Ethnopharmacol 1998; 22:307–313.25. Lozoya X, Navarro V, Garcia M, Zurita M. Solanum chrysotichum (Schldl.) a plant used in Mexico for the treatment of skin mycosis. J Ethnopharmacol 1992; 36:127–132.26. Kalus U, Pruss A, Bystron J, et al. Effect of Nigella sativa (black seed) on subjective feeling in patients with allergic diseases. Phytother Res 2003; 17:1209–1214.27. Bernstein JE, Parish LC, Rappaport M, et al. Effects of topically applied capsaicin on moderate and severe psoriasis. J Am Acad Dermatol 1986; 15:504–507.28. Ellis CN, Berberian B, Sulica VI, et al. A double blind evaluation of topical capsaicin in pruritic psoriasis. J Am Acad Dermatol 1993; 29:438–442.29. Bedi MK, Shenefelt PD. Herbal therapy in dermatology. Arch Dermatol 2002; 138:232–242.30. Huang WF, Wen KC, Hsiao ML. Adulteration by synthetic therapeutic substances of traditional Chinese medicines in Taiwan. J Clin Pharmacol 1997; 37:344–350.31. Heinerman J. Healing Herbs and Spices. Paramus, NJ: Prentice Hall, 1996;350.32. Bauza E, Dal Farra C, Berghi A, et al. Date palm kernel extract exhibits anti-aging properties and significantly reduces skin wrinkles. Int J Tissue React 2002; 24:131–136.

Herbs in Cosmeceuticals 34933. Vonau B, Chard S, Mandalia S, et al. Does the extract of the plant Echinacea purpurea influence the clinical course of recurrent genital herpes? Int J STD & AIDS 2001; 12:154–158.34. Ledezma E, DeSousa L, Jorquera A. Efficacy of ajoene, an organo sulfer derived from garlic, in the short term therapy of tinea pedis. Mycoses 1996; 39:393–396.35. Baumann LS. Cosmeceutical critique: chamomile. Skin and Allergy News, July 2003;43.36. Kim SJ, Lim MH, Chun IK, Won YH. Effects of flavonoids of Ginkgo biloba on proliferation of human skin fibroblast. Skin Pharmacol 1997; 10:200–205.37. Joyeux M, Lobstein A, Anton R, Mortier F. Comparative antilipoperoxidant, antinecrotic and scavenging properties of terpenes and biflavones from Ginkgo and some flavonoids. Plant Med 1995; 61:126–129.38. Muir A, Robb R, McLaren M, et al. The use of Ginko biloba in Raynaud’s disease: a double blind placebo controlled trial. Vasc Med 2002; 7:265–267.39. Parsad D, Pandhi R, Juneja A. Effectiveness of oral Ginko biloba in treating limited, slowly spreading vitiligo. Clin Exp Dermatol 2003; 28:285–287.40. Baumann LS. Cosmeceutical critique: grape seed extract. Skin Allergy News 2003;26.41. Baumann LS. Cosmeceutical critique: pycnogenol. Skin Allergy News 2004;36.42. Pittler MH, Ernst E. Horse chestnut seed extract for chronic venous insufficiency. Arch Dermatol 1998; 143:1356–1360.43. Wobling RH, Leonhardt K. Local therapy of herpes simplex with dried extract of melissa officinalis. Phyto Med 1994; 1:25–31.44. Katiyar SK, Korman NJ, Mukhtar H, Agarwal R. Protective effects of silymarin against photocarcinogenesis in a mouse skin model. J Natl Cancer Inst 1997; 89:556–566.45. Chatterjee L, Agarwal R, Mukhtar H. Ultraviolet B radiation induced DNA lesions in mouse epidermis: an assessment using a novel 32P-postlabeling technique. Biochem Biophys Res Commun 1996; 229:590–595.46. Singh RF, Agarwal R. Flavonoid antioxidant silymarin and skin cancer. Antioxid Redox Signal 2002; 4:655–663.47. Sharquie KE, AL-Obaidi HK. Onion juice (Allium cepa), a new topical treatment for alopecia areata. J Dermatol 2002; 29:343–346.48. Wiesenauer M, Ly¨dtke R. Mahonia aquifolium patients with Psoriasis vulgaris— an intraindividual study. PhytoMed 1996; 3:231–235.49. Gieler U, Von der Weth A, Heger M. Mahonia aquifolium— a new type of topical treatment for psoriasis. Dermatol Treat 1995; 6:31–34.50. Murad H, Shellow VRW. Pomegranate extract both orally ingested and topically applied to augment the SPF of sunscreens. Cosmet Dermatol 2001; 14:43–45.51. Wiseman H, O’Reilly JD, Adlercreutz H. Isoflavone phytoestrogens consumed in soy decrease F-2-isoprostance concentrations and increases resistance of low-density lipoprotein to oxidation in humans. Am J Clin Nutr 2000; 72:395–400.52. Wei H, Spencer JM, Gelfand J, et al. The isoflavone genistein: a new agent in dermatology. Cosmet Dermatol 2001; 2:13–19.53. Schempp CM, Windeck T, Hezel S, Simon JO. Topical treatment of atopic dermatitis with St. John’s wort cream—a randomized, placebo controlled, double blind half-side comparison. Phytomedicine 2003; 10:31–37.54. Walton SF, McKinnon M, Pizzutto S. Acaricidal activity melaleuca alternifolia (tea tree oil). Arch Dermatol 2004; 140:563–566.55. Baumann LS. Cosmeceutical critique: tea tree oil. Skin and Allergy News, November 2002; 14.56. Blake J. Tea for you. Life Section. Vol. 1. Boise, ID: The Idaho Statesman, 2004 pages 4 (February 22).57. Spencer JM. Chemoprevention of skin cancer and photoaging. Cosmetic Dermatol 2001; 14:25–28.58. Katiyar SK, Elmets CA, Argarwal R, et al. Protection against ultraviolet-B radiation-induced local and systemic suppression of contact hypersensitivity and edema responses in C3H/HeN mice by green tea polyphenols. Photochem Photobiol 1995; 62:855–861.

350 Thornfeldt59. Elmets C, Singh D, Tubesing K, et al. Cutaneous photoprotection from ultraviolet injury by green tea polyphenols. J Am Acad Dermatol 2001; 44:425–432.60. Zhao F, Zhang YJ, Jinx H, et al. Green tea protects against psoralen plus ultraviolet A induced photochemical damage to skin. J Invest Dermatol 1999; 113:1070–1075.61. Zhao J, Jinx, Yaping E, et al. Photoprotection effect of black tea extracts against UVB induced phototoxicity in skin. Photochem Photobiol 1999; 70:637–644.62. Uehara M, Sugiuru H, Sakurai K. A trial of oolong tea in management of recalcitrant atopic dermatitis. Arch Dermatol 2001; 137:42–44.63. Linden KG, Carpenter PM, McLaren CE, et al. Chemoprevention of non melanoma skin cancer: experience with a polyphenol from green tea. Recent Results Cancer Res 2003; 163:165–171.64. Hey IC, Jamieson M, Ormerod AD. Randomized trial of aromatotherapy. Arch Dermatol 1998; 134:1349–1352.65. Korting HC, Schafer-Kerting M, Hart H, et al. Anti-Inflammatory activity of hamamelis distillate applied topically to the skin. Br J Clin Pharmacol 1993; 44:315–318.66. Brown DJ, Dattner AM. Phytotherapeutic approaches to common dermatologic conditions. Arch Dermatol 1998; 1:15–17.67. Kamikeura A, Takahashi T. Procyanidin B-2 extracted from apples, promote hair growth, a laboratory study. Br J Dermatol 2002; 146:41–51.68. Tesoriere L, Butera D, Pintaudi AM, et al. Supplementation with cactus pear (Opuntia ficus- indica) fruit decreases oxidative stress in healthy humans: a comparative study with vitamin C. Am J Clin Nutr Aug 2004; 80:391–395.69. Li Y, Metori K, Koike K, et al. Improvement in turnover rate of stratum cerneum in false aged model rates by the administration of geniposidic acid in Eucommoia Ulmoides Oliver leaf. Biol Pharm Bull 1999; 22:582–585.70. Aburjai T, Natsheh FM. Plants used in cosmetics. Phytother Res 2003; 17:987–1000.71. Baumann LS. Cosmeceutical critique: olive oil. Skin and Allergy News, August 2004;38.72. Saleem M, Alam A, Sultana S. Attenuation of benzoyl peroxide mediated cutaneous oxidative stress and hyperproliferative response in the prophylactic treatment of mice with spearmint (Mentha spicata). Food Chem Toxicol 2000; 38:939–948.73. Baumann LS. Cosmeceutical critique. Lavender Skin and Allergy News, September 2003;33.

20Topical Anti-inflammatoriesBryan B. Fuller and Dustin R. SmithDepartment of Biochemistry and Molecular Biology, University of OklahomaHealth Sciences Center, Oklahoma City, Oklahoma, U.S.A.INTRODUCTIONInflammatory skin diseases are extremely common dermatological problems that presentin a variety of forms, from occasional rashes accompanied by skin itching and redness tomore chronic conditions such as atopic dermatitis, rosacea, seborrheic dermatitis, andpsoriasis. Combined, these conditions affect over 35 million Americans who annuallyspend over $2 billion to treat their symptoms. This chapter will provide an overview of theinflammation process, review current drug, over-the-counter (OTC), and cosmetic topicaltreatments for several inflammatory diseases, discuss research approaches that can be usedto identify new anti-inflammatory compounds to treat various aspects of inflammation,and finally, provide an overview of how topical formulations containing novel anti-inflammatory compounds can be developed and characterized.BIOLOGY OF SKIN INFLAMMATIONSkin inflammation, which is characterized by redness, swelling, heat, itching, and pain,can exist in either an acute or chronic form with acute disease frequently progressing toa more chronic condition. Acute inflammation can result from exposure to UV radiation(UVR), ionizing radiation, allergens, or to contact with chemical irritants (soaps, hair dyes,etc.). Assuming that the triggering stimulus is eliminated, this type of inflammationis typically resolved within one to two weeks with little accompanying tissue destruction.A chronic inflammatory condition, however, can last a lifetime, and cause considerabledamage to the skin. Some of the cellular and biochemical events which occur in the skinin response to a triggering stimuli (e.g., UVR, chemical, or antigen) and which lead toan inflammatory response are shown in Figure 1. Within minutes of exposure of skin to aninsult there is a rapid release of inflammatory mediators from keratinocytes and fibroblastsand from afferent neurons. In response to a triggering stimulus, keratinocytes producea number of inflammatory mediators including PGE-2 and TNF-alpha as well as thecytokines, IL-1, IL-6, and IL-8. Dermal fibroblasts also respond to the insult and to IL-1produced by keratinocytes by increasing production and secretion of cytokines includingIL-1, IL-6, IL-8 as well as PGE-2. One of the principal actions of PGE-2 produced andsecreted by both keratinocytes and fibroblasts is to increase vasodilation and vascular 351

352 Fuller and SmithFigure 1 Diagram of cellular events which occur during a cutaneous inflammatory response.permeability. In addition, PGE-2 aids in the degranulation of mast cells and increases thesensitivity of afferent neuronal endings. The increased sensitivity of nerve endings byprostaglandins and cytokines results in the release of neuropeptides, including substanceP and calcitonin gene related peptide (CGRP) (1). Neuron depolarization also increasesresulting in the sensation of pain. Substance P and CGRP released by neurons, along withPGE-2, cause degranulation and release of histamine from mast cells, and they alsostimulate the cell to produce a variety of inflammatory cytokines. If IgE is bound to itsreceptor on mast cells, exposure of skin to an IgE specific antigen can also trigger thedegranulation and activation of the mast cell (2,3). Increased vasodilation and vascularpermeability by PGE-2 and histamine leads to increased blood flow and extravasation offluid from blood vessels. This causes visible redness and swelling in the inflamed area.The increased production of inflammatory mediators by keratinocytes and fibroblasts,particularly TNF-alpha and IL-1, leads to the expression of intracellular adhesionmolecules, such as VCAM and ICAM, on endothelial cells of the blood vessels (4).These proteins, as well as P and E selectin, serve as anchoring elements for monocytes andneutrophils passing through the blood. The attachment of these leukocytes to the adhesionmolecules slows their movement through the bloodstream and finally causes their firmadhesion to the endothelial wall (5). In the presence of chemokines, particularly IL-8produced and released by both keratinocytes and fibroblasts, the adherent leukocytesundergo chemotaxis and migrate from the blood vessel out into the skin where they act toscavenge the area of debris and also produce additional inflammatory mediators.The initial acute response occurs within minutes of the insult to the skin and involves theproduction of inflammatory mediators, the degranulation of mast cells, and thevasodilation of blood vessels (6). The subsequent movement of neutrophils andmonocytes into the “wounded” area typically takes up to 48 hours to occur. If thetriggering stimulus is eliminated, inflammatory mediator production by keratinocytes,

Topical Anti-inflammatories 353fibroblasts, and mast cells ceases, the influx of leukocytes to the “wounded” area decreasesand inflammation subsides. In contrast to acute inflammation which typically resolves in one to two weeks, chronicinflammation results from a sustained immune cell mediated inflammatory response withinthe skin itself and is long-lasting. Antigen presenting cells (APCs) in the skin, calledLangerhans cells in the epidermis and dendritic cells (DCs) in the dermis, can be activated byinnate mechanisms and by exposure to the inflammatory cytokines, IL-1 and TNF-alpha,produced by fibroblasts and keratinocytes in response to a triggering stimulus. The activatedAPCs bind to and transport skin antigens (allergens) through the lymphatics during whichtime they undergo a maturation process. This maturation step allows the APCs to efficientlypresent the antigen to T-lymphocytes. This presentation, in turn, triggers the maturation ofa specific subset of na¨ıve T-lymphocytes into memory cells and the activation of residentantigen specific T-lymphocytes. The skin-homing T-lymphocytes, which express a cellsurface epitope, termed cutaneous lymphocyte antigen (CLA), migrate to the involved area ofskin, and adhere to endothelial cell walls initially through an interaction between the CLAexpressed on the surface of the T-lymphocyte and E-selectin expressed on endothelial cells(7). Other specific receptors on T-lymphocytes, which aid in the binding and chemotaxis ofthese cells into the skin, include CCR4 and LFA1 (8). Once T-lymphocyes have migrated intothe skin from the circulation, they not only undergo proliferation, but also produce and secretea wide range of inflammatory mediators as well as matrix-eroding enzymes, such as matrixmetalloproteinase-1 (MMP-1; collagenase). Cytokines produced by T-lymphocytes canstimulate fibroblasts and keratinocytes to produce additional cytokines and chemokines, andcan also induce the expression of a variety of tissue-destructive enzymes by fibroblasts,including MMP-1 (collagen), MMP-3 (stomelysin-1) and MMP-9 (gelatinase B). As long asthe antigen or insult stimulus persists in the skin, the inflammatory response will continue,resulting in significant and serious tissue destruction (9). Inflammatory processes in the skin, particularly those triggered by long-termexposure to solar radiation, not only cause the more obvious symptoms of redness, swelling,and itching, but also trigger molecular pathways that escalate the aging process. Actinicaging, or photoaging, that occurs following prolonged exposure of the skin to ultraviolet(UV) light from the sun results in increased cytokine production with attendant activation ofgenes in both keratinocytes and fibroblasts that cause erosion of the normal skin structure.Matrix metalloproteinases (MMPs), which break down the skin extracellular matrix causingsagging and wrinkling, are stimulated in sun-exposed skin. Furthermore, dermal fibroblastsynthesis and assembly of collagen, which is required to maintain and restore theextracellular matrix, is inhibited while elastin production is over- stimulated, leading toelastosis. It is now widely accepted that sun-exposed skin in most individuals remains ina constant state of low level UV-induced inflammation, and that this “smoldering”inflammation is responsible for the signs of skin aging that appear in middle age (10–12).PRESCRIPTION AND OVER-THE-COUNTER TREATMENTSFOR INFLAMMATION AND MECHANISM OF ACTIONSteroidsGiven the complexity of the inflammatory process in skin, developing topical products thatcan effectively resolve the myriad of inflammatory disease states that exist is challenging.By far the most effective and commonly used prescription drugs for treating inflammationare the corticosteroids, particularly the glucocorticoid related steroids. They are very

354 Fuller and Smitheffective for many forms of eczema, including atopic dermatitis, allergic contactdermatitis, seborrheic dermatitis (in concert with an anti-fungal agent), and have someutility in ameliorating the symptoms of psoriasis. They are not particularly effective,however, in treating acute inflammation, like UVR-induced sunburn, which is notprimarily an immune cell driven inflammatory response. Corticosteroids can be usedtopically or orally. Topical corticosteroids have been classified into groups based onpotency. For example, the corticosteroid clobetasol proprionate is ranked as a very potentsteroid, while betametasone diproprionate and fluocinolone acetonide can range frompotent to moderately potent. OTC topicals containing hydrocortisone are, of course, theleast potent (13). Although newer methods are being studied, topical steroid potency is stilldetermined using the MacKenzie vasoconstrictor assay established over 40 years ago.In this assay, a topical steroid is applied to the forearm and the extent and duration of skinblanching due to vasoconstriction assessed by visual examination and rated on a scale of 0(normal skin, no blanching) to 4 (intense blanching). Although subject to variability, theassay has proved to be a reliable estimate of corticosteroid potency (14). Given the efficacy of corticosteroids in treating many different types of skininflammation as well as efficacy in treating autoimmune-based inflammatory diseases suchas rheumatoid arthritis, asthma, lupus erythematosus, and allergic rhinitis, considerableresearch has been directed toward understanding their mechanism of action. Corticosteroids act on target cells by binding to the glucocorticoid receptor presentprimarily in the cytosol. This binding “activates” the receptor, resulting in its translocationto the nucleus. The steroid hormone receptor complex then binds, as a homodimer, to DNAregulatory elements along the promoter regions of specific genes. This binding usuallyresults in the up-regulation of gene activity but can also cause transcriptional repression ofthe target gene (15). The effectiveness of corticosteroids as inhibitors of inflammationstems from the ability of the steroid activated glucocorticoid receptor complex to interferewith the activation of genes regulated, principally, by two transcription factors, NF-kappaB and AP-1 (16,17). These two transcription factors are primarily responsible for thetranscriptional activation of a wide variety of pro-inflammatory genes including those forcytokines IL-1, IL-2, IL-3, IL-4, IL-6, IL-11, IL-12, and IL-13, TNF-alpha, and GM-CSF,the chemokine genes IL-8, RANTES, MCP-1, the adhesion molecules ICAM-1, VCAM-1,and E-selectin, the rate-limiting enzyme for PGE-2 production, COX-2, and the matrix-metalloproteinase genes, including MMP-1 (18). A diagram showing the signaling pathway in cells that leads to the activation of eitherNF-kappa B or AP-1 and, thus, to the activation of inflammatory genes is shown in Figure 2.Briefly, when a surface receptor on a target cell binds a specific ligand, such as a hormone orcytokine, the receptor is “activated” and this in turn leads to the activation of a signalcascade within the cell. The signaling pathway involves a variety of kinases which aresequentially activated. In the case of the NF-kappa B activation pathway, one of thesekinases, IKK, when activated, phosphorylates the protein IkB. This protein, in itsunphosphorylated state, binds to NF-kappa B in the cytosol and prevents NF-kappa B fromtranslocating to the nucleus and activating target genes. When IkB is phosphorylated byIKK, it dissociates from NF-kappa B and is degraded. Once freed from the IKB, NF-kappa Bcan translocate to the nucleus where it binds to the promoter region of specific genes andactivates them (19). As mentioned above, while many inflammatory genes are activated by NF-kappa B,others are regulated by the transcription factor AP-1. This transcription factor is a dimerconsisting of either a Jun-Fos heterodimer or a Jun-Jun homodimer. For most cytokinegenes, only the Jun-Fos heterodimer functions as a transcriptional activator. As is shown inFigure 2, binding of a ligand such as IL-1 or TNF-alpha to its receptor activates a signaling

Topical Anti-inflammatories 355 IL-1 R/TLR4 IL-1 or Plasma membrane IRAK LPS IL-1 RAcp/CD14 MyD88 NIK MEKK 1 IKK MEKK 3/6 IKβ NF-κB JNK p38 Proteolytic AP-1Degradation NF-κB MMP-1 IL-8 TNF-α IL-12 Induced MCP-1 Inhibited IL-6 COX-2 CollagenFigure 2 Intracellular signaling cascade leading to the activation of inflammatory genes.cascade that involves sequential activation of a variety of kinases, some of which aremembers of the MAP kinase family. Either one of two members of this family, JNK (c-JunN-terminal kinase) or p38 map kinase, when activated by this signaling cascade,phosphorylates, and activates c-Jun and this forms a dimer with the Fos protein to form thefunctional transcription factor. The Jun-Fos heterodimer will only form if Jun is firstphosphoryated by JNK. The Jun-Fos heterodimer forms the AP-1 complex that activatesinflammatory target genes (16). While some genes are regulated only by either NF-kappa B or AP-1 otherinflammatory genes have both an NF-kappa B and AP-1 binding site in their promoterregions and, thus can be regulated by either or both transcription factors. Recent datasuggests that the control of gene activity by either AP-1 or NF-kappa B depends on boththe placement of the transcription factor binding site along the promoter region of the geneand on the level of expression of the transcription factor. To some extent the transcriptionfactor binding site that is closest to the start of transcription plays a predominant role inregulating the activity of the gene. Thus, for example, the MCP-1 gene is stronglyregulated by the AP-1 site that lies close to the transcription start site even though there arethree NF-kappa B binding sites in the promoter of this gene. Examples of the placement ofNF-kappa B and AP-1 transcription factor binding sites in the promoter regions of someinflammatory genes are shown in Figure 3. As mentioned above, the anti-inflammatory activity of corticosteroids comes fromtheir ability to repress either the activation or activity of the NF-kappa B and AP-1transcription factors thereby suppressing transcription of genes coding for inflammatorymediators. In the case of NF-kappa B, the actual mechanism of action of the glucocorticoidreceptor complex in repressing inflammatory genes activated by this transcription factor isnot well understood, but evidence suggests a couple of likely possibilities. One mechanism

356 Fuller and SmithFigure 3 Diagram of transcriptional elements that regulate the activation of inflammatory genes.involves the steroid activated glucocorticoid receptor up-regulation of the gene codingfor IKB. This produces a cellular excess of this protein which then complexes to andinactivates NF-kappa B, preventing its translocation to the nucleus. Other data suggests that the glucocorticoid receptor does not block the translocationof NF-kappa B but rather inhibits either binding of the transcription factor to its regulatorysite in the promoter region of target genes or alternatively interferes with NF-kappa B’sability to activate the target gene after binding the promoter region (19–22). Regardless ofwhich specific mechanism is correct, the end result of corticosteroid activation of theglucocorticoid receptor is the repression of NF-kappa B activity and a down-regulation ofinflammatory gene activity. In regard to the suppression of the AP-1 stimulation of genes,recent evidence suggests that glucocorticoids block AP-1 phosphorylation and activationby two mechanisms. First, glucocorticoids can suppress AP-1 activity by physicallyinteracting with the Jun component of the dimer, thereby blocking its binding to fos andpreventing the formation of an active complex. Secondly, recent studies show thatglucocorticoids stimulate the transcription of the MAPK phosphatase-1 gene therebyincreasing its abundance in the cell and blocking the phosphorylation of Jun (16). While the glucocorticoids have been shown to be extremely effective in suppressingthe activation of pro-inflammatory genes because of their ability to block NF-kappa B andAP-1 functioning, steroids produce a variety of undesirable side effects. First, due to theirpotent inhibition of genes involved in an immune cell driven inflammatory response,they have an overall immune suppressive effect. Prolonged use of glucocorticoids leads toa reduction in B- and T-lymphocyte populations, and a reduced ability to fight skininfections. Further, steroids adversely affect the ability of dermal fibroblasts to synthesizecollagen and at high doses they reduce the proliferation rate of these cells. Consequently,long-term use of topical steroids can lead to skin thinning and a decrease in the dermalmatrix. Other potential negative side effects caused by prolonged use of steroids include

Topical Anti-inflammatories 357altered carbohydrate metabolism, suppression of the hypothalamic-pituitary-adrenal axis,increased osteoporosis, and increased risk of developing cataracts. Due to the undesirable side effects which limits the length of time steroids can beused to treat inflammatory diseases, non-steroidal topical therapeutics have beendeveloped to treat inflammation. One group of drugs, the non-steroidal anti-inflammatorydrugs (NSAIDs) have been used for many years as oral drugs to control inflammatoryresponses.Non-steroidal Anti-inflammatory Drugs (NSAIDS)The most well-known of all the NSAIDS, aspirin, has been used for over 100 years to controlvarious forms of inflammation and today Americans consume over 80 billion tablets of aspirina year. NSAIDS are available in OTC and prescription forms. Common OTC forms areibuprofen, naproxen, aspirin, and acetaminophen. Those available with a prescription includecelecoxib (Celbrexw), diclofenac (Votarenw), etodolac (Lodinew), indomethacin (Indocidw),ketoprofen (Orudisw) and Rofecoxib (Vioxxw) to name a few. While many topical forms ofNSAIDs including Voltaren Emulgelw, Indocidw (indomethacin), Nidolw (nimesulide),Feldene gelw (piroxicam), Oruvailw (ketoprofen), and Pennsaidw (diclofenac) are available inEurope and elsewhere without prescription, in the U.S. none are available as either OTC orprescription drugs (23). One topical prescription NSAID that has received FDA approval inthe U.S. is Solarezew (diclofenac) which is indicated for the treatment of actinic keratoses(24). Perhaps due the availability of topical NSAIDS in Europe but not in the U.S., a number ofnon-FDA approved topical NSAID products have now emerged for sale without aprescription on various Web sites. These include such products as ProzReliefw (12%ibuprofen) and IbuCream (10% ibuprofen). When one examines the published data on the efficacy of topical NSAIDS in treatingvarious inflammatory symptoms, the results show considerable disparity. A statisticalanalysis of clinical data from a wide number of trials with various topical NSAIDpreparations for treating inflammation associated with arthritis concluded that while relieffrom symptoms was higher in the NSAID group versus the placebo group for the firsttwo weeks, after that time, there was no measurable difference between the two treatmentgroups (25). Many other reports, however, do suggest that topical NSAID treatment forjoint pain provides relief beyond that observed with the placebo group (26,27). A veryrecent clinical study with over 200 patients suffering from knee osteoarthritis found thatthe topical application of diclofenac provided significantly more effective relief from painand stiffness than the vehicle control group (28). In another recent study, the product,Nidolw, which contains 2% of the COX-2 inhibitor, nimesulide, was found to besignificantly more effective than topical diclofenac in reducing the pain of shoulderperiarthritis (29). Considering that few studies have yet to evaluate topical formulationscontaining newer NSAIDs, including the specific COX-2 inhibitors, and considering thatfew topical formulations for NSAIDs have been developed and optimized, there isa considerable amount of research to be carried out to fully assess the efficacy of topicalNSAIDs in treating inflammation (30,31). Certainly, it seems likely that a topicalpreparation of a potent NSAID that delivers adequate levels of an effective COX inhibitorthrough the skin would likely be effective in treating a variety of inflammatory conditionsin which PGE-2 is indicated as a causative factor. Such products would be preferred overthe use of oral dosing because of minimal risk topically applied NSAIDs present forstomach irritation. The mechanism of action of NSAIDs involves the inhibition of prostaglandinproduction, particularly PGE-2. The common target for NSAIDS is the enzyme

358 Fuller and Smithcyclooxygenase (COX), which exists in two forms, COX-1, and COX-2. While most olderversions of NSAIDS including aspirin, ibuprofen, and acetaminophen are not selectiveinhibitors of any particular form of COX, newer drugs have been designed to targetprimarily COX-2. The effort to design COX-2 specific inhibitors stems from findingsthat COX-1 plays a protective role in preserving the stomach lining, and thus, NSAIDs thattarget both COX-1 and COX-2 can erode the stomach lining and cause ulcer formation whentaken orally (32,33). This deleterious side effect would however, likely be significantlyreduced with topically applied NSAIDS. If so, COX inhibitors, whether specific for COX-2or not, could be used with equal effectiveness in treating symptoms of inflammation. Perhaps one of the most obvious and effective uses of a topical NSAID would be totreat the symptoms associated with sunburn. This type of inflammation is primarily drivenby the UVR-induced production of PGE-2, which, as mentioned above, causesvasodilation, enhances sensitivity of nerve endings, causes histamine release from mastcells, and stimulates the production of additional inflammatory mediators in fibroblasts.By blocking or reducing the UVR-induced production of PGE-2 from keratinocytes andfibroblasts it should be possible to minimize the onset and progression of a sunburn.Thus, it seems likely that the topical use of a COX inhibitor might be able to not only slowthe progression of a sunburn but decrease the magnitude of the UVR induced erythema.At present in the U.S. there are no topical prescription or OTC drugs that either effectivelyprevent the onset of sunburn (other than sunscreens that simply block UVR at the skin’ssurface) or eliminate existing erythema resulting from a sunburn. Topical steroids havebeen shown to reduce the onset of erythema resulting from a minimal erythema dose(MED) of 2 but are ineffective at higher MED values (34). Further, they cannot reverseexisting UVR-induced erythema. Studies with topical NSAIDs have shown that these are effective in both retardingthe onset of UVR-induced erythema and decreasing the magnitude of the sunburnresponse. Topical indomethacin (1%) if administered immediately after sun exposureis more effective than steroids, being able to block the onset of sunburn produced bya 6 MED dose of UVB radiation (34). Further, topical application of the COX-2 inhibitor,celecoxib, after UVB irradiation of skin reduced erythema, edema, PGE-2 levels, thenumber of sunburn cells, and dermal infiltration of neutrophils (35). The topical NSAID,diflofenac (branded Solarezew), which is approved for use in the U.S. to treat actinickeratoses, has been shown to reduce sunburn symptoms when applied within four hours ofthe initial onset of sunburn (36). It is quite likely that other NSAIDS would be similarlyeffective in reducing the intensity of a sunburn if applied topically, and may also show thesame efficacy as topical diclofenac in treating actinic keratoses. Interestingly, severalstudies implicate PGE-2 as a causative factor in skin cancer, and results from mouseexperiments show that topical application of a PGE-2 inhibitor lowers the UVB-inducednumber of papillomas detectable 12 weeks after UVB dosing (37–40).ImmunomodulatorsA newer type of NSAIDS is represented by the immunomodulators. Two anti-inflammatory drugs that have received FDA approval for topical use are theimmunomodulators, Tacrolimus and the related drug Pimecrolimus. These drugs, alongwith cyclosporine, which exerts its effects through the same mechanism of action, hadtheir origin as immunosuppressive agents used to prevent organ rejection after transplantsurgery (41). Although cyclosporine has been used fairly successfully for years as an oraltherapeutic for psoriasis, attempts to show that a topical formulation of it is efficacious forthis disease have been unsuccessful. Both Pimecrolimus and Tacrolimus have been

Topical Anti-inflammatories 359approved for topical use in treating atopic dermatitis, but not for psoriasis. However,clinical studies show that systemically delivered Tacrolimus, like cyclosporine, is aneffective therapeutic for psoriasis. As is the case with the glucocorticoids,the immunomodulators inhibit the production of inflammatory mediators but unlike thecorticosteroids, both Tacrolimus and Pimecrolimus are more cell specific in that theytarget primarily mast cells and T-lymphocytes. The drugs have fewer inhibitory effects onLangerhans cells/DC, fibroblasts, and keratinocytes (42). Thus, the skin thinningcomplications seen with topical corticosteroids are eliminated (43,44). Tacrolimus, Pimecrolimus, and cyclosporine all repress inflammatory genes in targetcells through a common mechanism that involves the repression of activity of a ubiquitouscalcium-activated phosphatase, calcineurin, that is involved in the activation of specificinflammatory genes (45). When specific receptors on T-cells bind to an antigen, thisbinding activates the receptor causing an increase in intracellular calcium. The increasedcalcium causes the activation of calmodulin which then binds to the calcium-dependentenzyme calcineurin and activates it. The activated calcineurin enzyme is a phosphatase,which can dephosphorylate the cytosolic subunit of a transcription factor, nuclear factor ofactivated T-cells, cytosol (NFATc). The dephosphorylation of the cytosolic NFAT subunitallows it to translocate to the nucleus where it forms a complex with the nuclear subunit ofNFAT (NFATn) whose synthesis was induced by the signaling cascade initiated by theantigen binding to the T-cell surface receptor. Once the NFAT dimer has formed in thenucleus, it can bind to the promoter region of several inflammatory genes including thosefor IL-2, IL-3, IL-4, and TNF-alpha (46,47). A diagrammatic representation of calcineurinactivation is shown in Figure 4. When the drugs Tacrolimus, pimecrolimus, or cyclosporine enter the cell they bindto a cytosol protein, either FKBP for Tacrolimus or Pimecrolimus or Cyclophilinfor cyclosporine. Once formed, this complex is able to bind to and inactivate calcineurin.Figure 4 Diagram of calcineurin and NFAT activation.

360 Fuller and SmithThe now inactive calcineurin can no longer dephosphorylate NFATc, which results in thetranscription factor remaining unactivated and in the cytosol. Thus, the NFATn protein inthe nucleus has no binding partner and cannot bind to and activate inflammatory genes (46).One of the genes in T-cells that is inhibited by Tacrolimus is the IL-2 gene, which isnecessary for full T-cell activation. Thus, in the presence of these immunomodulators,T-lymphocytes do not differentiate in response to antigen stmulation. In addition to theirinhibitory effect on inflammatory gene regulation, these immunomodulators inhibit thedegranulation of mast cells, a property which may help explain their efficacy in treatingsome of the symptoms of atopic dermatitis. While Tacrolimus and other calcineurin inhibitors are much more specific thancorticosteroids in terms of the types of cells they act on, they still inhibit a wide varietyof inflammatory genes by inactivating calcineurin and blocking NFAT activation.Another class of immunomodulators, called biologic response modifiers (BRM) or simply“biologics” because they are made from living organisms, have been developed over thepast five years (48–50). These are essentially “designer” drugs because they target a specificevent or mediator involved in inflammation. Anti-inflammatory drugs in this categoryinclude the TNF-alpha inhibitors, Enbrel (etanercept), Remicade (infliximab), and Humira(adalimumab) (51–53). Of these Enbrel has received FDA approval for psorasiatic arthritisand more recently for severe psoriasis. Remicade and Humira have been approved forarthritis and approval for psoriasis is pending. Enbrel is a fusion protein containing theextracellular TNF-alpha binding region of the TNF-alpha receptor.It is injected twice aweek by the patient at home. Remicade is a humanized monoclonal antibody to TNF-alphaand is injected intravenously. A second and third dose at two weeks and six weeks afterinitial dosing is recommended for arthritis (54). Humira is another anti-TNF monoclonalantibody designed to bind TNF-alpha, thereby preventing its attachment to and activation oftarget cells. Humira is injected every other week by the patient at home. In addition to the TNF-alpha blockers other BRM drugs that suppress immuneresponses through different mechanisms have been approved for use in treating variousforms of inflammation (55). Two of these, Raptiva (Efalizumab) and Amevive (Alefacept)have been approved as injectables for treating arthritis. Amevive, the first FDA approveddrug for psoriasis, is a dimeric fusion protein containing the CD-2 binding site of theleukocyte antigen, LFA-3. When injected (once a week) Amevive binds to the CD2binding site on T-lymphocytes thereby preventing binding between the LFA-3 antigenpresent on APC and the CD2 binding site on T-lymphocytes. Thus, the lymphocytes arenot activated by antigen presentation. Another “humanized,” “biologic” therapeutic whichis injected weekly is the monoclonal antibody, called Raptiva, which binds to CD11a,which is part of the LFA-1 protein expressed on leukocytes. By occupying this binding siteRaptiva prevents the leukocytes from binding an adhesion molecule, ICAM, which ispresent on endothelial cells. By preventing the adhesion of T-lymphocytes to the bloodvessel wall, Raptiva prevents the activation of T-lymphocytes as well as their movementinto the skin, thereby reducing the level of T-cell mediated inflammation. CD11a is alsoexpressed on the surface of B-lymphocytes, monocytes, neutrophils, natural killer cells,and other leukocytes. Thus, Raptiva has the potential to down-regulate responses by otherimmune cells further reducing inflammatory responses (52). These new protein-based “biologic” immunomodulators, although effective anduseful for treating various dermatological conditions, are, however, not without sideeffects. Because of their potent immunosuppressive effects, particularly on T-lymphocytes,the risk of infection among patients taking these medications is elevated (56–58). Enbrel,for example, has been found, in post-marketing use, to cause serious infections, sepsis, andeven fatalities in patients predisposed to infections, and this warning is now included with

Topical Anti-inflammatories 361the drug information. Further, as is the case with all of protein-based biological responsemodifier drugs, none are capable of being delivered topically because of their size. Given the myriad of immune driven events which occur in skin in response to exposureto antigens or other external stimuli, it is easy to see why immunomodulators and biologics areeffective in treating inflammatory diseases such as atopic dermatitis and psoriasis. In the caseof Tacrolimus and Pimecrolimus, by blocking the calcineurin pathway, these drugs cansuppress the activity of the TNF-alpha and IL-2 genes in T-lymphocytes, thus preventing theactivation of these lymphocytes as well as preventing their binding to adhesion proteins alongthe endothelium. Further, recent studies have shown that the calcineruin/NFAT pathway isactive in epidermal keratinocytes and inhibited by either cyclosporine or Tacrolimus (47).Since keratinocytes produce a variety of inflammatory mediators such as IL-1 and TNF-alphawhich, in turn, exert effects on a number of cells including fibroblasts (up-regulate PGE-2,cytokines), mast cells (degranulation) and endothelial cells (increased expression of adhesionmoledule, ICAM, and VCAM, an inhibitory effect on IL-1 and TNF-alpha production wouldslow the production of inflammatory mediators and suppress the movement of immune cellsinto the skin. Similarly, the BRMs can be expected to be effective treatments for atopicdermatitis, and psoriasis based on their designed function of either blocking TNF-alpha actionor T-lymphocyte activation. However, as mentioned these drugs can only be used by injectionand not applied topically.Other Anti-inflammatory OTC and Prescription DrugsThere are a large number of FDA approved topical drugs that are useful for treating varioustypes of inflammatory dermatological conditions but which are not steroids, NSAIDs, orimmunomodulators. One well-known example of this class is the antibacterial/anti-protozoal drug, metronidazole, which is used to treat rosacea, a skin disease that affects 14million Americans (59,60). Rosacea is sometimes characterized mistakenly as adult-acnebecause patients present with a reddened face and acne-like symptoms. Individuals with thisdisease experience redness, pain, and itching on the face, chest, back, and as the diseaseprogresses small blood vessels and small papules appear. Severe rosacea involves the oculararea and causes disfigurement to the nose, termed, rhinophyma. The causes of rosacea arenot known, although there appears to be some genetic predisposition for the disease.Metronidazole (sold under the trade name Metrogelw) has been shown to be effective inalleviating some of these symptoms and, although the mechanism of action is unknown,efficacy is not thought to be related solely to its antimicrobial activity. Rosacea is alsotreated with the oral antibiotic tetracycline, but again, the mechanism of action is not known.Other topical non-steroidal, non-NSAID treatments for rosacea include azaleic acid,sodium sulfacetamide, and Accutane (61). While somewhat effective none of these productsresolve all of the redness and other symptoms of rosacea. Other non-steroidal, non-NSAID topical products used to treat inflammatoryconditions such as eczema, psoriasis, and seborrheic dermatitis include coal tar, tazarotene(a retinoid derivative), anthralin, and even the simple OTC keratolyic compound, salicylicacid. However, for most inflammatory conditions the most effective treatments are stillthe corticosteroids, the immune modulators and recently the “biologics.”ANTI-INFLAMMATORY COSMECEUTICAL “ACTIVES”The demand for effective non-prescription topical products to treat inflammatory diseasessuch as eczema, atopic dermatitis, seborrheic dermatitis, and even psoriasis has led to the

362 Fuller and Smithintroduction of products based on either novel synthetic chemicals or on botanical“actives” which claim to be effective anti-inflammatory compounds. Some of the manypurported botanical anti-inflammatory “active” ingredients in cosmeceutical productsinclude bee pollen, curry extract, calendula extract, chamomile, jewelweed, green teaextract, geranium essential oil, aloe, bilberry, tea tree oil, lavender essential oil, boswellia,and willow bark, to mention only a few. Given the abundance of botanicals which claimanti-inflammatory activity, is there any scientific evidence to suggest that any actuallyhave inhibitory effects on the production or action of inflammatory mediators in the skin?The answer is yes for a few botanically derived ingredients. Clearly the botanicallyderived substance most widely studied for its anti-inflammatory activity is curcumin, theactive ingredient in turmeric, the root used in curry dishes. A large number of scientificstudies published in peer-reviewed scientific journals over the past 5–10 years have shownremarkable and potent anti-inflammatory activities of curcumin (62). In fact, givencurcumin’s broad inhibitory effects on the production of inflammatory mediators bya wide number of cell types including immune cells, the compound could be classified asan immune suppressor or at the very least an immune modulator. Curcumin is effective inblocking both AP-1 and NF-kappa B driven inflammatory genes including COX-2, IL-8,IL-1, IL-12, and TNF-alpha (63). An example of the potency of curcumin in blocking IL-1induced inflammatory gene expression in human fibroblasts is shown in Figure 5. Note thatcurcumin at concentrations below 10 mM can suppress the IL-1 induced increase in PGE-2and IL-8. The compound is also very effective in blocking TNF-alpha production innormal human fibroblasts. Although the mechanism of action of curcumin in suppressing the expressionof inflammatory genes is not completely understood, it appears that at least one mechanisminvolves a block of the intracellular signaling pathway that leads to AP-1 and NF-kappa Bactivation (64). Recent evidence suggests that this blockade occurs near the start of thesignaling pathway, that is, at the activated receptor, e.g., the IL-1 activated receptor (65). Another plant derived “active” that has been shown through rigorous scientificstudies to have anti-inflammatory activity is quercetin, a flavonoid derived from severalplants and fruits, including apples. Its efficacy as an antioxidant and anti-inflammatoryseems to provide some substantiation for the old expression, “an apple a day keeps thedoctor away.” Recent studies have shown that quercetin, like curcumin, can blockNF-kappa B driven genes and thus prevent the production of a variety of inflammatorymediators (66,67). Other plant derived compounds that have been scientifically shown to(A) 75 Control (B) 400 Control IL-1 IL-1 50 300 25PGE2 (ng/105 cells) IL-8 (ng/105 cells) 200 100 00 100 80 60 40 20 10 00 100 80 60 40 20 10 Curcumin (µM) Curcumin (µM)Figure 5 Effect of curcumin on inflammatory mediator production. Cultured dermal fibroblastswere treated with IL-1 and curcumin for 24 hours. Cell culture media was removed and assayed forthe production of (A) PGE2 and (B) IL-8.

Topical Anti-inflammatories 363have anti-inflammatory activities, at least in cell culture model systems, includeresveratrol, derived from grapes, boswellic acid, derived from Boswellia, the polyphenolEpigallocatechin gallate, derived from green tea, and bisabolol, derived from Chamomile.All of these compounds have been shown to exert some anti-inflammatory effect on cellsin culture, either inhibiting the production of PGE-2, cytokines, chemokines, adhesionmolecules, or other molecules involved in the inflammatory process.BIOLOGICAL SCREENING ASSAYS TO IDENTIFY NOVELANTI-INFLAMMATORY COMPOUNDSThe search for novel anti-inflammatory compounds that can be successfully formulatedinto either prescription or cosmetic topical products that show efficacy in treatingdermatological conditions requires the availability of appropriate skin cell culture-basedassays. Clearly, the cell types needed for such studies must include, at a minimum, normalhuman keratinocyte and fibroblast cell strains. In addition, because chronic skininflammatory disease involves the activity of immune cells, cultures of human monocytesand T-lymphocytes should also be incorporated into the screening strategy. Finally, whenone considers the important role that adhesion molecules, expressed on the surface ofendothelial cells, play in directing leukocytes into the skin, being able to assess the effectof putative anti-inflammatory compounds on adhesion molecule expression in culturedendothelial cells would add an additional important screening capability. Once the cell culture models have been established, the appropriate screening assaysmust be selected. These screens should focus on the effect that a potential anti-inflammatory molecule has on the expression of one or more key inflammatory mediators.Due to the fact that one of the most common activators of skin inflammation is sunlight,specifically UVB radiation, the determination of a compound’s ability to block theinduction of pro-inflammatory PGE-2 by UVR in both keratinocytes and fibroblastsrepresents a logical first step in the screening process. In addition, because skininflammation is often triggered by contact with chemical irritants or allergens, the use oftetradecanoylphorbol acetate (TPA), which is a potent “irritant” stimulator of inflammatorymediators in skin, provides an additional model for the analysis of anti-inflammatoryactivities of test compounds. Finally, because IL-1 is one of the most important mediatorsand propagators of inflammation and is rapidly induced by an inflammatory stimulus, suchas UVR, determining the ability of a potential anti-inflammatory compound to block eitherthe production or action of IL-1 is a critically important initial screening study (68–70).ELISA-Based ScreeningTo carry out initial screening experiments, cultured cells are first treated with the potentialanti-inflammatory molecule followed by treatment with the inducing agent (ex. IL-1, UVR,TPA), which up-regulates the expression of inflammatory mediators. After a period of time(six to 24 hours), the media is removed and tested for the production of a particularinflammatory mediator using an enzyme-linked immunosorbent assay (ELISA).The ELISA method is based on the recognition of a particular antigen, such as someinflammatory mediator of interest, by a specific antibody, called the capture antibody.While there are many different forms of this assay, one of the simplest variations, the“sandwich assay,” is shown in Figure 6. In this assay, the capture antibody is typically boundto a well in a plastic plate. When the media containing the inflammatory mediator of interestis added to the well, the bound capture antibody binds to the antigen. After binding, the well

364 Fuller and Smithis then washed and an additional antibody, called the detection antibody, is added to thewell. The detection antibody also binds to the antigen, but in addition this antibody containsa “tag” (for example, an enzyme that reacts with a colorless substrate to produce a coloredproduct) which allows for the amount of bound antigen to be quantified. Thus, if the culturemedia being tested contains a high amount of the antigen being measured, e.g., IL-1, thena high amount of detection antibody will bind, and a pronounced color reaction will occurwhen substrate is added. If, however, the anti-inflammatory compound blocks theproduction of the inflammatory mediator, for example, IL-1, then when the culture mediumis added to the assay well, there will be little antigen to bind the capture antibody, andconsequently very little detection antibody will bind. The result is very little color formationwhen the substrate is added. The advantage of ELISA methods is that they are rapid, can accommodate a largenumber of samples simultaneously, require very little material for assay (a few microlitersof culture medium), are very sensitive (pmole range), and are cost-effective. CommercialELISA-based assays are available for most cytokines and chemokines, and thus, media fromcell cultures can be assayed simultaneously for a variety of inflammatory mediators. Figure 7 shows a flow chart of a screening strategy designed to identify anti-infammatory compounds. As is shown, all putative anti-inflammatory compounds arefirst screened for the ability to block the IL-1, TPA, or UVR induction of PGE-2, one ofthe most important inflammatory mediators produced in skin. Although there areexceptions, typically if a candidate anti-inflammatory compound cannot inhibit signalingpathways leading to increased PGE-2 production, it is unlikely to block the productionof other inflammatory mediators. Compounds that effectively block PGE-2 productionat a concentration of 100 mm or less are then subjected to more demanding dose-responsestudies and are tested for their ability to block additional inflammatory cytokines andchemokines. For these screening assays, it is important that, where possible, only primarycell strains of human fibroblasts and keratinocytes be used since the use of normal cellsincreases the probability that results from in vitro studies will be predictive of effects of agiven compound when applied topically. Unfortunately, when screening protocols areused for leukocytes, it is difficult to obtain enough normal cells for such studies, and thus,permanent T-lymphocytes and monocyte cell lines are used. tag detector antibody antigenCapture antibody Capture antibody + antibody sandwich antigenFigure 6 Sequence of steps for enzyme-linked immunosorbent assay.

Topical Anti-inflammatories 365 Candidate Drug Dermal Fibroblasts KeratinocytesELISA IL-1 induced PGE-2 UV-induced PGE-2 UV induced PGE-2 TPA-induced PGE-2 production production production production MMP-1 IL-6 IL-8 LTB4 MMP-1 TNF-α IL-1 IL-6 IL-8 ELISA Inflammation and Aging-Specific Northern Assays Inflammation and Aging-Specific Northern Assays MMP-1 IL-6 Col-1 COX-2 IL-8 MMP-1 TNF-α IL-1 IL-6 IL-8 Gene Array Analysis (5,500 + genes) Gene Array Analysis (5,500 + genes) IL-2 IL-8 MMP-1 TNF- IL-1 IL-6 IL-8 Inflammation Specific Northern Assays Inflammation Specific Northern Assays IL-2 IL-8 MCP-1 IL-8 IL-12ELISA TPA/CD3-stimulation LPS-stimulation ELISA Jurkat T-Cells Candidate Drug THP-1 MonocytesFigure 7 Screening strategy for assessment of anti-inflammatory activity of a candidate drug. The results of studies with one putative anti-inflammatory compound are shown inTable 1. The compound was found to effectively inhibit the expression of severalinflammatory mediators produced in skin cells in response to various stimuli includingUVR, TPA, and IL-1. The table lists the concentration of this particular compound that iseffective at inhibiting the induction of an inflammatory mediator by 50% (IC50).Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR)While ELISAs are an excellent method for obtaining information on the ability of a givencompound to inhibit a wide variety of inflammatory mediators, it cannot determine HOWthe anti-inflammatory compound is working. For example, if a compound is identified thatinhibits PGE-2 production in keratinocytes, is the compound acting as a direct COX-2inhibitor, as do most NSAIDS, or is it acting at the gene level to inhibit the activation of theCOX-2 gene or other genes necessary for PGE-2 production? The method of reversetranscriptase-polymerase chain reaction (RT-PCR) is commonly used to quickly assess theexpression levels of a particular gene, and thus can determine if an anti-inflammatorycompound has any suppressive (or stimulatory) effect on a particular gene (71).The method uses the enzyme reverse transcriptase to reverse transcribe mRNA isolatedfrom experimental tissue or cultured cells into complementary DNA (cDNA). This cDNAis then denatured and incubated with DNA primers that hybridize (anneal) specifically tothe cDNA of interest. Once the primers are attached to the cDNA, a new DNA strand isproduced by enzymatic extension of the hybridized primers followed by denaturing thenewly formed double-stranded DNA. This process of primer annealing, extension, andstrand separation is repeated as much as 40 times and this results in the logarithmicamplification of a specific region of the gene of interest (Fig. 8). The amplified productsare then separated by gel electrophoresis, stained with the fluorescent DNA binding dyeethidium bromide, and visualized under UV light. By quantitating the intensity of the

366 Fuller and SmithTable 1 Screening Strategy for Assessment of Anti-inflammatory Activity of a Candidate Drug Human dermal fibroblasts IC50 (mM)Inflammatory mediator Stimulus—UVR 50 mJ Stimulus—IL-1a 100 pg/mlPGE-2 5 0.01IL-6 Not tested 50IL-8 10 50TNF-a Not tested Not TestedMMP-1 50 10 Human epidermal keratinocytes (% Inhibition-100 mM)Inflammatory mediator Stimulus—UVR 75 mJ Stimulus—TPA 32 nMPGE-2 100 100IL-6 100 100IL-8 100 100TNF-a 100 100MMP-1 100 100fluorescence of the amplified PCR products, which, in turn, is proportional to the amountof DNA product made, it is possible to determine the relative abundance of a particularmRNA, and thus to determine what effect any compound had on the activity of theinflammatory mediator gene.Gene ArraysThe use of ELISA, RT-PCR, and Northern and Western blot analyses are very useful inidentifying specific inflammatory mediators which are inhibited by anti-inflammatorycompounds. However, when one is designing topical formulations for treating aninflammatory skin condition, it is not only necessary to identify the inflammatorymediators that can be inhibited by topical application of a lotion or gel containing a givenFigure 8 Diagram of the polymerase chain reaction (PCR) showing how gene sequences areamplified.

Topical Anti-inflammatories 367anti-inflammatory compound, but it is also important to have some knowledge of whatbeneficial genes and proteins may be inhibited by the topical product. For example,although corticosteroids are potent anti-inflammatory agents when used topically, theyhave negative side effects including the inhibition of collagen production in the skin, thereduction of the immune response to a point where a risk of skin infections increases, andat high doses, inhibition of fibroblast proliferation. Thus, to develop an effective and safetopical anti-inflammatory product that does not damage skin structure and function, it isimportant to determine what potentially beneficial genes in keratinocytes, fibroblasts, andimmune cells, for example, IL-10, collagen III, or tissue inhibitor of metalloproteinase(TIMP), may be suppressed by the anti-inflammatory compound. One of the mosteffective methods for screening anti-inflammatory compounds for both their positive andnegative effects on gene expression is the use of gene array technology (72). With thistechnique it is possible to assess the expression level of hundreds to thousands of genessimultaneously. Gene arrays are membrane filters or glass slides to which are bound smallpieces of known and/or unknown (EST-expressed sequence tags) human genes. A typicalnylon gene array filter may contain as few as fifty or as many as 5000 different genesequences on a single filter, and some arrays have even been designed with specific tissuesor diseases in mind, such as inflammation. The sequence of steps involved in a gene arrayanalysis is shown in Figure 9. The first step involves isolating mRNA from untreated cells(control group) and from cells exposed to some experimental condition (experimentalgroup). After hybridization, any unbound cDNA is washed away and the hybridizedcDNA is detected and quantified. Since the location and identity of each gene on the filteris known, by comparing the quantified spots on the array produced from the control groupto those spots produced from the experimental group, one can determine if a particulargene in the experimental group is up-regulated or down-regulated compared to the control Merged ArrayControl Experimental Increased Cells or expression tissue compared to Isolate control mRNA Decreased expression compared to control mRNA Compare Array Convert to cDNA and label cDNA Hybridize to arrays Control Array Experimental ArrayFigure 9 Steps involved in gene array analysis.

368 Fuller and Smithgroup. Given the complexity of gene arrays, a computer software program is used to aid inthe quantification and analysis of the large amount of data that is obtained. The softwareproduces an “overlay” image of the filters from both the control and experimental groups,calculates the difference in expression level for each gene between the two groups, andthen converts this relative expression data into a color image. For example, a gene that isup-regulated in the experimental group compared to the control group is shown asa green spot on the computer generated image, while a gene that is down-regulated in theexperimental group is shown as a red spot. By using this method the effect of anycompound on the expression of genes that code for pro- and anti-inflammatory mediatorsas well as other genes expressed in epidermal and dermal cells can be rapidly determined.An example of the use of this technology is shown in Figure 10. In this experiment humanfibroblasts were treated with quercetin and the effect of this compound on the expressionof inflammatory and dermal matrix altering genes determined. The cDNA array imagesfrom untreated (A) or quercetin (B) treated fibroblasts captured by the phosphoimagerwere merged and colorized by the computer software to yield the image in panel C. Genesthat were down-regulated in quercetin treated fibroblasts relative to those in untreated cellsare displayed by the software as either red or yellow while those genes up-regulated byquercetin are displayed as green. In this study, quercetin was found to lower the expressionof MCP-1 and collagenase (MMP-1) while up-regulating a gene that blocks MMP activity(TIMP-1). Table 2 shows the results of an array analysis of genes that are up- and down-regulated by quercetin in TPA-treated keratinocytes. Note that quercetin up-regulatesgenes that are play a role in protecting the dermal matrix and down-regulates matrixdestroying genes.DEVELOPMENT OF EFFECTIVE TOPICAL FORMULATIONSAlthough screening assays are critical for identifying new anti-inflammatory compounds,unless these compounds can be formulated into a topical product that delivers the compoundacross the stratum corneum and down to the target cells in the epidemis and/or dermis, theproduct will be ineffective. The steps to developing an effective topical product involve: (i)assessing likelihood of skin penetration from molecular weight and log P values, (ii)determining solubility and stability of the anti-inflammatory compound in acceptableformulation solvents, (iii) preparing prototype formulations that are physically stable andwhich maintain biological activity of the compound, (iv) testing the prototype formulationby Franz cell percutaneous absorption analysis to determine the rate and quantity ofcompound that can penetrate into human skin, and (v) subjecting the formulation to placebo-controlled clinical studies to determine topical efficacy in a patient population. The stratum corneum is an effective barrier against entry of foreign objectsinto the skin, and this includes most proteins, peptides, and even small molecules. Thus, thedevelopment of topical products which allow penetration of compounds into the skin is not atrivial undertaking. Typically, unenhanced formulations may “deliver” 0.1% to 1% ofa “biologically active” compound across the stratum corneum. Even formulations that areengineered to optimize delivery of a given compound may result in, at best, 10% of theapplied dose moving across the stratum corneum and down into the skin. In addition,if the molecule to be delivered into the skin is highly hydrophobic, it will likely pass easilyinto the stratum corneum but not move into the more aqueous environment of the epidermis(73). Thus, a significant percentage of the active compound in the product will never diffusethrough the skin to reach the target cells. To aid in formulation development of a given“active” compound, the use of log P values has become popular to predict efficacy in skin

Topical Anti-inflammatories 369Figure 10 Gene array filters showing hybridization signals (black dots) from (A) untreated and(B) quercetin treated fibroblasts were “merged” and colorized by software analysis to show genesthat are upregulated or downregulated (shown here in gray scale) by this compound. (C) In themerged image, arrows point to 2 genes, MCP-1 and MMP-1, that are downregulated in fibroblaststreated with quercetin and one gene, TIMP-1, that is upregulated by this compound.penetration of a given molecule. Log P measurements show the degree to which a givencompound will partition between water and octanol (or other non-miscible solvent). Forexample, a compound that has a Log P of 1 will prefer an organic solvent to an aqueous oneby a factor of 10. A compound with a log P of 0 has an equal affinity for water or an organicsolvent. From a topical formulation perspective, compounds that have a logP of around 2.5will likely have a fairly high probability of skin penetration from a suitable formulation (74).In addition to log P values, the ability of any compound to penetrate the stratum corneumdepends on its size. Compounds with molecular weights above 1000 are not going to easilymove through the stratum corneum regardless of their log P value. Two other factors thatinfluence skin penetration of any compound from a formulation are the solubility and

370 Fuller and SmithTable 2 Effects of Quercetin on Gene Expression in TPA-Treated Human EpidermalKeratinocytes Determined by Integriderm DermarrayeUpregulated DownregulatedTissue inhibitor of metalloproteinases-2 Collagenase-1 (MMP-1) (TIMP-2) Stromelysin-2 (MMP-10)Tissue inhibitor of metalloproteinases-3 (TIMP-3) MTI-MMP (MMP-14) ADAM 9Serine proteinase inhibitor Urokinase-type plasminogen activator (uPA)Proliferating cell nuclear antigen Plasminogen activator inhibitor I (PAI-1)Metallothionein Plasminogen activator inhibitor II (PAI-2)Keratin 6 Monocyte chemotactic protein-1Keratin 14 RANTESKeratin 16 Envoplakin Interleukin-8 Cystatin Involucrin Small proline rich protein-1concentration of the compound in the formulation. Those formulations that contain a near-saturated (or even super-saturated) concentration of a compound will deliver more of thecompound into the skin. Conversely, the more soluble a compound is in the formulationthe less potential it will have for leaving the formulation and entering the skin. To increasethe movement of compounds into the skin, a number of penetration enhancers may be used.These are solvents that temporarily disrupt the integrity of the stratum corneum allowingmolecules to penetrate this layer of skin. Although over 300 penetration enhancers areknown, ony a few are used routinely for topical formulation development. Commonenhancers used in cosmetic formulations include simple alcohols, propylene glycol, oleicacid, ethoxydiglycol, polyolprepolymer-2 (and PP-14 and PP-15), some terpenoids,cyclodextrins, urea, and sodium lauryl sulfate to name a few (75,76).Percutaneous Absorption AnalysisOnce a compound’s size, log P value, and solubility properties in various acceptableformulation solvents have been determined, the next step in formulation developmentinvolves either measuring the penetration through skin of the compound dissolved ina single solvent or its skin penetration from simple formulations. Regardless of whichapproach is taken, measuring a compound’s “flux” through skin requires the use of sometype of diffusion cell. The most common apparatus for measuring the penetration oftopical formulations through skin is the Franz diffusion cell, shown in Figure 11. The unitconsists of an upper chamber into which the test formulation is applied and the lowerreservoir chamber which is filled with buffer. A piece of human skin (animal skin ora synthetic membrane is sometimes used) is mounted in between the two chambers andheld in place with a clamp. The formulation to be tested is applied to the stratum corneumsurface of the mounted skin and at various times, samples of the lower reservoir bufferare removed and assayed for the presence of the anti-inflammatory compound in the

Topical Anti-inflammatories 371formulation. For compounds that are not made radioactive, the presence of the compoundin the lower chamber of the Franz cell is typically determined by high-performance liquiddramatography (HPLC) analysis. In order to obtain results which more accurately reflectthe rate of skin penetration that will be obtained in vivo, human skin, either dermatomed orfull thickness, should be used. The use of Franz diffusion cell analysis to measurepercutaneous absorption of anti-inflammatory compounds from topical formulationsprovides information needed to optimize the formulation prior to initiating clinical studies.Based on dose-response studies in cell culture systems, it is possible to predict what levelof skin penetration a given anti-inflammatory compound likely needs to attain to showefficacy in vivo. Formulations can be modified and re-tested by Franz cell analysis until thepredicted “flux rate” of compound into the skin is achieved. It is useful to keep in mind that, as a general rule, compounds which show efficacy inblocking inflammatory mediators in cell culture systems with IC50 values of less than100 uM (preferably 10 uM) have a reasonable chance of being efficacious when appliedtopically, assuming the flux rate of the compound from the formulation is optimized.However, topical formulations containing anti-inflammatory compounds that are onlyeffective in cell culture at concentrations higher than 100 uM have a low probability ofbeing good anti-inflammatory products because of the difficulty of delivering enoughof the compound into the skin and to the target cells over a long enough period of time tobe effective. In our laboratory, compounds with anti-inflammatory IC50 values higher than100 uM are not considered for product development. Another consideration when developing topical formulations concerns “residencetime” of the active ingredient. To effectively treat inflammatory conditions, a topicalformulation must not only deliver enough of the active ingredient into the skin to beeffective, but should also deliver the active continuously over many hours. Typicallya topical product is applied to the affected area twice a day, once in the morning and oncein the evening. Thus, the time between applications can be as much as 12 hours. If thetopical formulation delivers a high level of the anti-inflammatory compound into the skinfor a short period of time, for example one hour, the compound is going to reach the targetcells at a high enough concentration to begin to inhibit inflammation, but after an hourthe concentration falls as the active continues to traverse the skin and dissipate into thecapillary beds. When one considers that only about 1–2 ml of any topical product is donor horseshoe clampcompartment membranesampling port receptor compartment for analysis optional water jacketFigure 11 Diagram of Franz diffusion chamber.

372 Fuller and Smithapplied to 100 cm2 of skin, developing formulations that deliver enough of the active intothe skin continuously over a 12-hour period is not a trivial undertaking. Obviously, if thebioactive compound is effective at nanomolar levels, the product can be designed as an“unenhanced” formulation, which will result in a slower rate of skin penetration andtheorectically provide a longer residence time or “depot” of drug needed to affect cellfunctioning for a 12-hour period. Further, if the water solubility of the active compound islow, it is likely to be retained in the stratum corneum, and only move into the edidermisslowly at a low concentration. If the compound’s bioactivity is in the nanomolar range thislow rate of movement into the epidermis will be ideal for maintaining a high residencetime in the skin.Assessment of Anti-inflammatory Activity by UVR Clinical StudyAlthough careful and thorough analysis of the biological activities of a given anti-inflammatory compound using a variety of cell culture models can provide information onwhich inflammatory conditions a given compound is likely to be effective in treating, andalthough skin penetration studies will aid in the development of a formulationthat theoretically delivers adequate levels of the compound into the skin, of course theonly way to know if the topical formulation is truly effective in treating inflammatoryconditions is to conduct clinical studies. In this regard, there are several differentapproaches to designing and implementing a clinical study. The least scientificallycredible study design is one in which no placebo is run, where there is no blinding of eitherthe clinical investigator or patients, and where the efficacy of a product formulation issimply determined comparing some parameter (redness, tone, skin roughness, etc.) at theend of the treatment period to baseline readings determined at the beginning of the study.In order to determine the efficacy of a novel anti-inflammatory compound in a formulation,it is necessary to conduct clinical studies under blinded, placebo-controlled conditions,where the efficacy of the formulation containing the anti-inflammatory “active” is statis-tically compared to the placebo group. One of the easiest and quickest clinical studies to conduct to assess the potential anti-inflammatory activity of a topical formulation is a UVR erythema study. In this protocol,the patient is exposed to a 3 MED dose of UVB radiation from a light source that irradiatesa small area (20 mm diameter) of skin. Multiple areas on the inner arm are irradiated.Immediately after irradiation, one spot is left untreated while a second spot is treated withthe topical formulation containing the anti-inflammatory compound. The third irradiatedarea is treated with a “vehicle” lotion that is identical to the treatment lotion but does notcontain the putative anti-inflammatory compound. For these studies it is important that theskin is not pre-treated with the test lotions. The reason for this is that if the putative anti-inflammatory compound in the formulation absorbs UV light, then applying the productbefore irradiation may result in protection from erythema simply because of the UVabsorbing properties of the compound. At hourly intervals after irradiation, surfacespectrophotometric measurements and photographs of the treated areas are taken toquantify the level of erythema. Clinical photographs of one patient from a study conductedon a novel anti-inflammatory compound developed in our laboratory are shown inFigure 12. The photograph shows that even 24 hours after irradiation and after a singleapplication of an anti-inflammatory formulation, the area treated with this formulation hasmarkedly less erythema than the area treated with the vehicle formulation (the exactformulation but without the anti-inflammatory compound).

Topical Anti-inflammatories 373Figure 12 Effect of anti-inflammatory topical formulation on UVB radiation-induced sunburn24 hours post-irradiation.CONCLUSIONSBy using multiple cell culture-based inflammatory mediator assays to identify the anti-inflammatory capabilities of a given compound, followed by the development of topicalformulations that are analyzed by Franz cell percutaneous absorption analysis to ensure thatadequate amounts of the compound are being delivered into the skin, it is possible todevelop novel topical anti-inflammatory products that have a very high probability of beingeffective treatments for a variety of inflammatory skin conditions. There are a number ofbotanically derived compounds which have been shown to have excellent anti-inflammatory activity, and results of screening assays in our laboratory suggest thatperhaps as many as 50 fairly common botanically derived compounds could be developedinto topical anti-inflammatory products that would effectively lower the level of manyinflammatory cytokines and chemokines in the skin including PGE-2, IL-1, TNF-alpha,MCP-1, IL-12, and IL-8. Further, these compounds can not only block the productionof cytokines but can also suppress the ability of a target cell to respond to a given cytokine orchemokine. When one considers the known deleterious side effects that have been reportedfor the anti-inflammatory steroids and recently for the newer class of oral or injectableanti-inflammatory immunomodulator drugs, it seems that the development of topical anti-inflammatory products that are less immunosuppressive and which are delivered directly tothe affected areas of the skin instead of systemically might represent a safer approach. Suchproducts could be designed to reduce or “reset” cytokine and chemokine levels in affectedareas of the skin to a more non-inflamed “ground state.” Such a product would reduce theinflammatory response but yet leave the immune system intact to fight infection and toconduct surveillance. From our research it appears very likely that a number of botanicallybased compounds could be formulated into topical products to meet this goal.REFERENCES 1. Richardson JD, Vasko MR. Cellular mechanisms of neurogenic inflammation. J Pharmacol Exp Ther 2002; 302:839–845. 2. Sawynok J. Topical and peripherally acting analgesics. Pharmacol Rev 2003; 55:1–20.

374 Fuller and Smith 3. Lee JL, Mukhtar H, Bickers DR, Kopelovich L, Athar M. Cyclooxygenases in the skin: pharmacological and toxicological implications. Toxicol Appl Pharmacol 2003; 192:294–306. 4. Catalina MD, Estess P, Siegelman MH. Selective requirements for leukocyte adhesion molecules in models of acute and chronic cutaneous inflammation: participation of E- and P- but not L-selectin. Blood 1999; 93:580–589. 5. Ley K. The role of selectins in inflammation and disease. Trends Mol Med 2003; 9:263–268. 6. Esche C, de BA, Beck LA. Keratinocytes in atopic dermatitis: inflammatory signals. Curr Allergy Asthma Rep 2004; 4:276–284. 7. Kupper TS, Fuhlbrigge RC. Immune surveillance in the skin: mechanisms and clinical consequences. Nat Rev Immunol 2004; 4:211–222. 8. Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest 2004; 113:651–657. 9. Nathan C. Points of control in inflammation. Nature 2002; 420:846–852.10. Fisher GJ, Choi HC, Bata-Csorgo Z, et al. Ultraviolet irradiation increases matrix metalloproteinase-8 protein in human skin in vivo. J Invest Dermatol 2001; 117:219–226.11. Jenkins G. Molecular mechanisms of skin ageing. Mech Ageing Dev 2002; 123:801–810.12. Ma W, Wlaschek M, Tantcheva-Poor I, et al. Chronological ageing and photoageing of the fibroblasts and the dermal connective tissue. Clin Exp Dermatol 2001; 26:592–599.13. Brazzini B, Pimpinelli N. New and established topical corticosteroids in dermatology: clinical pharmacology and therapeutic use. Am J Clin Dermatol 2002; 3:47–58.14. Schwarb FP, Smith EW, Haigh JM, Surber C. Analysis of chromameter results obtained from corticosteroid-induced skin blanching assay: comparison of visual and chromameter data. Eur J Pharm Biopharm 1999; 47:261–267.15. Dostert A, Heinzel T. Negative glucocorticoid receptor response elements and their role in glucocorticoid action. Curr Pharm Des 2004; 10:2807–2816.16. De BK, Vanden BW, Haegeman G. The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: molecular mechanisms for gene repression. Endocr Rev 2003; 24:488–522.17. Hermoso MA, Cidlowski JA. Putting the brake on inflammatory responses: the role of glucocorticoids. IUBMB Life 2003; 55:497–504.18. Tak PP, Firestein GS. NF-kappaB: a key role in inflammatory diseases. J Clin Invest 2001; 107:7–11.19. Almawi WY, Melemedjian OK. Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids 1. J Mol Endocrinol 2002; 28:69–78.20. Necela BM, Cidlowski JA. Mechanisms of Glucocorticoid Receptor Action in Nonin- flammatory and Inflammatory Cells. Proc Am Thorac Soc 2004; 1:239–246.21. De Bosscher K, Schmitz ML, Vanden Berghe W, Plaisance S, Fiers W, Haegeman G. Glucocorticoid-mediated repression of nuclear factor-kappa Bdependent transcription involves direct interference witha´transactivation. PNAS 1997; 94:13504–13509.22. Scholzen TE, Brzoska T, Kalden DH, et al. Effect of ultraviolet light on the release of neuropeptides and neuroendocrine hormones in the skin: mediators of photodermatitis and cutaneous inflammation. J Investig Dermatol Symp Proc 1999; 4:55–60.23. Moore RA, Tramer MR, Carroll D, Wiffen PJ, McQuay HJ. Quantitative systematic review of topically applied non-steroidal anti-inflammatory drugs 20. BMJ 1998; 316:333–338.24. Jarvis B, Figgitt DP. Topical 3% diclofenac in 2.5% hyaluronic acid gel: a review of its use in patients with actinic keratoses 1. Am J Clin Dermatol 2003; 4:203–213.25. Lin J, Zhang W, Jones A, Doherty M. Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials. BMJ 2004; 329:324.26. Vaile JH, Davis P. Topical NSAIDs for musculoskeletal conditions. A review of the literature 1. Drugs 1998; 56:783–799.27. Grace D, Rogers J, Skeith K, Anderson K. Topical diclofenac versus placebo: a double blind, randomized clinical trial in patients with osteoarthritis of the knee 2. J Rheumatol 1999; 26:2659–2663.

Topical Anti-inflammatories 37528. Roth SH, Shainhouse JZ. Efficacy and safety of a topical diclofenac solution (pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial 1. Arch Intern Med 2004; 164:2017–2023.29. Spacca G, Cacchio A. Comparative efficacy of nimesulide and diclofenac gel in the treatment of local painful rheumatism. European Bulletin of Drug Research 2002; 10:5–11.30. Hadgraft J, Du PJ, Goosen C. The selection of non-steroidal anti-inflammatory agents for dermal delivery. Int J Pharm 2000; 207:31–37.31. Puri R, Sanghavi N. Evaluation of topical non-steroidal anti-inflammatory drugs using penetration enhancers. Indian J Pharmacol 1992; 24:227–228.32. James MW, Hawkey CJ. Assessment of non-steroidal anti-inflammatory drug (NSAID) damage in the human gastrointestinal tract 2. Br J Clin Pharmacol 2003; 56:146–155.33. Whittle BJ. Gastrointestinal effects of nonsteroidal anti-inflammatory drugs. Fundam Clin Pharmacol 2003; 17:301–313.34. Kaidbey KH, Kurban AK. The influence of corticosteroids and topical indomethacin on sunburn erythema 1. J Invest Dermatol 1976; 66:153–156.35. Wilgus TA, Ross MS, Parrett ML, Oberyszyn TM. Topical application of a selective cyclooxygenase inhibitor suppresses UVB mediated cutaneous inflammation 3. Prostaglandins Other Lipid Mediat 2000; 62:367–384.36. Nelson C, Rigel D, Smith S, Swanson N, Wolf J. Phase IV, open-label assessment of the treatment of actinic keratosis with 3.0% diclofenac sodium topical gel (Solaraze). J Drugs Dermatol 2004; 3:401–407.37. Brecher AR. The role of cyclooxygenase-2 in the pathogenesis of skin cancer 1. J Drugs Dermatol 2002; 1:44–47.38. Miyauchi-Hashimoto H, Kuwamoto K, Urade Y, Tanaka K, Horio T. Carcinogen-induced inflammation and immunosuppression are enhanced in xeroderma pigmentosum group A model mice associated with hyperproduction of prostaglandin E2 1. J Immunol 2001; 166:5782–5791.39. Seo JY, Kim EK, Lee SH, et al. Enhanced expression of cylooxygenase-2 by UV in aged human skin in vivo 1. Mech Ageing Dev 2004; 124:903–910.40. Tiano HF, Loftin CD, Akunda J, et al. Deficiency of either cyclooxygenase (COX)-1 or COX-2 alters epidermal differentiation and reduces mouse skin tumorigenesis. Cancer Res 2002; 62:3395–3401.41. Nghiem P, Pearson G, Langley RG. Tacrolimus and pimecrolimus: from clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis. J Am Acad Dermatol 2002; 46:228–241.42. Bos JD. Non-steroidal topical immunomodulators provide skin-selective, self-limiting treatment in atopic dermatitis 5. Eur J Dermatol 2003; 13:455–461.43. Gupta AK, Chow M. Pimecrolimus: a review 1. J Eur Acad Dermatol Venereol 2003; 17:493–503.44. Lazarous MC, Kerdel FA. Topical tacrolimus Protopic 1. Drugs Today (Barc) 2002; 38:7–15.45. Denton MD, Magee CC, Sayegh MH. Immunosuppressive strategies in transplantation 15. Lancet 1999; 353:1083–1091.46. Hogan PG, Chen L, Nardone J, Rao A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 2003; 17:2205–2232.47. Al-Daraji WI, Grant KR, Ryan K, Saxton A, Reynolds NJ. Localization of calcineurin/NFAT in human skin and psoriasis and inhibition of calcineurin/NFAT activation in human keratinocytes by cyclosporin A. J Invest Dermatol 2002; 118:779–788.48. Bohjanen KA, Prawer SE. New biologic therapies for psoriatic disease 1. Minn Med 2004; 87:34–36.49. Ruderman EM, Tambar S. Psoriatic arthritis: prevalence, diagnosis, and review of therapy for the dermatologist 1. Dermatol Clin 2004; 22:477–486.50. Mehlis SL, Gordon KB. The immunology of psoriasis and biologic immunotherapy 2. J Am Acad Dermatol 2003; 49:S44–S50.51. Yocum D. Effective use of TNF antagonists 1. Arthritis Res Ther 2004; 6:S24–S30.

376 Fuller and Smith52. Nickoloff BJ, Nestle FO. Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities 1. J Clin Invest 2004; 113:1664–1675.53. Williams JD, Griffiths CE. Cytokine blocking agents in dermatology 2. Clin Exp Dermatol 2002; 27:585–590.54. Pietrzak A, Chodorowska G, Jazienicka I, Junak-Bojarska A, Rolinsk J. New development in the treatment of psoriasis—infliximab 1. Ann Univ Mariae Curie Sklodowska [Med] 2003; 58:322–327.55. Mease P, Goffe BS. Diagnosis and treatment of psoriatic arthritis. J Am Acad Dermatol 2005; 52:1–19.56. Weber RW. Adverse reactions to biological modifiers 1. Curr Opin Allergy Clin Immunol 2004; 4:277–283.57. Fleischmann R, Yocum D. Does safety make a difference in selecting the right TNF antagonist? 2 Arthritis Res Ther 2004; 6:S12–S18.58. Imperato AK, Smiles S, Abramson SB. Long-term risks associated with biologic response modifiers used in rheumatic diseases 1. Curr Opin Rheumatol 2004; 16:199–205.59. Lindow KB. Rosacea. An overview of diagnosis and management 1. Nurse Pract 2004; 12:27–32.60. Wolf JE, Jr. The role of topical metronidazole in the treatment of rosacea 1. Cutis 2004; 73:19–28.61. Del Rosso JQ. Medical treatment of rosacea with emphasis on topical therapies 1. Expert Opin Pharmacother 2004; 5:5–13.62. Aggarwal BB, Shishodia S. Suppression of the Nuclear Factor-{kappa}B Activation Pathway by Spice-Derived Phytochemicals: Reasoning for Seasoning 1. Ann NY Acad Sci 2004; 1030:434–441.63. Joe B, Vijaykumar M, Lokesh BR. Biological properties of curcumin-cellular and molecular mechanisms of action. Crit Rev Food Sci Nutr 2004; 44:97–111.64. Sarkar FH, Li Y. Cell signaling pathways altered by natural chemopreventive agents. Mutat Res 2004; 555:53–64.65. Jobin C, Bradham CA, Russo MP. Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity. J Immunol 1999; 163:3474–3483.66. Middleton E, Jr., Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 2000; 52:673–751.67. Afaq F, Ahmad N, Mukhtar H. Suppression of UVB-induced phosphorylation of mitogen- activated protein kinases and nuclear factor kappa B by green tea polyphenol in SKH-1 hairless mice. Oncogene 2003; 22:9254–9264.68. Feghali CA, Wright M. Cytokines in acute and chronic inflammation. Front Biosci 1997; 2:d12–d26.69. Opal SM, DePalo VA. Anti-inflammatory cytokines. Chest 2000; 117:1162–1172.70. Murphy JE, Robert C, Kupper TS. Interleukin-1 and cutaneous inflammation: a crucial link between innate and acquired immunity. J Invest Dermatol 2000; 114:602–608.71. Joyce C. Quantitative RT-PCR. A review of current methodologies. Methods Mol Biol 2002; 193:83–92.72. Chittur SV. DNA microarrays: tools for the 21st Century. Comb Chem High Throughput Screen 2004; 7:531–537.73. Cronin MT, Dearden JC, Moss GP, Murray-Dickson G. Investigation of the mechanism of flux across human skin in vitro by quantitative structure-permeability relationships. Eur J Pharm Sci 1999; 7:325–330.74. Potts RO, Guy RH. Predicting skin permeability. Pharm Res 1992; 9:663–669.75. Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev 2004; 56:603–618.76. Moser K, Kriwet K, Naik A, Kalia YN, Guy RH. Passive skin penetration enhancement and its quantification in vitro. Eur J Pharm Biopharm 2001; 52:103–112.

21Topical Nutritional AntioxidantsKaren E. BurkeDepartment of Dermatology, Mount Sinai Medical Center andDepartment of Medicine, Cabrini Medical Center, New York, New York, U.S.A.INTRODUCTIONIn recent years, more and more cosmetic products have been formulated with antioxidants.These new products claim to “moisturize,” “protect,” and “rejuvenate” the skin. The skin naturally uses nutritional antioxidants to protect itself from free-radicaldamage. Indeed, many antioxidants—most prominently vitamins C and E, the tracemineral selenium (Se), the soy extract genistein and ubiquinone—have been proveneffective in protecting against ultraviolet (UV) damage to the skin and in actuallyreversing the appearance of aging by decreasing solar hyperpigmentation and smallwrinkles when applied to the skin. Also, a-lipoic acid and ubiquinone may retard andreverse intrinsic as well as photoaging. Topical application of these antioxidants can givefar higher concentrations in the skin than even maximal oral intake. However, the correctformulation is of utmost importance to attain eficacy. The challenge is to use the correctform of the antioxidant molecule, to keep the antioxidant active to attain a reasonableshelf-life for the product, and to achieve effective transcutaneous absorption that deliverseffectively high concentrations of the active antioxidant to the dermis as well as theepidermis.VITAMIN CBackgroundVitamin C (L-ascorbic acid) is the body’s major aqueous phase antioxidant and isabsolutely vital for life. All animals make their own vitamin C, except for humans andother primates, one species of Indian fruit-eating bat, and the guinea pig. In fact,a 130-pound goat synthesizes 13 grams of vitamin C per day, almost 200 times theAmerican Food and Drug Administration (FDA) requirement (1). Not only do otheranimals make hundreds of times the vitamin C we ingest, but also, when under stress, theycan make more than ten times their normal amount of vitamin C, a capability that wehumans do not have (1). 377

378 Burke Our skin is the organ that suffers most from environmental free-radical stress fromexposure to sunlight, cigarette smoke, and other pollution. Furthermore, this contactactually depletes the level of vitamin C in skin. Even minimal UV exposure of 1.6 minimalerythema dose (MED) decreases the level of epidermal vitamin C to 70% of the normallevel, and exposure to 10 MED decreases the vitamin C to only 54% (2). Exposure to 10parts per million of ozone in city pollution decreases the level of epidermal vitamin C by55% (3).Mechanisms of ActionVitamin C is itself not a sunscreen. Topical vitamin C protects against solar damageprimarily as an antioxidant which deactivates the UV-induced free radicals, mostsignificantly the superoxide anion, singlet oxygen, and the hydroxyl radical. Vitamin C isequally effective in protecting against both UVB (290–320 nm) and UVA (620–400 nm) (4).On both porcine and human skin, applying vitamin C decreases the acute erythema andsunburn suffered even when applied after sun exposure (4). Protection is confirmed byhistologic examination. Treatment of porcine skin in vivo with topical 10% vitamin Cdecreases the number of abnormal apoptotic “sunburn cells” by 40% to 60% (4) and reducesthe UV damage to DNA by 62% (4). Topical vitamin C further prevents UV-induced immonosuppression (5). Inapproximately one-third of humans, the activity of the immune system is inhibited afterexposure to sunlight. This immunosuppression is measured by the class of contacthypersensitivity to sensitizers such as poison ivy. Sunscreens only partially aid in theprevention of UV immunosuppression. Animal studies demonstrate that topical vitamin Cprevents this UV-induced loss of contact hypersensitivity as well as UVB-induced tolerance. Topical vitamin C is also directly anti-inflammatory (further accounting fordecreased erythema after sun exposure). Laser resurfacing causes redness for at least threeto four months. With vitamin C applied before and after laser resurfacing surgery, rednessis decreased after only two months (6). Dermatologic surgeons recommend using topicalvitamin C as long as possible prior to laser resurfacing and beginning again as early asfourteen days following surgery. Topical vitamin C can also be used effectively to treat theinflammation of rosacea (7). The main action of vitamin C on the skin is direct stimulation of collagen synthesis.Vitamin C is an essential cofactor for the two enzymes required for collagen synthesis,prolyl hydroxylase (which makes the collagen molecule stable) and lysyl hydroxylase(which cross-links the collagen to give structural strength) (8). Recent research has furtherdemonstrated that vitamin C acts directly on DNA to increase the transcription rate and tostabilize the pro-collagen messenger RNA, thus regulating and maintaining theintercellular amount of collagen (9). Exciting experiments have demonstrated that vitamin C also has anti-aging effects.Studies in vitro compared newborn with elderly (80–95 year-old) fibroblasts (10). Elderlycells proliferate in vitro at only one-fifth of the rate of newborn cells. However, whenvitamin C is added to the culture medium, the elderly cells actually proliferate better thannormal newborn fibroblasts. Even the newborn fibroblasts proliferate almost four timesbetter when exposed to vitamin C (10). Not only do fibroblasts increase proliferation in the presence of vitamin C, but theyalso synthesize more collagen. Newborn fbroblasts synthesize a larger percentage ofcollagen than elderly cells, but again, when elderly cells are exposed to vitamin C in vitro,

Topical Nutritional Antioxidants 379they produce more collagen than the normal, newborn fibroblasts (10). Surprisingly, alsothe newborn cells double the amount of collagen synthesized (10). Vitamin C further reverses the adverse appearance of photoaging by inhibitingtyrosinase (11), thereby fading unattractive solar lentigos. Because L-ascorbic acid mayinhibit elastin biosynthesis (12), it may reduce the solar elastosis of photoaged skin. Another important action of vitamin C on the skin is that topical vitamin C actuallyincreases the synthesis of several very specific lipids of the skin surface (13). Not onlydoes this mean that vitamin C helps the natural moisturization of the skin, but it alsoenhances the protective barrier function of the skin (14).Challenges in FormulationTo optimize percutaneous absorption and full activity of vitamin C, the preciseformulation is of utmost importance (15). Fortunately, the skin level of vitamin C canbe increased significantly by topical application. Topical absorption was proven byradioactive-labeling studies in pigs. After treatment with 10% vitamin C cream, 8.2% wasfound in the dermis, and 0.7% was in the blood (4). Formulations containing 5%, 10%,15%, 20%, or 25% vitamin C were tested: after 24 hours, 20% resulted in the highest skinlevels, with maximized concentration in the skin after three days (16). Indeed, the level ofvitamin C in the skin attained by topical application was over 27 times the level attained byhigh oral intake (16). Since L-ascorbic acid is an inherently unstable molecule—making it an excellentantioxidant—creation of an effective topical delivery system is crucial. Many productscontain stable derivatives which are not metabolized by the skin (such as ascorbyl-6-palmitate or magnesium ascorbyl phosphate) and therefore have no activity (16). Otherformulations do not result in measurable absorption of vitamin C because they are notat the correct pH. Delivery of L-ascorbic acid depends upon removing the ionic chargeachieved optimally at a pH of 3.5 (16). Having the pH below the pKa of ascorbic acid(pHaZ4.2) gives optimal activity as an antioxidant.Substantiation of EfficacyAs cited above in the presentation of “Mechanisms of Action,” the effcacy of topicalvitamin C in neutralizing reactive oxygen species (ROS), protecting against both UVA andUVB damage, stimulating collagen synthesis, preventing UV immunosuppression,alleviating infammation, decreasing UV-induced pigmentation, and enhancing surfacemoisturization and skin barrier function has been repeatedly documented incontrolled experiments. Clinically, daily application of topical vitamin C 15% can partially reverse theappearance of photoaged skin. Improvement can be noted in as little as two to four monthswith optimal correction after at least four to six months. As shown in Figures 1 and 2, smallwrinkles decrease and solar lentigines fade. Thus vitamin C not only prevents but alsoreverses much of the damage induced by UV.VITAMIN EBackgroundLike vitamin C, vitamin E is an essential nutrient, not synthesized by humans and suppliedonly by oral intake. The main natural sources are fresh vegetables, vegetable oils, cereals,

380 BurkeFigure 1 Decrease in small periorbital rhytides after daily application of vitamin C serum 15%(SkinCeuticals) for one year. Source: Photo courtesy of SkinCeuticals, Dallas, Texas, U.S.A.and nuts. Natural vitamin E is the most important lipid-soluble, membrane-boundantioxidant in the body. Vitamin E is especially abundant in stratum corneum, deliveredthere by sebum (17,18). Its concentration is highest at the lower levels of the stratumcorneum with a decreasing gradient outward. As the outermost defense of the body, thestratum corneum is first to absorb the oxidative stress of sunlight and pollution. Vitamin Eis depleted in the process, so topical application can be particularly advantageous,especially since the lipophilic structure makes it cosmetically attractive for applicationand absorption.Mechanisms of ActionThe redox and free radical chemistry of vitamin E are well-documented (19). The majorantioxidant role is the arrest of chain propagation by scavenging lipid peroxyl radicals.One molecule of tocopherol has the ability to scavenge two peroxyl radical molecules (20).Figure 2 Lightening of UV-induced lentigines and hyperpigmentation after daily application ofvitamin C serum 15% (SkinCeuticals) for one year. Source: Photo courtesy of SkinCeuticals, Dallas,Texas, U.S.A.

Topical Nutritional Antioxidants 381Figure 3 Interactions of low molecular weight antioxidants. The reactions which directly quenchoxygen free radicals (RO†) are indicated by the dark gray arrows (RO†/RO); the reactionsregenerating these antioxidants are also indicated by the light gray arrows. Reactions with arrowstouching are directly linked. RO† generated in a cell membrane is reduced by tocopherol, forming atocopheryl free radical which can in turn be quenched within the membrane by ubiquinol or at themembrane-cytosol junction by ascorbate (vitamin C). RO† generated in cytosol is directly reduced byascorbate. The oxidized dehydroascorbate is reconverted to ascorbate by glutathione (GSH). Botha-lipoic acid and dihydrolipoic acid (DHLA) directly reduce oxygen free radicals. Also DHLA is itselfa potent reducing agent which regenerates the oxidized forms of vitamin C, vitamin E, and oxidizedglutathione (GSSH); this linkage is indicated by an asterix. Source: Adapted from Refs. 21, 22.As shown in Figure 3, several hydrophilic coantioxidants, such as ascorbate andglutathione, regenerate vitamin E from the tocopheryl radical and thereby enhance theantioxidant capacity of vitamin E (21–23). Also, ubiquinol (coenzyme Q10) protectsa-tocopherol from photo-oxidation by recycling (24). There is extensive scientific evidence from animal studies that vitamin E isphotoprotective. Topical vitamin E [even the metabolically less potent racemic or esterforms (see “Challenges in Formulation” below)] significantly reduces acute erythema,edema, and sunburn (25–30) if applied prior to UV exposure or (in some studies)immediately after. This has been confirmed histologically by decreased “sunburn cells”(27) and by electron microscopy showing epidermal cell repair and anti-inflammatoryeffects (28). Less DNA photodamage after UV with concomitant decreased p53 expressionhas been observed (29). Topical all-rac-a-tocopheryl acetate applied before UV exposureprotected the hairless mouse epidermis against decreased DNA-thymidine incorporationand lipid peroxidation; given orally, this protected only against lipid peroxidation (30).This protection results from antioxidant (31) and/or anti-inflammatory activity (32,33).

382 Burke UV radiation directly alters DNA and induces free redicals (34,35) and epidermallipid peroxidation (36), thereby initiating and promoting skin cancer (37). Vitamin Eprotects the skin from this chronic damage by: (i) quenching free radicals [as confirmedin vitro by protection by reducing radiation-induced lipid peroxidation (38)], and (ii)protecting specific membrane proteins containing Se or sulfur (39). Indeed, all-rac-a-tocopherol has been shown to prevent epidermal chemical carcinogenesis (40–42) as wellas UV-induced photocarcinogenesis (43–46). In hairless mice both oral (43) and topical all-rac-a-tocopherol combined withascorbic acid (44) increased the latency period and decreased the number of UV-inducedtumors. In Skh:2 hairless mice, both topical d-a-tocopherol (5%) and d-a-tocopherylsuccinate (5%) as well as oral d-a-tocopheryl acetate signifcantly retarded the onset anddecreased the incidence of UV-induced skin tumors; the topical succinate was lesseffective than the other two forms (25).Challenges in FormulationSeveral forms of vitamin E exist in natural dietary sources. The form which isfound in mammalian tissues and has by far the greatest biologic activity is pure,nonesterified d-a-RRR-tocopherol (47,48) which has three methyl groups on the 6-chromalring (Fig. 4). Humans use predominantly a-tocopherol because a specific a-tocopheroltransfer protein selectively transfers a-tocopherol into lipoproteins (49). The other naturalforms are beta, gamma, and delta which contain only one or two methyl groups on the6-chromal ring. Relative to the alpha form, the beta, gamma, and delta RRR-tocopherolsgive only 42%, 72%, and 40%, respectively, of the protection against post-UV edema (50).The synthetic form is “dl” or “all-rac,” a mixture of eight stereoisomers. Not only is thedecreased activity of the all-rac mixture of vitamin E important (51), but also the mixed all-rac form of vitamin E has been reported to cause allergic contact dermatitis (52) anderythema multiforme (53) when applied topically. No such adverse reactions have beenreported with pure d-a-tocopherol. Instead of the pure d-a-tocopherol, the synthetic isomers are esterified (to acetatesand succinates) for use in commercial vitamins and some topical formulations because theesters are far more stable. The ester vitamin E acetate has been shown to be absorbed intothe skin (54–56). This ester must be hydrolyzed to the active free tocopherol form beforethere is any biologic activity, a reaction which readily occurs in the stomach after oralingestion or in cell and organ culture, but there is conflicting evidence as to what extentFigure 4 Molecular structures of tocopherols.

Topical Nutritional Antioxidants 383this conversion occurs, especially in the stratum corneum (57–59). Thus the antioxidantpotential of esterified vitamin E is far less than the natural tocopherol form (60). There isgreater bioconversion in the lower nucleated epidermal cells (58,59) depending on theformulation (61). UVB exposure may enhance this conversion (62). Stabilization of the non-esterified d-a-tocopherol to give a product an effective longshelf-life is a challenge in formulation. The stability can be enhanced by packaging indark, sealed ampules for one application-only delivery, by formulating within liposomes,or by stabilizing chemically, often using other antioxidants. (Patents are pending for thelatter two methods).Substantiation of EfficacyThe scientific evidence of the benefcial role of vitamin E in protection from UV damagewas discussed in detail above. Vitamin E has several other possible therapeutic roles indermatology. Many anecdotal reports support the use of topical vitamin E to enhancewound-healing and to prevent hypertrophic scars; however, the benefits are controversial.Two controlled studies failed to show scar prevention by topical vitamin E (63,64). Thestability and formulation of the topical vitamin E used may have effected theseinconclusive studies. New research on diabetic mouse models suggests involvement ofoxidative stress in diabetic wound healing showed significantly improved wound healingwith topical vitamin E (65,66). Vitamin E may have a role in treating atopic dermatitis.Forty-three patients treated with oral vitamin E for eight months showed improvement andnear-remission concomitant with a 62% decrease in serum IgE levels (67). Furthermore, very exciting recent evidence suggests that oxidative stress is involvedin the pathophysiology of melanoma and nonmelanoma cancer (68) and that vitamin Eslows melanoma growth by promoting tumor cell apoptosis and inhibiting vascularendothelial growth factor-mediated angiogenesis (69,70). Of great interest to the cosmeceutical formulations, there is the clinical evidence thattopical vitamin E is indeed effective in reversing the appearance of photoaging. Figure 5demonstrates the dramatic correction of periorbital wrinkles after four months of once-daily application of 5% d-a-tocopherol cream. Histologic confirmation of correction of theUV-induced epidermal hypertrophy with thickened stratum corneum, increased apoptotic“sunburn cells” in the basal layer, and disruption of dermal collagen and elastin wasdemonstrated in mice after eight weeks of topical treatment (KE Burke, L Ricotti, EGGross, unpublished observation). Resolution of post-UV inflammation was also observed.Further electron microscopic analysis confirmed correction of collagen and elastin fiberFigure 5 Correction of periorbital wrinkles after four months of once-daily treatment with 5%d-a-tocopherol cream.

384 Burkedamage and demonstrated repair of UV-induced disruption of collagen fibers andbasement membrane anchoring fibrils. This correction of UV damage by topical d-a-tocopherol (5%) is as effective as that of topical tretinoin (retinoic acid), the “goldstandard” of topical anti-aging.SELENIUMBackgroundSelenium (Se) was recognized to be an essential trace element in humans and animals inthe late 1950s. A decade later, anticarcinogenesis was suggested by statistical correlationof decreased cancer mortality with increased Se in the diet in the United States (71).Scientific evidence indicates that indeed Se plays a role in cancer prevention (72–76).Se was shown to inhibit growth and to stimulate programmed cell death in a variety of cellculture studies, including human tumor cell lines in vitro (77). Hundreds of animal studiesdemonstrate that Se can reduce tumor yields: moderate Se supplementation at levels abovethe dietary requirements has been shown to decrease the number of tumors induced byseveral chemical carcinogens and viruses and to reduce the incidence of spontaneousmammary tumors (78) as well as the growth of other transplanted tumors (78). Some, but not all, epidemiological studies have found a reduced risk for severalkinds of cancer associated with a higher blood concentration of Se (79,80). A decreased Seconcentration and glutathionine peroxidase (GPX) activity in blood and, interestingly, anincrease of these parameters in malignant tissue was found in lung cancer patients (80).An initial study of 240 non-melanoma skin cancer patients in good general healthdemonstrated a significantly lower mean plasma Se concentration than control subjectswithout skin cancer (81). In fact, those patients whose blood concentrations were in thelowest decile had 4.4 times the incidence of skin cancer as those in the highest decile (81). In a 10-year prospective study of 1312 patients with a history of basal cellor squamous cell carcinomas of the skin, Se treatment did not protect against furtherdevelopment of such skin cancers; however, it did reduce total cancer incidence,total cancer deaths, and the incidence of lung, colorectal, prostate, and total non-skincancer (82,83).Mechanisms of ActionThere is extensive evidence that Se prevents the accumulation of free radicals, therebyprotecting from UV damage and fortifying the immune system. Se is an essential cofactorfor the intracellular antioxidant enzymes GPX and thioredoxin reductase (TDR) (84). Se isincorporated covalently into proteins of this GPX-TDR family of selenoenzymes (85) aswell as into other selenoproteins (86) that may mediate some of the protective effects of Seon UVB-induced cell damage. Through the activities of these enzymes, Se quenches freeradicals which would otherwise damage DNA proteins and cellular membranes. Precise molecular mechanisms are being extensively researched. Protection ofkeratinocyte DNA was demonstrated by decreased 8-hydroxy-2-deoxyguanosineformation after UV irradiation (87,88), though there was no protection from pyrimidinedimer formation (87). There is evidence that L-selenomethionine (SeMet) induces a DNArepair response in human fibroblasts in vitro (89), perhaps by redox regulation of the DNArepair branch of the p53 pathway (90). In fact, different chemical forms of Se differentlymodify p53 (each by phosphorylation of specifc cysteine and threonine residues) to induceDNA repair or apoptosis after DNA damage (91). Further cellular protection has been

Topical Nutritional Antioxidants 385demonstrated by a decrease in UVB-induced lipid peroxides in keratinocytes (87) andfibroblasts (92) by pre-treatment with SeMet. Finally, in vitro both SeMet and Se sulfide protect keratinocytes (87,93,94),melanocytes (87,93), and apoptosis (87,95). Interestingly, keratinocytes have twice theGPX activity of fibroblasts which correlates with greatly increased resistance to UVA-induced cell death for keratincytes (96). The fact that Se may prevent UV-induced celldeath by p53-independent pathways is evidenced by the demonstration that pre-incubationof cultured human keratinocytes with sodium selenite or SeMet protects from UVB-induced apoptosis without decreasing levels of UVB-induced p53 (97). Se may also be of particular importance in pigmentation through TDR. Located onkeratinocyte membranes, TDR prevents UV oxidation of thioredoxin (which wouldotherwise enhance tyrosinase synthesis of dihydroxyphenylalanine, the precursor ofmelanin) (98,99). Se has other advantageous action on the skin. Clinically, a direct anti-inflammatoryeffect by oral sodium selenite in Selye granuloma induction in rats was demonstrated(100). This anti-inflammatory action might be a direct result of decreased oxidativedamage to cell membranes. Finally, Se also increases cellular immune responses by several mechanisms,including increasing interleukin IL-2 receptor function (101–103) (thus making cells moreresistant to oxidative stress) and through enhanced production of eicosanoids (101).Effective Topical FormulationTopical preparations containing Se sulphide are frequently used for the treatment of tineaversicolor, seborrheic dermatitis, and dandruff. However, the Se from these preparations isnot absorbed by the skin (104). Se can be effectively absorbed transdermally when appliedas SeMet, giving increased skin and liver levels of Se after topical application of 0.02%SeMet to mice (105).Substantiation of EfficacyTopical SeMet was shown to be effective in protecting against acute and chronic UVdamage to the skin. Concentrations as low as 0.02% increased the MED in humans (106)and decreased acute erythema and blistering as well as later UV-induced tanning and skincancer in Skh:2 mice (105).Figure 6 Correction of periorbital wrinkles after four months of once-daily treatment with 0.05%L-selenomethioinine lotion.

386 Burke Furthermore, topical SeMet is highly effective not only in preventing but also inreversing the appearance of photoaging. As shown clinically in Figure 6, periorbitalrhytides are decreased significantly in a 56-year-old woman after four months of once-daily application of SeMet (0.05%) cream. This enhancement of repair of chronic photoaging at the cellular and molecular levelwas confirmed by histologic and electron microsopic analysis in mice (107). UV-inducedhyperkeratosis and epithelial hyperplasia markedly decreased; irregular, damagedcollagen was replaced with newly synthesized, fine fibrillar homogeneous collagen;solar elastosis was repaired; and UV-induced infammation resolved—all as (or more)effectively as comparable treatment with topical tretinoin (107). Electron microscopyconfirmed repair of dermal collagen and basement membrane anchoring fibrils.NEW COMBINATIONS OF ANTIOXIDANTSVitamin C with Vitamin EAs shown in Figure 3, the skin uses predominantly vitamin C to protect the aqueousenvironment and vitamin E to protect membranes from lipid peroxidation. Since vitamin Cis naturally present intracellularly in relatively high concentrations, L-ascorbic acid notonly acts directly as an antioxidant and as an essential cofactor in the synthesis of collagen,but also regenerates oxidized membrane vitamin E, so that the vitamin E need not bereplaced (108). Oral vitamin C with E in high doses protects against UV-induced erythemain humans (109,110) whereas either vitamin alone is less effective (110). Alone eachtopical L-ascorbic acid (15%) and a-tocopherol (1%) give two-fold protection, whereascombined they provide four-fold protection against UV-induced erythema and thiaminedimer formation in porcine skin (111). This protection from UV-induced erythema (112)and tanning (113) by vitamins C and E combined with melatonin was further demonstratedin humans. Fortunately, mixing these hydrophilic and lipophilic antioxidants in a topicalformulation stabilizes each (111) for a cosmetically attractive application.Vitamins C and E with Ferulic AcidFerulic acid is a potent phenolic antioxidant found ubiquitously and in high concentrationsin the cell walls of grains, fruits, and vegetables where it is conjugated with mono-, di-, andpoly-saccharides and other compounds (114,115). As a potent antioxidant, ferulic acidprotects membranes from lipid peroxidation and is synergistic with ascorbic acid (116).Anticarcinogenesis has been demonstrated for pulmonary (117) and colon cancers (118).Topical ferulic was shown to inhibit UVB-induced erythema (119). In a topical preparation,ferulic acid stabilized vitamins C and E and added substantial synergistic photoprotectiondoubling efficacy as measured by both erythema and sunburn cell formation from four-foldto eight-fold (120). Inhibition of apoptosis correlated with decreased thymine dimerformation and reduced induction of both caspase-3 and downstream caspase-7 (120).Vitamin E with L-SelenomethionineIn many biologic systems, vitamin E and Se often act synergistically. Borek et al. (121)demonstrated that Se and RRR-a-tocopheryl succinate act alone by different mechanismsto prevent radiogenic and chemically induced transformation in vitro. They furthershowed that there was additive protection when both were used together (121).

Topical Nutritional Antioxidants 387 Comparing and combining topical SeMet with oral d-a-tocopheryl acetate andtopical d-a-tocopherol (122), the topical combination was less effective than topicalvitamin E alone in prolonging the onset and in decreasing the incidence of UV-inducedskin cancers in mice (122). Topical SeMet with oral vitamin E was more effective thaneither alone. In reducing UV-induced pigmentation, topical SeMet with topical or withoral vitamin E was more effective than any one antioxidant alone, particularly during thefirst eight weeks of UV exposure (122). Topical SeMet (alone or with vitamin E)prevented all blistering after initial UV exposure.SOY EXTRACT: GENISTEINBackgroundGenistein is an isoflavone isolated from soy, the structure of which is shown in Figure 7.Recent interest in genistein has been stimulated by epidemiological studies whichcorrelate diets high in soy with reduced incidence of cardiovascular disease (123),osteoporosis (123), and certain cancers in humans (124–126). The direct anticarcinogenic action of genistein is documented. Animal studiesdemonstrate protection against bladder, breast, colon, liver, lung, prostate, and skin cancerwith oral genistein (124,127), and dietary soy inhibits chemically induced skin cancer inmice (128). Growth of many in vitro cancer cell lines is inhibited by genistein (127).Genistein also arrests the growth and induces the differentiation of malignant melanomacells in vitro (129) and inhibits pulmonary metastases of malignant melanoma cells in vivo(130,131).Mechanism of Action and Substantiation of EfficacyThe mechanism by which genistein inhibits carcinogenesis may be through inhibitionof tyrosine protein kinases, the enzymes which phosphorylate proteins necessary forthe regulation of cell division and transformation (132). Of particular importance isphosphorylation of TPK-dependent epidermal growth factor receptors which are related totumor promotion, including initiation of transcription factors, release of inflammatorymediators (as prostaglandins), and stimulation of cell proliferation (133). Genistein wasfound to downregulate both UVA- and UVB-induced EGF-R phosphorylation in humanepidermoid carcinoma cells in vitro (134,135). In mouse skin, genistein also blocks theUVB-induced expression of the photo-oncogenes c-fos and c-jun which promote cellFigure 7 The molecular structure of genistein.

388 Burkeproliferation in oncogenesis (136). Similarly, genistein retards UV-induced apoptoticchanges—including caspace-3 and p21-activated kinase 2 activation of human epidermalcarcinoma cells (137) and phosphokinase C-delta in human keratinocytes (138). Genistein is also a potent antioxidant. Genistein scavenges peroxyl free radicals,thereby protecting against lipid peroxidation in vitro (139) and in vivo (140). Thedecreased incidence of cardiovascular disease with high soy diets may be due togenistein’s inhibiting the oxidation of low density lipoprotein (LDL) cholesterol in bothaqueous and lipophilic environments. Of direct importance in protection from UV-inducedskin damage, genistein has been shown to inhibit in vitro chemical and UV-induced DNAoxidation (141) as well as psoralen plus UVA (PUVA) DNA damage (142,143). The factthat genistein also reduces erythema and histologic inflammation caused by PUVA mayhave implications for PUVA therapy by reducing possible short- and long-termadverse reactions. Topical genistein (10 mmol/cm2) protects against acute and chronic UV damage tothe skin (134,135). After exposure of Skh:1 hairless mice to UVB, topical genisteinblocked acute skin burns and inhibited UVB-induced cutaneous wrinkling, asdemonstrated clinically in Figures 8 and 9 (134,135). Histologic analysis confirmed thattopical genistein blocks the signs of chronic photodamage—epidermal hyperplasia andreactive acanthosis with nuclear atypia (Fig. 10) (134,135). At a molecular level, UV-induced damage to DNA (as measured by the biomarker 8-hydroxy-20-deoxyguanosine)was reduced (144). Inhibition of acute UV-induced erythema with topical genistein(5 mmol/cm2) was also demonstrated in humans (134,135): Topical genistein(applied 30 minutes before UVB) inhibited by 1 MED the UVB-induced erythema, asshown in Figure 11. Thus, topical genistein may protect human skin against photodamage. Equally impressive is the fact that topical genistein also inhibits skin cancer,a consequence of chronic UVB damage. Both the incidence and the multiplicity of UVB-induced skin tumors in Skh:2 hairless mice were reduced by about 90% after 25 weeks ofUVB exposure (134,135). Figure 12 shows protection from carcinogenesis ofrepresentative mice treated with genistein before UVB exposure. Also, after chemicalinduction and promotion of skin tumors, topical genistein inhibited tumor cell number by60–75% (144). Another possible dermatologic benefit of genistein is as a phytoestrogen. The skinhas both alpha and beta nuclear estrogen receptors (145) through which estrogen bindingcan regulate linked genes of proliferation and differentiation. Genistein has a 30-foldFigure 8 Effect of genistein on UVB-induced acute skin burns in mice were treated topically with5 mmol genistein 60 minutes before UVB at a dose of 1.8 kJ/cm2 for 10 days. Photographs weretaken 24 hours after last UVB irradiation. (A) Negative control (sham irradiation), (B) vehicle beforeUVB, (C) 5 mmol genistein before UVB. Source: From Ref. 135.

Topical Nutritional Antioxidants 389Figure 9 Effect of genistein on UVB-induced chronic photodamage in mice. Skh:1 hairless micewere treated topically with 5 mmol genistein 60 minutes before or five minutes after twice-weeklyUVB at a dose of 0.3 kJ/cm2 for four weeks. Photographs were taken 24 hours after last UVBirradiation. (A) Negative control (sham irradiation), (B) vehicle plus UVB, (C) 5 mmol genisteinbefore UVB, (D) 5 mmol genistein after UVB. Source: From Ref. 135.higher affinity for ER-beta than ER-alpha (146), but a greater ER-alpha agonist activitythan ER-beta (147). Though estradiol has 700-fold more ER-alpha and 45-fold more ER-beta activity than genistein, the possible biologic effect of genistein through dietary soyisoflavones may be important. Oral (148,149) and topical estrogen (150,151) increase thecollagen content of skin which diminishes with aging. This effect is especially dramatic inwomen during and after menopause (152). Genistein may reduce the atrophic appearanceFigure 10 Effect of genistein on histological alterations in mice exposed to UVB. Skh:1 hairlessmice were treated topically with 5 mmol genistein 60 minutes before UVB at a dose of 0.3 kJ/cm2twice weekly for four weeks. Mice were killed 24 hours after the last UVB irradiation and skinspecimens were taken for histology. (A) Negative control (sham irradiation), (B) vehicle plus UVB,(C) 5 mmol genistein before UVB. Source: From Ref. 135.

390 BurkeFigure 11 Effect of genistein on UVB-induced erythema in human skin. The study was performedin the phototherapy unit in the Department of Dermatology, Mount Sinai Hospital. UVB fluences useda range from 0 to 100 mJ/cm2. Genistein was applied to dorsal skin either 60 minutes before orfive minutes after UVB exposure. Photographs were taken 24 hours after UVB irradiation. A minimalerythema dose (MED) for this individual was 40 mJ/cm2. Lane 1: Vehicle before UVB; lane 2: notreatment before or after UVB; lane 3: 1mmol genistein/cm2 of skin before UVB; lane 4: 1mmolgenistein/cm2 of skin after UVB; and lane 5: dose response of topical genistein applied before UVB (1MED) at a dose ranging from 0.05 to 5 mmol/cm2. Source: From Ref. 135.of aging skin both by preventing photodamage through inhibition of metalloproteinases inhuman skin (independent of sunscreen effect) and by stimulating collagen synthesis.Indeed, genistein does increase collagen gene expression in fibroblasts in vitro (153). Thus, topical genistein shows promise not only in protecting the skin against acuteand chronic photodamage but also in enhancing the diminished collagen synthesis ofnormal intrinsic aging.Challenges in FormulationAs described above, topical 5 mmol genistein has been studied extensively and has beenproven to protect from UV damage. Unlike vitamin C, genistein is a stable molecule.Unlike vitamin E and Se, genistein is absorbed transcutaneously to give protectiveactivity. The only challenge in formulation is to have a pure source of genistein withoutother soy contaminants.ALPHA-LIPOIC ACIDBackgroundR-Alpha lipoic acid (a-LA) is synthesized in the mitochondria of plants and animals,including humans. Natural a-LA is covalently bound to proteins via lysine; thus onlyminimal free a-LA enters the circulation after biosynthesis or eating a-LA-rich food (22).The lipoamide is a required co-factor for two enzymes in the citric acid cycle. It is alsoessential for the formation of a cofactor required in nucleic acid synthesis and for themetabolism of branched-chain amino acids.

Topical Nutritional Antioxidants 391Figure 12 Representative photograph of inhibition of photocarcinogenesis in mice treated withgenistein. (A) Hairless mice irradiated with 0.3 kJ/m2 thrice weekly for 25 weeks. (B) Mice treatedwith 1 mmol genistein before UVB exposure. (C) Mice treated with 5 mmol genistein before UVBirradiation. Source: From Ref. 135. With oral supplements of free a-LA, unbound a-LA is transported to tissues (22).Free a-LA is rapidly metabolized by the liver, so that the half-life in blood afterabsorption is only about 30 minutes, limiting the amount delivered (22). High tissue levelsare short-lived since most free a-LA is rapidly reduced to dihydrolipoic acid (DHLA), asshown in Figure 13 (21,22). Notwithstanding this transient availability, free a-LA has been shown to betherapeutic for autoimmune liver disease by binding autoantibodies, heavy metalintoxication by trapping circulating metals, diabetic polyneuropathy by preventingoxidative damage, and mushroom poisoning (22). Although not normally found insignificant amounts in the skin, a-LA is a good candidate for topical application (21,154): † As a small, stable molecule, it could successfully be percutaneously absorbed. † As a potent antioxidant it might protect from UV and other free radical environmental changes; † Because it is soluble in both aqueous and lipid environments, it can interact with oxidants and antioxidants in many cellular compartments.

392 BurkeFigure 13 The molecular structures of a-lipoic acid and dihydrolipoic acid.Mechanisms of ActionTopical a-LA with its metabolite DHLA could protect the skin from oxidative stress inseveral ways. Both a-LA and DHLA are highly effective antioxidants, as summarized inTable 1 (22). DHLA is actually the more potent form. Both successfully scavenge ROSin vitro and in vivo. However, pro-oxidant activity has been observed. This occurs whenan antioxidant reacts with a ROS scavenger, forming a product that is more harmful thanthe scavenged ROS. Fortunately a-LA can act as an antioxidant against the pro-oxidantactivity of DHLA (22). Both a-LA and DHLA further provide antioxidant activity bychelating Fe2C and Cu2C(a-LA) and Cd2C (DHLA) (22). DHLA, unlike a-LA, has the capacity to regenerate the endogenous antioxidantsvitamin E, vitamin C, gluthatione, and ubiquinol, as illustrated in Figure 3. This is clearlyTable 1 Antioxidant Activity of a-Lipoic Acid and Dihydrolipoic Acid (DHLA) a-Lipoic acid DHLAAntioxidant C CC C C Scavengers reactive oxygen species (ROS) C K Chelates metals: Fe2C, Cu2C K C Cd2C K C Regenerates endogenous antioxidants (vitamin E, vitamin C, K C C C glutathione, ubiquinol) Repairs oxidatively damaged proteinsPro-oxidantAbbreviations: C, indicates activity; CC, indicates greater activity; K, indicates no activity.Source: Adapted from Ref. 22.

Topical Nutritional Antioxidants 393of great importance for skin, since UV exposure directly depletes especially ubiquinoneand vitamin E as well as vitamin C, thereby stressing the other linked antioxidants (154).Regeneration of these major membrane and cytosol antioxidants gives cascadingprotection. Increases in the other important antioxidants (intracellular glutathione andextracellular cysteine) are noted when a-LA is added to cell cultures (22). Vitamin Edeficient animals do not show symptoms (weight loss, neuromuscular abnormalities) whensupplemented with a-LA (155). Although a-LA is a potent antioxidant, it provides no effective protection against UV-induced erythema or cell damage measured as sunburn cells (156). However, a-LA (but notDHLA) acts as an anti-inflammatory agent by reducing the production and inhibiting thebinding of transcription factors such as nuclear factor-kappa B (NF-kappa B), therebyindirectly affecting the gene expression of inflammatory cytokines such as tumor necrosisfactor-a (TNF-a) and interleukins (157). DHLA (but not a-LA) can repair oxidativelydamaged proteins, which in turn regulate the activity of proteinase inhibitors such as a l-AP,an inflammatory modulator (158). As antioxidants, both a-LA and DHLA are directly anti-inflammatory by virtue of their quenching oxidants secreted by leukocytes andmacrophages at sites of inflammation (158). a-LA may prove to retard and correct both intrinsic and extrinsic aging of theskin as well as other organs (159). By damaging DNA, the ROS continuously formedin normal metabolism may be largely responsible for the functional deterioration oforgans with aging. A decrease in cellular protein and DNA as well as in a-LA levelshas been measured in aged rat liver, kidney, and spleen (160). Supplementation witha-LA increases nucleic acid and protein levels in the elderly organs (160). Similarly,the age-related decrease of mitochondiral function in cardiac and brain cells can beimproved with a-LA supplementation (161). Clearly, aging skin might similarlybenefit.Formulationa-LA has been found to penetrate rapidly into murine and human skin to dermal andsubcutaneous layers. Two hours after application of 5% a-LA in propylene glycol,maximum levels of a-LA were attained in the epidermis, dermis, and subcutaneous tissue(154). The stratum corneum concentration of a-LA predicted the penetration and levels inthe underlying skin. 5% of the a-LA was converted to DHLA in both the epidermis anddermis, leading the researchers to conclude that both keratinocytes and flbroblasts reducea-LA (154).EfficacyTo evaluate possible improvement to photodamage, a split-face study was done on 33women (162). Topical application twice daily of 5% lipoic acid cream for 12 weeksdecreased skin roughness by 50.8% (as measured by laser profilometry) when comparedwith the placebo. Clinical and photographic evaluation showed reduction in lentigenes andfine wrinkles in this and one other study (163). Clearly, topical a-LA should be furtherinvestigated by quantitative techniques to confirm these results and to elucidatemechanisms of action.

394 BurkeUBIQUINONEBackgroundUbiquinone (coenzyme Q10, Figure 14) is so named because it is ubiquitous in virtuallyall living cells, excluding some bacteria and fungi, although the level is quite variable.Since most human tissues synthesize ubiquinone, it is not considered to be a vitamin. Ubiquinone is primarily located in the inner mitochondrial membrane where it isessential for the production of the ATP required for all vital cellular functions (164). Untilrecently, ubiquinone was thought to function only in energy transduction; however, withthe discovery that ubiquinone is also an antioxidant within subcellular membranes,new roles are now being recognized. Ubiquinone can regenerate reduced tocopherol, asdepicted in Figure 3. In fact, within membranes the amount of ubiquinone is from three tothirty times that of tocopherol (165). Without ubiquinone, the regeneration of tocopherolwould be very slow (166,167).Mechanisms of ActionThe fact that ubiquinone can serve not only as an energy generator but also as anantioxidant in the skin has been investigated (168,169). In cultured human keratinocytesexposed to hydrogen peroxide, the detrimental increase in the activity of phosphotyrosinekinase was suppressed and the loss of glulathione was prevented (169). Ubiquinone (0.3%)also suppressed the UVA-induced reduction of mitochondrial membrane potential infibroblasts from both young and old human donors (169). Finally, the UV-inducedoxidative damage to DNA in keratinocytes in vitro was reduced significantly withubiquinone (169). Ubiquinone can retard loss of hyaluronic acid and slowdown of cell division—bothmanifestations of intrinsic aging. Aged human fibroblasts in vitro produce lessglycosaminoglycan and proliferate more slowly than young cells. The addition ofubiquinone increased levels of glycosaminoglycan as well as rates of cell division (169). Ubiquinone further protects from the UVA-induced degradation of collagen. Bothubiquinone and vitamin E were shown in vitro to suppress fibroblast production of UVA-induced collagenase, thereby markedly retarding collagen breakdown (169). Ubiquinonesuppressed collagenase expression over a longer period of time than did vitamin E.Figure 14 The molecular structure of ubiquinone. The “head” of the ubiquinone molecule is afully substituted quinone ring which does not allow addition reactions with thiol groups in the cell(such as GSH). Ubiquinones vary by the length of the “tail”: Q10 has 10 isoprene units. Humans cansynthesize Q10 out of the other coenzymes Q1 to Q9, though this ability decreases with age.

Topical Nutritional Antioxidants 395Figure 15 Reduction of wrinkles with ubiquinone. Silicone replicas of the skin, analyzed bylaser profilometry, show a significant reduction in the depth of periorbital fine lines and wrinkles ina 46-year-old female after 10 weeks of twice-daily application of ubiquinone cream (Eucerin Q10Anti-Wrinkle Sensitive Skin Creme). Source: From Ref. 168.FormulationThe concentration of ubiquinone is highest in organs with high rates of metabolism such asheart, kidney, and liver, where it functions as an energy transfer molecule (164). In skin,the level of ubiquinone is relatively low, with 10-fold higher levels in the epidermis than inthe dermis (169). Thus, the epidermis might potentially benefit from topical ubiquinone.Indeed it has been demonstrated that ubiquinone can be topically absorbed. Application ofubiquinone in ethanol to porcine skin achieved 20% penetration into the epidermis and27% into the dermis (169).Substantiation of EfficacyUbiquinone’s antioxidant action in skin was confirmed in vitro by sophisticated ultra-weakphoton emission (UPE) (169). Increased antioxidants result in decreased UPE. Elderlyvolar skin demonstrated 33% reduction in antioxidant activity when compared withyoung skin. This was corrected after one week of twice-daily topical application of 0.3%ubiquinone. After UVA irradiation, a decrease in antioxidant activity was noted; this losswas significantly corrected with topical 0.3% ubiquinone. The efficacy of ubiquinol in reversing photoaging was further studied clinically(168). Ubiquinol cream (0.3%) was applied to one-half of the face and placebo to the otheronce daily for six months. Casts were made of the periorbital rhytides. The improvementcan be appreciated in the photographs shown in Figure 15. Quantitative microtopographydemonstrated a 27% reduction in the mean wrinkle depth. Another clinical measure of photoaging is stratum corneum cell size. With deceasedcell turnover time in aged skin, comeocytes become larger. Treatment once daily forsix months with ubiquinone cream decreased corneocyte size equivalent to rejuvenation of20 years (168). Thus, ubiquinone is be an effective antioxidant protecting the dermal matrixfrom both intrinsic and extrinsic aging, making it a potentially important cosmeceutical.SUMMARYNutritional antioxidants represent a novel category of cosmeceuticals. There is no doubt thathigher levels are achieved in the skin through topical application than with oral

396 Burkesupplementation, thus providing a protective antioxidant reservoir in the skin. Currentresearch indicates that topical vitamin E and C and L-SeMet provide UV photoprotectionand reverse photoaging. Ubiquinone and genistein may provide photoprotection. Inaddition, they as well as topical a-lipoic acid may retard both intrinsic aging andphotoaging. There is further evidence that a-lipoic acid and ubiquinone may also reversephotoaging. Thus, topical antioxidants continue to be an important area ofcosmeceutical research.REFERENCES 1. Pauling L. How to Live Longer and Feel Better. New York: W.H. Freeman & Company, 1987. 2. Shindo Y, Wit E, Han D, et al. Dose response effects of acute ultraviolet irradiation on antioxidants and molecular markers of oxidation in murine epidermis and dermis. J Invest Dermatol 1994; 23:470–475. 3. Thiele JJ, Traber MG, Tsang KG, et al. In vivo exposure to ozone depletes vitamins C and E and induces lipid peroxidation in epidermal layers of murine skin. Free Radic Biol Med 1997; 23:85–91. 4. Darr D, Combs S, Dunsten S, et al. Topical vitamin C protects porcine skin from ultraviolet radiation-induced damage. Br J Dermatol 1992; 127:247–253. 5. Nakamura T, Pinnell SR, Darr D, et al. Vitamin C abrogates the deleterious effects of UVB radiation on cutaneous immunity by a mechanism that does not depend on TNF-alpha. J Invest Dermatol 1997; 109:20–24. 6. Alster T, West TB. Effect of vitamin C on postoperative CO2 laser resurfacing erythema. Dermatol Surg 1998; 24:331–334. 7. Bergfeld W, Pinnell S. Topical vitamin C. Dialogues in dermatology. Am Acad Dermatol 1996; 38:1. 8. Kivirikko KI, Myllyla R. Post-translational processing of procollagens. Annu NY Acad Sci 1996; 11:250–253. 9. Savini I, Catei V, Rossi A, et al. Characterization of keratinocyte differentiation induced by ascorbic acid, protein kinase C involvement and vitamin C homeostasis. J Invest Dermatol 2002; 118:372–379. 10. Phillips CL, Combs SB, Pinnell SR. Effects of ascorbic acid on proliferation and collagen synthesis in relation to donor age of human dermal fibroblasts. J Invest Dermatol 1994; 103:228–232. 11. Maeda K, Fukuda M. Arbutin: mechanism of its depigmenting action in human melanocyte culture. J Pharmacol Exp Ther 1996; 276:765–769. 12. Davidson JM, Luvalle PA, Zola O, et al. Ascorbate differentially regulates elastin and collagen biosynthesis in vascular smooth muscle cells and skin fibroblasts by pretranslational mechanisms. J Biol Chem 1997; 272:345–352. 13. Uchida Y, Behne M, Quiec D, et al. Vitamin C stimulates sphingolipid production and markers of barrier formation in submerged human keratinocyte cultures. J Invest Dermatol 2001; 117:1307–1313. 14. Catiel-Higournenc, Ferrais C, Guey C, et al. Private communications, L’Oreal Advanced Research Laboratories, Clichy and Aulnay-sous-Bois, France, 1998. 15. Pinnell SR, Madey DL. The benefits of topial vitamin C (L-Ascorbic Acid) for skin care and UV protection. Aesth Surg J 1998; 18:126–134. 16. Pinnell SR, Yang HS, Omar M, et al. Topical L-Ascorbic Acid, Percutaneous Absorption Studies. Dermatol Surg 2001; 27:137–142. 17. Podda M, Weber C, Traber MG, et al. Simultaneous determination of tissue tocopherols, tocotrienols, ubiquinols, and ubiquinones. J Lipid Res 1996; 37:893–901. 18. Thiele JJ. Oxidative targets in the stratum corneum, a new basis for antioxidative strategies. Skin Pharmacol Appl Skin Physiol 2001; 14:87–91. 19. Traber MG, Sies H. Vitamin E in humans: demand and delivery. Annu Rev Nutr 1996; 16:321–347.

Topical Nutritional Antioxidants 39720. Thiele JJ, Schroeter C, Hsieh SN, et al. The antioxidant network of the stratum corneum. Curr Probl Dermatol 2001; 29:26–42.21. Podda M, Zollner TM, Grundmann-Kollmann M, et al. Activity of a-lipoic acid in the protection against oxidative stress in skin. Curr Probl Dermatol 2001; 29:43–51.22. Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol 1997; 29:318–331.23. Packer JE, Slater TF, Willson RL. Direct observation of a free radical interaction between vitamin E and vitamin C. Nature 1979; 278:737–738.24. Stoyanovsky DA, Osipov AN, Quinn PJ, et al. Ubiquinone-dependent recycling of vitamin E radicals by superoxide. Arch Biochem Biophys 1995; 323:343–351.25. Burke KE, Clive J, Combs GF, et al. Effects of topical and oral vitamin E on pigmentation and skin cancer induced by ultraviolet irradiation in Skh, 2 hairless mice. Nutr Cancer 2000; 38:87–97.26. Potapenko A, Abijev G, Pistsov M, et al. PUVA-induced Erythema and changes in Mechanoelectrical properties of skin inhibition by Tocopherols. Arch Dermatol Res 1984; 276:12–16.27. Wallat S. Natural source of vitamin E for skin care. La Grange, IL: Henkel Symposium, 1989.28. Mazenus K, Mulzzuddin N, Kasman K, et al. The use of antioxidants in providing protection from chronic suberythemal UVB exposure. 16th IFSCC Conf. Oct 1990; Vol. 1: pp.24–34.29. Berton TR, Conti CJ, Mitchell DL, et al. The effect of vitamin E Acetate on ultraviolet- induced mouse skin Carcinogenesis. Mol Carcinog 1998; 23:175–184.30. Record IR, Dreosti IE, Konstantinopoulos M, et al. The infuence of topical and systemic vitamin E on ultraviolet light-induced skin damage in hairless mice. Nutr Cancer 1991; 16:219–225.31. Trevithick J, Xiong H, Lee S, et al. Topical Tocopherol Acetate Reduces Post-UVB, Sunburn associated Erythema, Edema and Skin Sensitivity in Hairless Mice. Arch Biochem Biophys 1992; 296:575–582.32. Kamimura M. Anti inflammatory activity of Vitamin E. J Vitaminol 1972; 18:204–209.33. Landuik S. The role of antioxidants in skin care and protection. Veris Research Summary. La Grange, IL: Veris Research Inf Service, 1997:1–8.34. Pathak MA, Stratton K. Free radicals in human skin before and after exposure to light. Arch Biochem 1968; 123:468–476.35. Moody CS, Hassan HM. Mutagenicity of oxygen free radicals. Proc Natl Acad Sci USA 1982; 79:2855–2859.36. Meffert H, Diezel H, Sonnichson N. Stable lipid peroxidation products in human skin: detection, ultraviolet light-induced increase, pathogenic importance. Specialia 1976; 32:1397–1398.37. Imlay JA, Chin SM, Linn S. Toxic DNA damage by hydrogen peroxide through the fenton reaction in vivo and in vitro. Science 1988; 240:640–642.38. Borek C. The induction and regulation of radiogenic transformation in vitro, cellular and molecular mechanisms. In: Grunberger D, Goff S, eds. Mechanisms of Cellular Transformation by Carcinogenic Agents. New York: Pergamon, 1987:151–195.39. Diplock AT, Lucy JA. The biochemical modes of action of vitamin E and selenium: a hypothesis. FEBS Lett 1973; 29:205.40. Odukoya O, Hawach F, Shklar G. Retardation of experimental oral cancer by topical vitamin E. Nutr Cancer 1984; 6:98–104.41. Slaga TJ, Bracken WM. The Effects of antioxidants on skin tumor initiation and aryl hydrocarbon hydroxylase. Cancer Res 1977; 37:1631–1635.42. Borek C. Vitamin E as an anticarcinogen. Ann NY Acad Sci 1989; 570:417–519.43. Black H, Lenger W, McCann V, et al. Relation of UV dose to antioxidant modification of photocarcinogenesis. J Am Coll Toxicol 1983; 2:201–207.44. Bissett D, Chatterjee R, Hannon D. Protective effect of a topically applied Antioxidant plus an antiinflammatory agent against ultraviolet radiation-induced chronic skin damage in the hairless mouse. J Soc Cosmet Chem 1992; 43:85–92.45. Gensler H, Magdaleno M. Topical vitamin E inhibition of immunosuppression and tumorigenesis induced by ultraviolet irradiation. Nutr Cancer 1991; 15:97–106.46. Gerrish K, Gensler H. Prevention of photocarcinogenesis by dietary vitamin E. Nutr Cancer 1993; 19:125–133.47. Mayer P, Pittermann W, Wallat S. The effects of vitamin E on the skin. Cosmet Toilet 1993; 108:99–109.

398 Burke 48. Burton GW, Traber MG, Acuff RV, et al. Human plasma and tissue a-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. Am J Clin Nutr 1998; 67:669–684. 49. Azzi A, Breyer I, Feher M, et al. Specific cellular responses to a-tocopherol. J Nutr 2000; 131:369–375. 50. Potokar M, Holtmann W, Werner-Busse A. Effectiveness of vitamin E protecting against UV light—comparative testing of the natural tocopherols on the skin of the hairless mouse. Fat Sci Technol 1990; 92:406–410. 51. Gensler HL, Aickin M, Peng YM, et al. Importance of the form of topical vitamin E for prevention of photocarcinogenesis. Nutr Cancer 1996; 26:183–191. 52. Hart M, Vitamin E. A contact sensitizer. Schoch Lett 1990; 40:48. 53. Saperstein H, Rapaport M, Rielschel RL. Topical vitamin E as a cause of erythema multiforme like eruption. Arch Dermatol 1984; 120:906–908. 54. Kamimura M, Matsuzawa T. Percutaneous absorption of a-tocopheryl acetate. Vitaminology 1968; 14:151–159. 55. Norkus EP, Bryce GF, Bhagavan HN. Uptake and bioconversion of a-tocopheryl acetate to a-tocopherol in skin of hairless mice. Photochem Photobiol 1993; 57:613–615. 56. Trevischick JR, Mitton KP. Topical application and uptake of vitamin E acetate by the skin conversion to free vitamin E. Biochem Mot Biol Int 1993; 31:869–878. 57. Nabi Z, Tavakkol A, Dobks M, et al. Bioconversion of vitamin E acetate in human skin. Curr Probl Dermatol 2001; 29:175–186. 58. Rangarajan M, Zatz JL. Kinetics of permeation and metabolism of a-tocopherol and a- tocopheryol acteate in Micro-Yucatan pig skin. J Cosmet Sci 2001; 52:35–50. 59. Baachong W, Artmann C, Hueglin D, et al. Direct evidence for bioconversion of vitamin E acetate into vitamin E: an ex vivo study in viable human skin. J Cosmet Sci 2001; 52:155–161. 60. Beijersbergen van Hanegouwne GMJ, Junginger HE, de Vries H. Hydrolysis of RRR-a- tocopheryl acetate (vitamin E acetate) in the skin and its UV protecting activity (an in vivo study with the rat). J Photochem Photobiol B 1995; 29:45–51. 61. Rangarajan M, Zatz JL. Effect of formulation on the delivery and metabolism of a-tecopheryl acetate. J Cosmet Sci 2001; 52:225–236. 62. Kramer-Stickland K, Liebler DC. Effect of UVB on hydrolysis of a-tocopherol acetate to a- tocopherol in mouse skin. J Invest Dermatol 1998; 111:302–307. 63. Saumann LS, Spencer J. The effects of topical vitamin E on the cosmetic appearance of scars. Dermatol Surg 1999; 25:311–315. 64. Jenkins M, Alexander JW, MacMillan BG, et al. Failure of topical steroids and vitamin E to reduce postoperative scar formation following reconstructive surgery. J Burn Cars Rehabil 1986; 7:309–312. 65. Galeano M, Torre V, Deodato B, et al. Raxofelast, a hydrophilic vitamin E-like antioxidant, stimulates wound healing in genetically diabetic mice. Surgery 2001; 129:467–477. 66. Altavilla D, Saitta A, Cucinotta D, et al. Inhibition of lipid peroxidation restores impaired vascular endothelial growth factor expression and stimulates wound healing and angiogenesis in this genetically diabetic mouse. Diabetes 2001; 50:667–674. 67. Tsourel-Inkita E, Hercogova J, Lorti T, et al. Evaluation of dietary intake of vitamin E in the treatment of atopic dermatitis: a study of the clinical course and evaluation of the immunoglobulin E serum levels. Int J Dermatol 2002; 41:146–150. 68. Sander CS, Hamm R, Elsner P, et al. Oxidative stress in malignant melanoma and non- melanoma skin cancer. Br J Dermatol 2003; 148:913–922. 69. Malafa MP, Fokum FD, Smith L, et al. Inhibition of angiogenesis and promotion of melanoma dormancy by vitamin E succinate. Ann Surg Oncol 2002; 9:1023–1032. 70. Malafa MP, Fokum FD, Mowlavi A, et al. Vitamin E inhibits melanoma growth in mice. Surgery 2002; 131:85–91. 71. Shamberger RJ, Frost DV. Possible protective effect of selenium against human cancer. Cancer Med Assoc J 1969; 104:82–84. 72. Combs GF, Jr., Gray WP. Chemopreventive agents: selenium. Pharm Exp Ther 1998; 79:179–192. 73. Combs GF, Jr., Liu J. Selenium as a cancer preventive agent. In: Hatfield D, ed. Selenium: Molecular Biology and Role in Health. New York: Kluwer Academic, 2001:205–217.

Topical Nutritional Antioxidants 39974. Whanger PD. Selenium and its relationship to cancer: an update. Br J Nutr 2004; 91:11–28.75. Ip C. Lessons from basic research in selenium and cancer prevention. J Nutr 1998; 128:1845–1854.76. Combs GF, Jr. Current evidence and research needs to support a health claim for selenium and cancer prevention. J Nutr 2005; 135:343–347.77. Redman C, Scott JA, Baines AT, et al. Inhibitory effect of selenomethionine on the growth of three selected human tumor cell lines. Cancer Lett 1998; 125:103–110.78. Combs GF, Jr. Selenium. Nutrition and Cancer Prevention. In: Micozzi MS, Moon TE, eds. New York: Dekker, 1989:389–420.79. Willett WC, Stampfer MJ. Selenium and cancer. BMJ 1988; 297:573–574.80. Zachara BA, Marchaluk-Wisniewaka E, Maciag A, et al. Decreased selenium concentration and glutathione peroxidase activity in blood and increase of these parameters in malignant tissue of lung cancer patients. Lung 1997; 175:321–332.81. Clark LC, Graham GF, Crainse RG, et al. Plasma selenium and skin neoplasms: a case control study. Nutr Cancer 1984; 6:13–21.82. Clark LC, Combs GF, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. JAMA 1996; 276:1057–1063.83. Dufield-Lillico A, Slate E, Reid M, et al. Selenium supplementation and secondary prevention. J Natl Cancer Inst 2003; 19:1477–1481.84. Stadtman TC. Mammalian selenoenzymes. Ann NY Acad Sci 2000; 894:399–402.85. McKenzie RC. Selenium, ultraviolet radiation and the skin. Clin Exp Dermtaol 2000; 8:631–636.86. Allan CB, Lacourciere GM, Steadman TC. Responsiveness of melanoproteins to dietary selenium. Ann Rev Nutr 1999; 19:1–16.87. Rafferty TS. Selenoprotein expression and protection from UV-induced skin damage. PhD Thesis. University of Edinburgh, 2000.88. Stewart MS, Cameron GS, Pence BC. Antioxidant nutrients protect against UVB-induced oxidative damage to DNA of mouse keratinocytes in culture. J Invest Dermatol 1996; 106:1086–1089.89. Seo YR, Sweeney C, Smith ML. Selenomethionine induction of DNA repair response in human fbroblasts. Oncogene 2002; 21:3663–3669.90. Seo YR, Kelley MR, Smith ML. Selenomethionine regulation of p53 by a ref 1-dependent redox mechanism. PNAS 2002; 99:14548–14553.91. Smith ML, Lancia JK, Mercer TI, et al. Selemium compounds regulate p53 by common and distinctive mechanisms. Anticancer Res 2004; 24:1401–1408.92. Mosan A, Morliere P, Marquis I, et al. Effects of selenium on UVA-induced lipid peroxidation in cultured human skin fibroblasts. Skin Pharmcol 1995; 8:139–148.93. Rafferty TS, McKenzie RC, Hunter JAA, et al. Differential expression of selenoproteins by human skin cells and protection by selenium from UVB-radiation-induced cell death. Biochem J 1998; 332:231–236.94. Stewart MS, Cameron CS, Pence DC. Antioxidants nutrients protect against UVB-induced oxidative damage to DNA of mouse keratinocytes in culture. J Invest Dermatol 1996; 106:1086–1089.95. Rafferty TS, Beckett GJ, Hunter JAA, et al. Selenium compounds inhibit ultraviolet B (UVB) induced keratinocyte cytoline production and cell death by apoptosis. J Invest Dermatol 1995; 110:653.96. Leccia M-T, Richard M-J, Joanny-Crisol F, et al. UVA-1 cytotoxicity and antioxidant defence in keratinocytes and fbroblasts. Eur J Dermatol 1998; 8:478–482.97. Rafferty TS, Beckett GJ, Walker C, et al. Selenium protects primary human keratinocytes from apoptosis induced by exposure to ultraviolet radiation. Clin Exp Dermatol 2003; 28:294–300.98. Schallreuter KU, Pittelkow MR, Wood JM. Free radical reduction by thioredoxin reductase at the surface of normal and vitiliginous human keratinocytes. J Invest Dermatol 1988; 87:728–732.99. Schallreuter KU, Hordinsky MK, Wood JM, et al. Thioredoxin reductase. Role in the radical reduction in different hypopigmentation disorders. Arch Dermtol 1987; 123:615–619.

400 Burke100. Roberts ME. Antiinflammation study II, antiinflammatory properties of selenium. Toxicol Appl Pharmacol 1963; 5:500.101. Spallholz TE, Boylan LM, Larson HS. Advances in understanding selenium’s role in the immune system. Ann NY Acad Sci 1990; 587:123–139.102. McKenzie RC, Rafferty TS, Beckett GJ. Selenium is an essential element for immune function. Immunol Today 1998; 19:342–345.103. Kiremidjian-Schumacher RM, Wiske HI, et al. Effect of selenium on the expression of high affinity interleukin-2 receptors. Proc R Soc Exp Biol Med 1992; 200:36–43.104. Cummins LM, Kimuka ET. Safety evaluation of selenium sulfide antidandruf shampoos. Toxicol Appl Pharmacol 1971; 20:89–96.105. Burke KE, Combs GF, Gross EG, et al. The effects of topical and oral L-selenomethionine on pigmentation and skin cancer induced by ultraviolet irradiation. Nutr Cancer 1992; 17:123–137.106. Burke KE, Bedford RG, Combs GF, et al. The effect of topical I-selenomethionine on minimal erythema dose of ultraviolet irradiation in humans. Photodermatol Photoimmunol Photomed 1992; 9:52–57.107. Burke KE. Method for the prevention and reversal of the extrinsic aging of the skin by transdermal application of selenamino acids and compositions therefore. U.S. Patent #5,330,757, July 19, 1994.108. Chan AC. Partners in defense, vitamin E and vitamin C. Can J Physiol Pharmacol 1993; 71:725–731.109. Eberlein-Konig B, Placzek M, Przybilla B. Protective effect against sunburn of combined systemic ascorbic acid (vitamin C) and d-a-tocopherol (vitamin E). J Am Acad Dermatol 1998; 38:45–48.110. Fuchs J, Kern H. Modulation of UV-light-induced skin inflammation by d-a-tocopherol and L ascorbic acid: a clinical study using solar simulated radiation. Free Radic Biol Med 1998; 25:1006–1012.111. Lin J, Selim A, Shea C, et al. UV photoprotection by combination topical antioxidants vitamins C and E. J Am Acad Dermatol 2003; 48:866–874.112. Dreher F, Gabard B, Schwindt DA, Malbach HI. Topical melatonin in combination with vitamins E and C protects skin from ultraviolet-induced erythema: a human study in vivo. Br J Dermatol 1998; 139:332–339.113. Quevedo WC, Holstein TJ, Dyckman J, McDonald CI. The responses of the human epidermal melanocyte system to chronic erythemal doses of UVR in skin protected by topical applications of a combination of vitamins C and E. Pigment Cell Res 2000; 13:190–192.114. Rica-Evans CA, Miller NJ, Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 1996; 20:933–956.115. Ou S, Kwok K-C. Ferulic acid: pharmaceutical functions, preparations and applications in foods. J Sol Food Agric 2004; 84:1261–1269.116. Trombino S, Serini S, Di Nicuelo F, et al. Antioxidant effect of ferulic acid in isolated membranes and intact cells: Synergistic interactions with a-tocopherol, beta-carotene, and ascorbic acid. J Agric Food Chem 2004; 52:2411–2420.117. Lesca P. Protective effects of ellegic acid and other plant phenols on benzo[a]pyrene-induced neoplasia in mice. Carcinogensis 1983; 4:1651–1653.118. Kawabata K, Yamamoto T, Hara A, et al. Modifying effects of ferulic acid on azoxymethano- induced colon carcinogenesis in F344 rats. Cancer Lett 2000; 157:15–21.119. Salja A, Tomakio A, Trombotta D, et al. In vitro and in vivo evaluation of caffeine and ferulic acids as topical photoprotective agents. J Pharm 2000; 188:39–47.120. Lin F-H, Lin J-Y, Gupta RD, et al. Ferulic acid stabilizes a solution of vitamins C and E and doubles its photoprotection of skin. J Invest Dermatol 2005; 125:826–832.121. Borek C, Ong A, Mason H, et al. Selenium and vitamin E inhibit radiogenic and chemically- induced transformation in vitro via diferent mechanisms. Proc Natl Acad Sci 1986; 83:1490–1494.122. Burke KE, Clive J, Combs GF, et al. The effects of topical L-selenomethionine with topical and oral vitamin E on pigmentation and skin cancer induced by ultraviolet irradiation in Skh:2 hairless mice. J Am Acad Dermatol 2003; 49:458–472.

Topical Nutritional Antioxidants 401123. Tham DM. Potential health benefits of dietary phytoestrogens: a review of the clinical, epidemiological and mechanistic evidence. J Clin Endocrinol Metab 1998; 83:2223–2225.124. Barnes S, Peterson TG, Coward L. Rational for the use of genistein-containing soy matrices in chemoprevention trials for breast and prostate cancer. J Cell Biochem Suppl 1995; 22:181–187.125. Messina M, Barnes S. The role of soy products in reducing risk of cancer. J Natl Cancer Inst 1991; 83:541–546.126. Messina M, Persky V, Setchell K, et al. Soy intake and cancer risk: a review of the in vitro and in vivo data. Nutr Cancer 1994; 21:113–131.127. Barnes S. Effect of genistein on in vitro and in vivo models of cancer. J Nutr 1995; 125:S777–S783.128. Limtrakul P, Sutrajit M, Semura R, et al. Suppressive effect of soybean milk protein on experimentally induced skin tumors in mice. Life Sci 1993; 53:1591–1596.129. Kiguchi K, Constantinou AI, Huberman E. Genestein-induced cell differentiation and protein linked DNA strand breakage in human melanoma cells. Cancer Commun 1990; 2:271–278.130. Menon LG, Kuttan R, Nair MG, et al. Effect of isoflavones genistein and daidzein in the inhibition of lung metastasis in mice induced by B16F-10 melanoma cells. Nutr Cancer 1998; 30:74–77.131. Li D, Yee JA, McGuire MH, et al. Soybean isoflavones reduce experimental metastasis in mice. J Nutr 1999; 29:1075–1078.132. Akiyama T, Ishida J, Nakagawa S, et al. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 1987; 262:5592–5595.133. Hunter T, Cooper JA. Protein-tyrosine kinase. Ann Rev Biochem 1985; 54:897–930.134. Wei H, Spencer J, Gelfand J, et al. The isofavone genistein: a new agent in dermatology? Cosmet Dermat 2001; 14:13–19.135. Wei H, Saladi R, Lu Y, et al. Isofavone genistein: photoprotection and clinical implications in dermatology. J Nutr 2003; 133:3811S–3819S.136. Wei H, Barnes S, Weng Y. The inhibition of tumor promoter-induced photo-oncogene expression mouse skin by soybean isoflavone genistein. Oncol Rep 1995; 3:125–128.137. Chan WH, Yu JS. Inhibition of UV irradiation-induced oxidative stress and apoptotic biochemical changes in human epidermal carcinoma A431 cells by genistein. J Cell Biochem 2000; 78:73–84.138. Fukunaga M, Oka M, Ichihashi M, et al. UV-induced tyrosine posphorylation of PKC delta and promotion of apoptosis in the HaCaT cell line. Biochem Biophys Res Commun 2001; 289:573–579.139. Hwang J, Sevanian A, Hodis HN, et al. Synergistic inhibition of LDL oxidation by phytoestrogens and ascorbic acid. Free Radic Biol Med 2000; 29:79–89.140. Wiseman H, O’Reilly JD, Adlercreutz H, et al. Isofavone phytoestrogens consumed in soy decrease F-2-isoprostane concentrations and increase resistance of low-density lipoprotein to oxidation in humans. Am J Clin Nutr 2000; 72:395–400.141. Wei H, Cal O, Rahn RO. Inhibition of UV light- and Fenton reaction-induced oxidative DNA damage by the soybean isoflavone genistein. Carcinogenesis 1996; 17:73–77.142. Liu ZS, Lu YH, Lebwohl M, et al. PUVA (d-methoxy-psoralen plus ultraviolet A) induces the formation of 8-hydroxy-20-deoxyguanosine and DNA fragmentation in calf thymus DNA and human epidermoid carcinoma cells. Free Radic Biol Med 1999; 27:127–133.143. Shyong EQ, Lu YH, Lazinsky A, et al. Effects of the isoflavone (genistein) on psoralen plus ultraviolet A radiation (PUVA)-induced photodamage. Carcinogenesis 2002; 23:317–321.144. Wei H, Bowen R, Zhang X, et al. Isoflavone genistein inhibits the initiation and promotion of two stage skin carcinogenesis in mice. Carcinogenesis 1998; 19:1509–1514.145. Brandenberger AW, Tee MK, Lee JY, et al. Tissue distribution of estrogen receptors alpha (er-alpha) and beta(er-beta) mRNA in the midgestational human fetus. J Clin Endocrinol Metab 1997; 82:3509–3512.146. Kuiper GG, Carlsson B, Grandien K, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrine 1997; 138:863–870.147. Barkhem T, Carlsson B, Nilsson S. Diferential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol Pharmacol 1998; 54:105–112.

402 Burke148. Castelo-Branco C, Duran M, Gonzalez-Merlo J. Skin collagen changes related to age and hormone replacement therapy. Maturitas 1992; 15:113–119.149. Maheux R, Naud F, Rioux M, et al. A randomized, double-blind, placebo-controlled study on the effect of conjugated estrogens on skin thickness. Am J Obstet Gynecol 1994; 170:642–649.150. Brincat M, Versi E, O’Dowd T, et al. Skin collagen changes in post-menopausal women receiving oestradiol gel. Maturitas 1987; 9:1–5.151. Varila E, Rantalia I, Oikarinen A, et al. The effect of topical oestradiol on skin collagen of post menopausal women. Br J Obstet Gynaecol 1995; 102:985–989.152. Affinto P, Palomba S, Sorrentino C, et al. Effects of postmenopausal hypoestrogenism on skin collagen. Maturitas 1999; 33:239–247.153. Greenwel P, Hu W, Kohanski RA, et al. Tyrosine dephosphorylation of nuclear proteins mimics transforming growth factor beta-1 stimulation of a-2 (1) collagen gene expression. Mol Cell Biol 1995; 15:6813–6819.154. Podda M, Traber MG, Packer L. Chapter 10: a-lipoate, antioxidant properties and effects on skin. In: Fuchs J, Packer L, Zimmer G, eds. Lipoic Acid in Health and Disease. New York: Dekker, 1997:163–180.155. Packer L, Tritscheler HJ, Wessel K. Neuroprotection by the metabolic antioxidant a-lipoic acid. Free Radic Biol Med 1997; 22:359–378.156. Pinnell SR, Lin J-Y, Lin P-H, et al. Alpha lipoic acid is ineffective as a topical photoprotectant of skin. Poster presentation, Washington, DC: 62nd Annual Meeting of the American Academy of Dermatology, 2004.157. Suzuki YJ, Aggarwal BB, Packer L. a-Lipoic acid is a potent inhibitor of NF-kB activation in human T cells. Biochem Biophys Res Commun 1992; 189:1709–1715.158. Packer L, Witt EH, Tritschler HJ. Alpha-lipoic acid as a biological antioxidant. Free Radic Biol Med 1995; 19:237–250.159. Podda M, Grundmann-Kollman M. Low molecular weight antioxidants and their role in skin ageing. Clin Exp Dermatol 2001; 26:578–582.160. Arivazhagan P, Panneerselvam C. Effect of DL-a-lipoic acid on tissue nucleic acid contents in aged rats. Pharmacol Res 2000; 42:223–226.161. Hagen TM, Ingersoll RT, Lykkesfeldt J, et al. (R)-a-Lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. PASEB J 1999; 13:411–418.162. Beitner H. Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% a-lipoic acid related to photoaging of facial skin. Br J Dermatol 2003; 149:841–849; Beitner H. Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% a-lipoic acid related to photoaging of facial skin. PASEB J 1999; 13:411–418.163. Perricone NV. Topical 5% alpha lipoic acid cream in the treatment of cutaneous rhytide. Aesthetic Surg J 2000; 20:218–222.164. Ernster L, Dallner G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta 1995; 1271:195–204.165. Turunen M, Sindelar P, Dallner G. Induction of endogenous coenzyme Q biosynthesis by administration of peroxisomal inducers. Biofactors 1999; 9:131–140.166. Quinn PJ, Fabisiak JP, Kagan VE. Expansion of the antioxidant function of vitamin E by coenzyme Q. Biofactors 1999; 9:149–154.167. Crane FL. Biochemical functions of coenzyme Q10. J Am Coil Nutr 2001; 20:591–598.168. Wrinkle Reduction Study. In: Eucerin Q10 Product Compendium 2003. Wilton, CT: Belersdorf Inc., 2003.169. Hoppe U, Bergemann J, Diem beck W, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors 1999; 9:371–378.

22What Is Next in Skin CareCosmetic Products?Lauren A. ThamanP&G Beauty, Sharon Woods Technical Center, Cincinnati, Ohio, U.S.A.The cosmetic industry has changed dramatically over the past 20 years with theintroduction of daily UV lotion in the late 1980s to fight future aging. No longer arewomen searching for hope in a jar but focusing on the latest over-the-counter breakthroughproducts with clinically demonstrated biological activity. This quest for skin health andyouthful beauty has driven many consumers to explore a variety of approaches. It has alsotriggered a renaissance in the world of skin care where health, beauty, and technology areconverging to create new and exciting opportunities. This frantic search for beauty and youth has stimulated a remarkable growth in theskin care industry. Skin care advances are moving quickly as they mirror advancingtechnology in pharmaceuticals and biotechnology. Global retail sales of anti-aging skincare products have increased 71% since 2000 (1). In 2004 skin care sales topped $12billion, with $7 billion of that being spent on facial treatments alone (2). As biotechno-logical and pharmaceutical research continues to result in technologic advances, skin carecompanies will continue to spend millions of dollars on incorporating these advances intoskin care products. The average woman will find more choices to aid her in the battleagainst aging, including customized products and new novel ingredients with increasedeffectiveness and more precise delivery.COSMECEUTICALSClearly cosmeceuticals are the fastest growing segment of the skin care market (3) andare currently the driving force in the field of skin care research (4). Cosmeceuticals arecosmetics that contain biologically active ingredients, and while these ingredients are notclassified as drugs, they do have documented functional treatment benefits. Whencosmeceuticals are labeled and marketed as cosmetics, they are not regulated by the FDA. Cosmeceuticals are used primarily to combat the effects of aging on the skin. Morewomen are yearning for healthy, youthful skin, fueling the demand for these anti-agingproducts. Younger women are also looking to these products as a preventive strategyagainst aging. Cosmetic companies are investing millions of dollars to develop new and 403

404 Thamanbetter actives for anti-aging products, and women of all ages are constantly trying thenewest product and consulting their dermatologists for therapeutic approaches to fight thesigns of aging. Retinoids are the most recognized anti-aging ingredient, comprising a family ofcompounds with structures and mechanisms of action that resemble those of vitamin A.Retinoids are essential nutrients which play a role in cell growth and differentiation (5).Tretinoin, the most popular retinoid, increases dermal collagen, cellular differentiation, andproliferation. It has been shown to improve skin’s global appearance, particularly affectingfine and coarse wrinkling, roughness, pigmentation, and sallowness (6,7). However,tretinoin is a drug regulated by the FDA. Retinol, first generation retinoid, is often added toover-the-counter cosmetics (8). Retinol must be converted to retinaldehyde and then to all-trans-retinoic acid within the keratinocyte to become active (9). Because retinol is acosmetic ingredient, it is not labeled as an active ingredient. While not labeled as such, manypublished studies demonstrate the significant biological action and efficacy of this cosmeticvitamin A derivative. Retinoids and other alternate metabolisms of vitamin A will continueto be key mainstay cosmeceutical ingredients. Another popular cosmeceutical affecting cellular proliferation is alpha-hydroxyacid (AHA). AHAs increase the type I collagen, mRNA, and hyaluronic acid content ofthe epidermis and dermis (3). They also renew the stratum corneum by promotingdesquamation. Glycolic acid, lactic acid, and malic acid are all examples of AHAs. Newergeneration polyhydroxy acids are also being studied; these PHAs provide additionalmoisturization compared to AHAs, and do not cause the irritating response associated withAHAs (10). They also possess antioxidant properties (10). A major class of cosmeceutical ingredients is antioxidants that mediate free-radicaldamage from UV radiation. Since the skin’s own supply of free-radical scavengers islimited, topical antioxidants, which scavenge free radicals and protect cells from damage,can attenuate skin damage from UV radiation. Topical antioxidants include vitamins Cand E, alpha-lipoic acid (ALA), and coenzyme Q10. In addition to their antioxidanteffects, these agents all have other documented anti-aging properties. Vitamin C hascollagen stimulating properties and has been shown to be photoprotective (4). Vitamin Edecreases free-radical production as well as inhibits collagenase production (11). ALA isa strong intracellular free-radical scavenger (12). It also has anti-inflammatory action,inhibiting the production of pro-inflammatory mediators (3). Coenzyme Q10 (ubiquinone)is present in every cell in the body and acts as a coenzyme in energy production. It has alsobeen shown to improve skin texture (13). One of the bigger challenges to the future use ofantioxidants is assuring biological activity from a cosmetic preparation and measuringthe antioxidant benefit in a clinical environment. As these challenges become resolved,a significant increase in use and benefit of these ingredients is expected. The renewed focus on health in today’s society has also created a niche for naturaland organic products. Women are interested in natural ingredients that make therapeuticclaims. This has led to increased popularity of skin care products containing plant ormineral ingredients, especially in the spa market. Organic advocates are willing to payextra for skin care products that are clearly organically produced (14). Therefore, oneof the hottest areas for cosmeceutical ingredients is the utilization and understanding ofbotanicals. Topical botanicals have been shown to combat reactive oxygen species, as wellas often having various secondary effects. Some strong botanicals include tetrahydro-curcumin, pycnogenol, silymarin, and soy extracts (15). The usage of botanicals for theiranti-inflammatory function continues to grow. Botanicals have been shown toblock inflammatory changes that may result in cutaneous aging. Some common anti-inflammatory botanicals include aloe vera, green tea, and allantoin (15). However, some

What Is Next? 405newer research suggests the molecular structure, as well as the formulation deliverysystem, strongly affects the biological activity of botanicals. Understanding the effectand potential of botanicals as cosmeceutical ingredients will likely continue to be a keyindustry focus. There are several different types of growth factors of both plant and animal originthat have been incorporated into cosmeceuticals. Furfuryladenine (kinetin), a syntheticplant growth factor that delays senescence of plant cells, has shown in vitro benefits inretarding cellular aging (16). Transforming growth factor-beta 1 is an important humangrowth factor with therapeutic potential because of its role in neocollagenesis (3). Humangrowth factors are relatively under explored by the cosmetic industry today and given thenegative public view associated with this class of ingredients it is unlikely that they will bea top focus area in the coming years. Stimulating the skin’s natural repair and rejuvenation system by topically addingskin functional ingredients like peptides, hyaluronic acid, niacinamide (vitamin B3),estrogen, and dimethylaminethanol will continue to show promise in improving theappearance and texture of skin. Delivering these relatively large molecules to thebiological key targeted area to maximize the effect remains the key barrier to skin agingdamage reversal or stimulation. Research in this area will continue with the next wave ofcosmeceutical ingredient breakthroughs.NUTRACEUTICALSNutraceuticals provide beauty benefits from the inside out; their goal is to enhance beautyby improving health. There are several dietary supplements that have been developed topromote skin health in particular. These supplements provide vitamins and nutrientsespecially involved in skin physiology. The challenge for the nutraceutical industry is todefinitively measure the benefit of these oral supplements in clinical testing. In the futureit is expected that more published clinical data will be available, as well as industry-regulated labeling systems to describe the claimed benefits.MEDICAL MIMICSThe growing demand for anti-aging products has led to the development of “medicalmimics.” These are new cosmetic alternatives to costly dermatologic procedures andsurgeries. “Facial relaxers” are gaining popularity as an alternative to Botox injection.Argireline, a synthetic peptide that has been touted to relax facial muscles by inhibiting theneurotransmitter catecholamine, has been advertised as having impressive wrinklereduction effect (17). Several companies have developed home products that mimicmicrodermabrasion. These products use lower dose crystals and sometimes a warmingagent to smooth, polish, and resurface the skin, producing results similar to officedermabrasion. Utilizing lower levels and less aggressive chemical peel acid ingredients,at-home chemical peels have also become popular. While home laser treatments are notyet available, it is expected that low dose home lasers are in the not so distant future forskin texture improvement and hair removal. It is expected that the “medical mimic” trendwill continue as women try to balance their busy lives.

406 ThamanCUSTOMIZED PRODUCTSThe genomics revolution has already begun to transform the pharmaceutical industry, andit is now making its mark on the cosmetic industry as well. At the heart of this revolution isthe ability to generate and assemble massive amounts of DNA sequence information.We are now able to identify key genes in biological processes such as skin aging througha method called gene expression profiling. Single nucleotide polymorphisms (SNPs)represent the genetic basis for inter-individual differences in disease susceptibility,including aging. The identification and mapping of these SNPs is an area of activebiotechnologic research. As a result of these advances, two promising applications of the genomics revolutionare beginning to develop: (i) the use of an individual’s DNA sequence information asthe basis for the development of improved clinical study design and preventative anddiagnostic strategies and (ii) the use of DNA sequence information to developpersonalized medicines and products. There are several factors that will influence whenand how the DNA sequencing will be applied to the development of cosmetic products(18). These include the progression of the science, consumers’ willingness to use theirDNA sequence for product choices, and market considerations. Ideally, this genetictechnology will allow cosmetic companies to identify specific skin qualities—such astexture, pigmentation, hydration, and wrinkles—and alter products to meet individualskin needs.SKIN TONE ALTERATIONSkin tone is an area of dissatisfaction for many women around the world. Clear, fair skintones are the goal in Asia, and skin lighteners have been popular there for many years.However, they are now gaining popularity in the west as well. They can also be used totreat disorders of hyperpigmentation, such as age spots. Tyrosinase is a key enzyme in theproduction of melanin. Phenolic skin lightening agents such as hydroquinone interferewith melanogenesis by acting as competitive inhibitors of tyrosinase, so that the skin isless pigmented. Non-phenolic skin lightening agents, including glucosamine, kojic acid,azelaic acid, and licorice extract, also inhibit tyrosinase activity. Skin lightening agents arenow being incorporated into bar soaps and color cosmetics as well. In western countries, where darker skin is often idealized, self-tanners continue toincrease in popularity. These usually contain dihydroxyacetone, which reacts with keratinprotein in the stratum corneum to form melanoidins to give the temporary brown color tothe skin. Because the stratum corneum is continually sloughed, the results are temporary.Manufacturers continue to work toward developing self-tanners that are odorless, quick todry, and unlikely to streak (19). They also are working to improve delivery systems,including wipes, sprays, and foams. Optical technology is now being incorporated into products to improve theappearance of skin. These new products do not change the skin at all, but when they areapplied to the skin, they improve its appearance. The basis for this technology is that tinyparticles can reflect and emit visible light from the skin. When used in cosmetics, theresultant reflected light can help hide wrinkles, large pores, and even cellulite and makethe skin appear healthier (20). Cosmetic companies continue to actively research and promote products to decreasecellulite. Ingredients such as caffeine, kiwi and green apple extracts, shiitake mushroomextract, gingko biloba, and seaweed extracts are all being incorporated into products

What Is Next? 407intended to firm the skin, increase elasticity, and decrease cellulite (21). Although noneof these products have delivered the cure, women everywhere continue to have hope.DELIVERY SYSTEMSActive research continues in the area of delivery systems for cosmetic products.Particulate delivery systems such as liposomes, which are tiny, hollow lipid spheres, areused to carry active ingredients into the skin. However, smaller, more specializedtransportation systems are being developed; these include nanoparticles, microcapsules,and millicapsules. Nanotechnology is making its way to the forefront of the cosmetic industry.Nanoparticles are solid hydrophobic spheres with an average particle size of less than onemicron; they have high cationic charge density to improve their deposition onto the targetsite and prevent them from being washed off during rinsing (22). This bioadhesive qualityalso reduces the need for reapplication. The hydrophobic quality of the nanospheres sustainsthe diffusion rate of the active ingredients, which allows their release over an extendedperiod of time. The nanospheres have improved stability when compared with emulsion-based delivery systems, such as liposomes. This enhanced stability prolongs product shelflife. In addition, the substance to be delivered does not have to be soluble in the vehicle,since it can be dispersed in the solid matrix. Incorporating an ingredient such as a sunscreeninto nanoparticles in a skin care product allows the product to block UV light, but does notinterfere with the look and feel of the lotion. As nanotechnology advances, it may enable thedevelopment of more customized and effective personal care products.NEW USERSMale grooming is one of the fastest growing sectors in the cosmetic industry (23). Thereare significant differences between men’s and women’s skin; men’s skin tends to be lessacidic, thicker, oilier, and hairier (24,25). By using products developed specificallyfor their skin type, men will achieve better results. Products being developed particularlyfor men include not only moisturizers, but also products to combat aging, self-tanners,blemish-control products, concealer products, and bath and shower products. Thesecosmetic products will be developed and promoted to seem masculine, so that the averagemale will feel comfortable using them. Consistent with this trend it is expected there willbe an increase in male visitors to the dermatologist’s office for cosmetic procedures.THE SKIN CARE MARKETMore effective anti-aging ingredients and formulations are being developed every day.Cosmetic alternatives to dermatological procedures will be increasingly available for theaverage woman, and technical innovations to cosmeceuticals will allow skin care productsto deliver active ingredients more effectively and with greater precision. Emerginggenetic-based technology will enable the development of targeted products that arecustomized to meet the needs of today’s individual man or woman. In addition, thegrowing concern for personal health will further expand the nutraceutical market. Withthe increase in consumer expectations and the continuation of changing trends, thecollaboration between the dermatology professional community and skin care productinnovators must continue to be fostered.

408 ThamanREFERENCES 1. Tsiantar D. The war on wrinkles. Time Mag 2005. 2. Deutsch CH. Cosmetics break the skin barrier. New York Times 2005. 3. Sadick N. Cosmeceuticals. Their role in dermatology practice. J Drugs Dermatol 2003; 2:529–537. 4. Farris PK. Topical vitamin C: a useful agent for treating photoaging and other dermatologic conditions. Dermatol Surg 2005; 31:814–817. 5. Bikowski JB. Mechanisms of the comedolytic and anti-inflammatory properties of topical retinoids. J Drugs Dermatol 2005; 4:41–47. 6. Gilchrest BA. A review of skin ageing and its medical therapy. Br J Dermatol 1996; 135:867–875. 7. Chandaratana RA. Tazarotene-first of a new generation of receptor-selective retinoids. Br J Dermatol 1996; 135:18. 8. Baumann L. Cosmetic Dermatology Principles and Practice. New York: The McGraw-Hill Companies, 2002:85–92. 9. Kurlandsky SB, Xiao JH, Duell EA, et al. Biological activity of all-trans retinol requires metabolic conversion to all-trans retinoic acid and is mediated through activation of nuclear retinoic acid and is mediated through activation of nuclear retinoic acid and dismediated through activation of nuclear retinoid receptors in human keratinocytes. J Biol Chem 1994; 269:32821.10. Grimes PE, Green BA, Wildnauer RH, Edison BL. The use of polyhydroxy acids (PHAs) in photoaged skin. Cutis 2004; 73:3–13.11. Ricciarelli R, Maroni P, Ozer N, Zingg JM, Azzi A. Age-dependent increase of collagenase expression can be reduced by alpha-tocopherol via protein kinase C inhibition. Free Radic Biol Med 1999; 27:729–737.12. Perricone N, Nagy K, Horvath F, Dajko G, Uray I, Zs-Nagy I. Alpha lipoic acid (ALA) protects proteins against the hydroxyl free radical-induced alterations: rationale for its geriatric topical application. Arch Gerontol Geriatr 1999; 29:45–56.13. Ghosh D, Murthy U. Antiaging benefits of a topical formulation containing coenzyme Q10: results of 2 clinical studies. Cosmet Dermatol 2002; 15:55–60.14. Global Cosmetic Industry, 171(12): 26, December 2003. ISSN: 0012-6527.15. Glaser DA. Anti-aging products and cosmeceuticals. Facial Plast Surg Clin N Am 2004; 12:363–372.16. Rattan SI, Clark BF. Kinetin delays the onset of ageing characteristics in human fibroblasts. Biochem Biophys Res Commun 1994; 201:665–672.17. Acetyl hexapeptide-3 (Argireline): an alternative to Botox or wishful thinking in a jar? from smartskincare.com (www.smartskincare.com/treatments/acetylhexapeptide.html).18. Tiesman JP, Internal P&G report. “Personalized” Products: The prospect for the use of genomic and genetic information for the development of “individualized” consumer products. 2002.19. Global Cosmetic Industry, 171(12): 26, December 2003. ISSN: 0012-6527.20. Global Cosmetic Industry, 170(5): 22(3), May 2002. ISSN: 0012-6527.21. Soap, Perfumery & Cosmetics, 77(7): 35, July 2004. ISSN: 0037-749X.22. Soap, Perfumery & Cosmetics, 77(2): 32, February 2004. ISSN: 0037-749X.23. Marketing Week, 26(29): 19, July 17, 2003. ISSN: 0141-9285.24. Perricone N. Taking care of your skin. In: The Wrinkle Cure. United States: Rodale/Reach, 2000:36–38.25. Williams S, Davids M, Reuther T, Kraus D, Kerscher M. Gender difference of in vivo skin surface pH in the axilla and the effect of a standardized washing procedure with tap water. Skin Pharmacol Physiol 2005; 18:247–252.

IndexAbscesses, 321 [Acne]Ac-EEMQRR. See acetyl-glutamate- erythromycin, 281, 284 estrogens, 287 glutamate-methionine-glutamine- face, 6 arginine-arginine facial cleansers, 279Acetone, 301 flutamide, 286N-acetyl-4-S-cystalminylphenol follicular epidermal hyperproliferation, (NA-CAP), 224 273–274Acetyl aminosugars, 243 formulation issues, 34N-acetylglucosamine (NAG), 243, 246–247 glycolic acid, 279–280Acetyl-glutamate-glutamate-methionine-gluta- hormonal therapy, 286–287 mine-arginine-arginine (Ac-EEMQRR), hydroxy acids, 279–280 176–178 inflammatory, 276Acid mantle, 52, 91 intralesional triamcinolone, 291Acne isotretinoin, 287–289, 290 adapalene, 277–279 lactic acids, 279–280 adjunctive acne products, 260–262 lasers, 291–292 alpha hydroxy acids, 262, 279–280 macrolide antibiotics, 284 anti-androgens, 286 minocycline, 284 antibiotics, 281–286 noninflammatory, 276 anxiety, 251 nutraceuticals, 262 astringents, 72–73 oral antibiotics, 281–286 azelaic acid, 281 oral contraceptives, 285, 286–287 benzoyl peroxide, 257–259, 281 oral supplements, 262 botanicals, 260, 320 OTC formulation advances, 254–268 capryloyl salicylic acid, 261 OTC medications, 251–268 clindamycin, 281, 284–285 OTC monograph, 252–253 clinical considerations, 252 OTC products formulation, 253 clinical imaging for OTC products, 266–268 pathogenesis key stages, 273–276 combination therapy, 262–266 photodynamic therapy, 291–292 comedone extraction, 290 phototherapy, 291–292 cyproterone acetate, 286 physical modalities, 290–291 development influences, 252 prevalence, 251, 273 doxycycline, 283–284 progestins, 286–287 economic impact, 251, 273 psychological impact, 251, 273 emotional impact, 251, 273 409

410 Index[Acne] Allergan, 133 quality of life, 251 Allergic contact dermatitis, 8, 9, 32–33, 314 retinaldehydes, 260–261 Allergies, eyelids, 8, 9 retinoids, 276–279 Allium cepa (onion), 334–335 salicylic acid, 245, 254–257, 279–280, 282 Allium sativa (garlic), 331 soaps, 55, 279 All-rac-alpha-tocopheryl acetate, 381 social impact, 251, 273 Aloe, 208, 318, 328 sodium sulfacetamide, 281 spironolactone, 286 Aloe barbadensis, 328 sulfur, 259–260 Aloe capensis, 328 sulfur/resorcinol combinations, 259–260 Aloe vera, 208, 328 sulfur–sodium sulfacetamide, 281 Aloesin, 208, 214, 224 syndets, 279 Alopecia, 313, 320 tazarotene, 277–279 Alopecia areata, 320 tea tree oil, 260 Alpha hydroxy acids (AHAs) tetracyclines, 281–283 acne, 262, 279–280 toners, 72–73, 74 anti-aging plus exfoliation, 240–241 topical antibiotics, 281 exfoliation, 237, 240–244 treatment methodologies, 273–292 moisturizer formulations, 119 tretinoin, 277–279 OTC acne medications, 262 trimethoprim/sulfamethoxazole, 285 skin lightening agents, 212–213, 228 ultraviolet radiation, 291 toners and astringents, 70 visible light, 291 See also glycolic acid; lactic acid Alpha-linolenic acid, 225Acne rosacea, 6 Alpha-lipoic acid, 196, 210, 225, 391–393Actinic cheilitis, 12, 320 Alpha-tocopherol, 210–211Active ingredients d-Alpha-tocopherol, 382 All-rac-alpha-tocopheryl acetate, 381 antiperspirants, 128–129 Altitude effect on skin cancer incidence, 154 sunscreens, 156, 157 Aluminium chloride, 132, 228 UV filters, 136–137, 139, 145 Aluminium oxide, 239Acute inflammation, 351–353 American Academy of Dermatology, 146Acyl isethionates, 41 American Cancer Society, 146–147Adapalene, 277–279 American Society for Photobiology, 147Adjunctive acne products, 260–262 Amevive, 360Adverse reactions. See side effects Amino filaggrin acids, 192–193Aesculus hippocastanum (horse chestnut), 318, Aminolevulinic acid, 291 Amino peptides, 197–198 333–334 Amphoteric surfactants, 42Aesthetics Anal fissures, 321 Ananas comosus (pineapple), 319, 346 antiperspirants, 130–131 Anaphylaxis, 313 sunscreens, 141, 143–144 Anatomy and physiologyAging body, 22 body cleanser choice, 56–57 eyelids, 8–9 chronological skin aging, 136 face, 4–6 formulation issues, 28–29 feet, 15 photo-induced skin aging, 136 female genitalia, 25 See also anti-aging hands, 13Agrimony (Agrimonia eupatoria), 342 lips, 11AHAs. See alpha hydroxy acids male genitalia, 25–26Alcohol, 301 nails and cuticles, 17Alcohol ethoxylates, 42 neck, 21Alcohol-free toners, 73 scalp, 19Alkyl ether sulfates, 41 underarms, 23Alkylphenyl ethoxylates, 42Alkyl sulfates, 41Allantoin, 328

Index 411Androgenic hormones, 274, 275 AntioxidantsAngioedema, 317 alpha-lipoic acid, 391–393Anionic surfactants, 41 cosmeceuticals, 196–197Anise (Pimpinella anisum), 328–329 future trends, 404Antelaea azadirachta (neem), 334 genistein, 387–391Anti-aging new combinations, 386–387 selenium, 384–387 alpha-hydroxy acids, 240–241 soy extract, 387–391 dimethylaminoethanol, 178–179 topical nutritional antioxidants, 377–395 flavonoids, 181 ubiquinone (coenzyme Q10), 393–395 formulations, 167–183 vitamin C, 174, 377–379, 386 hydroxy acids, 181, 240–241 vitamin E, 379–383, 386–387 keto acids, 181 kinetin, 179–180 Antiperspirants, 24, 123–134 medical mimics, 405 approved active ingredients, 128–129 moisturizers, 181 definition, 124 N-acetylglucosamine, 246–247 efficacy, 126–128 peptides, 176–178, 182 formulating for the customer, 130–131 plant extract components, 181 formulation approved active ingredients, salicylic acid, 246 128–129 triterpenoids, 180 formulation variations, 129–130 ubiquinone, 181 functions, 127, 128 vitamin A, 167–170, 182 history, 123–124 vitamin B3, 170–174, 182 hyperhidrosis, 131–132 vitamin C, 174–176, 378 medical approaches, 131–134 See also aging new active formulations, 131Antiandrogens, 286 recommended and approved uses, 127Antibiotics regulatory status, 124–126 benzoyl peroxide combination, 257–258, AP-1 transcription factor, 354–356 281 Aphthous stomatitis, 320 oral, 281–286 Apocrine sweat glands, 5, 23 patient concerns, 285 Apple (Malus domestica), 338 resistance, 285–286 Application behavior using antiperspirants, 130 topical, 281 Approved active ingredientsAnti-inflammatories astringents, 74 antiperspirants, 128–129 benzoyl peroxide, 257 OTC acne products, 252–253 botanicals, 362–363 Approved uses, antiperspirants, 127 cosmeceutical actives, 362–363 Arbutin, 208, 214 ELISA-based screening, 363–365 Armpits. See underarms formulations development, 368–373 Arnica (Arnica montana), 318, 338 gene array analysis, 367–368 Ascorbic acid. See vitamin C immunomodulators, 358–361 Ashiness, 57, 58–59 NSAIDS, 357–358 Aspirin, 357 OTC medications, 353–361 Astringents. See toners and astringents percutaneous absorption analysis, Atopic dermatitis, 9, 31–32 Avena sativa (oat), 345 370–372 Azelaic acid, 207, 224, 281 prescription treatments, 353–361 RT-PCR, 365–366 Bacterial infections, 322 screening assays, 363–368 Barrier augmentation, 101–107 skin inflammation biology, 351–353 Barrier defects on face, 6 steroids, 353–357 Barrier deterioration, dry skin cycle, 97–98 toners, 74 Barrier functions topical, 351–373 UV radiation clinical study, 372–373 alpha-hydroxy acids, 241 stratum corneum lipids, 81–84

412 IndexBars, 55, 56 [Botanicals]Basic cleanser formulations, 120 inflammation, 322–323Basic skin care processes, 115–116 mucocutaneous complications, 312–317Bathing devices, 238 OTC acne medications, 260Behavior modification for preparation types, 310, 311 processing, 310–311 photoprotection, 160 regulatory issues, 311Benzophenones, 158, 159 sales growth, 309Benzoyl peroxide, 253, 257–259, scientifically rational, 312, 337–342 severe complications, 312, 313–317 264–265, 281 skin lightening agents, 226Beta hydroxy acids, 280. See also salicylic acid sourcing material, 298–299Betaines, 42 species identification, 299Betulae folium (white birch), 342 species selection, 298Bidens tripartita (burr marigold), 319 therapeutic uses, 312, 320–327Bilayer-forming lipid, 100–101 toners, 69Binding of surfactants to stratum corneum topical, 297–305 viral infections, 322 proteins, 47–49Bioequivalency, 190 Botox, 133Biofilms, 6 Botulinum toxin A injections, 133Biological screening assays, 363–368 Brand names of cleansers, 280Biologic response modifiers, 360–361 Bruises, 320Bionic acids, 237, 241–244 Buff puffs, 238Biophysics of stratum corneum, 81–84 Burns, 320Biotin, 18 Burr marigold (Bidens tripartita), 319Bites, 320 Butcher’s broom (Ruscus aculeatus), 343Bitter orange (Citrus aurantium), 329 4-N-butylresorcinol, 224Bittersweet nightshade (Solanum C12 ionic surfactants, 44 dulcamara), 342 Cactus pear (Opuntia ficus-indica), 338Bitter taste, 320 Cajuput (Melaleuca leucadendra), 343Blackheads. See codemos Calcineurin, 359–360Black nightshade (Solanum nigrum), 329 Calendula officinalis (marigold), 345Black seed (Nigella sativa), 329 Calluses, 16Black tea, 336–337 Caltha palustris (marsh marigold), 313, 314,Bleeding, 317, 320Blistering, 313 316, 327Bloodroot (Sanguinaria canadendid), 304 Camellia sinensis (teas), 336–337Blue light-fluorescence light imaging, 263, Camptotheca acuminata Decne, 330 Cancer, 153–162 266–267 Candidiasis, 320Body, 22–23, 56–59 Capryloyl salicylic acid, 261Botanicals Capsella bursa-pastoris (shepherd’s purse), 346 Capsicum annuum (cayenne), 318, 330 acne, 320 Carcinogenesis, 313 adverse reactions, 311–319 Carcinoma, 320 anti-inflammatories, 362–363 Care needs astringents, 69 background, 309–310 body, 23 bacterial infections, 322 eyelids, 10 combination cautions, 312, 318–319 face, 7–8 cosmeceuticals, 190, 200 feet, 16 fungal infections, 322 female genitalia, 25 future trends, 404–405 hands, 14–15 German Commission E approved herbs, 312, lips, 12–13 342–347 growing conditions, 310 harvesting, 299–300 hyperpigmentation, 321

Index 413[Care needs] Clothing for photocarcinogenesis reduction, male genitalia, 26 159–160 nails and cuticles, 19 neck, 22 CO2 resurfacing lasers, 228–229 scalp, 20–21 CO2 super critical fluid extraction, 301 underarms, 24 Codemos, 276 Coenzyme Q10 (ubiquinone), 181, 196,Carica papaya (papaya), 318, 340Casual lipid, 45–46 393–395Cationic surfactants, 41–42 Collagen synthesis, 378Cayenne (Capsicum annuum), 318, 330 ColorCell signaling, 197–199Cellulite, 406–407 skin/formulation issues, 29–30Cellulitis, 322 toners and astringents, 70Centers for Disease Control and Prevention, Column chromatography, 302 Combination therapies 147 anti-aging formulations, 182Ceramides botanicals, 312, 318–319 OTC acne medications, 262–266 biosynthesis increasing agents, 103–107 skin lightening, 231, 232 dry skin, 94–96 Comedones, 34, 290 dry skin cycle, 100 Comfrey (Symphytum officinale), 328 environmental effects on stratum Compatability skin, 42–45, 49 corneum, 93–94 sunscreens, 140–141 stratum corneum, 81–84, 93–94 toners and astringents ingredients, 73 structure, 82 water hardness/cleansers, 49Chaste tree (Vitex agnus-castus), 318, 343 Compliance barriers for antiperspirants,Cheilitis, 12, 320Chemical exfoliation, 237, 239–247 129–130Chemical peels, 227–228 Condyloma acuminata, botanicals, 326Chemical sunscreens, 157–159 Conjuctivitis, 313Children, 28 Contact allergy, toners and astringents, 75Chinese medicine, 213 Contact blistering, 313Chinese olive (Canarium species), 314 Contact dermatitisCholesterol, 83, 102–103Chromatography, 299 complication-causing botanicals, 315Chronic inflammation, 353 formulation issues, 32–33Chronological aging, 136, 188–189 Contusions, 320Cinnamates, 158, 159, 312 Copper chelation, 209Cinnamic acid, 213 Copper peptides, 198Citrus aurantium (bitter orange), 329 Corneocyte envelopes, 87–90, 96Claims, toners and astringents, 73–74, 75 Corneocytes, 7, 98–99Cleansers and cleansing Corneodesmolysis, 84–87, 107 acne, 279 Corneodesmosomes, 84–87, 94, 107 basic formulations, 120 Corns, 16 basic skin care processes, 115–116 Corticosteroids, 354–357 benzoyl peroxide, 257, 258–259 Cosmeceuticals brand names, 280 anti-inflammatories, 362–363 cloths, 55 botanicals, 190, 200, 309–347 efficiency tests, 36–40 categories, 192–199 gentle skin cleansing significance, 120 dermatology role, 187–202 personal, 35–59 formulation selection, 199–200 personal cleansing products, 35–40 future, 200–202, 403–405 pH, 279, 280 history and background, 187–188Clindamycin, 281, 284 regulatory guidelines, 191–192Clinical imaging, 266–268 sales growth, 189 skin lightening agents, 222, 225–226 skin structure and function response, 189–190

414 IndexCosmetic elegance, 118–119 DiseasesCosmetic extracts, 300–304 body, 22–23Cosmetic surgery, 74 eyelids, 9–10Cosolubilizers, 69 face, 6–7Costs, 140, 200 feet, 15–16COX inhibitors, 357–358 female genitalia, 25Creams, 119, 130 hands, 13–14Critical micelle concentration, 36 lips, 11–12Cross-disciplinary knowledge base, 1 male genitalia, 26Cross-polarized light imaging, 263, 266 nails and cuticles, 17–18Cucurbita pepo (pumpkin), 340 neck, 21Cu-GHK. See tripeptide copper glycine-histi- scalp, 19–20 underarms, 24 dine-lysineCurcuma domestica, 330 DMAE. See dimethylaminoethanolCurcuma longa, 330 DNA fingerprinting, 299Curcumin, 318, 330, 362 DNA synthesis, 93Customized products future trends, 406 Doxycycline, 283–284Cuticles, 16–19 Dry skin, 71–72, 79–108Cyclical models, 96–99 Dyspigmentation, 315Cyclosporine, 358–360, 361Cyproterone acetate, 286 Eccrine glands, 5 EchinaceaD-alpha-tocopherol, 382Dandruff, 19–20 Echinacea angustifolia, 318, 331Date palm (Phoenix dactylifera), 330–331 Echinacea pallida, 331Deanol. See dimethylaminoethanol Echinacea purpurea, 331Decubitus, 325 Economic impact of acne, 251, 273Dehydroepiandrosterone sulfate Eczema, 6, 9–10, 14, 16, 31 Edematous, 315 (DHEA-S), 198, 274 EfficacyDelipidization, 45–47 alpha-lipoic acid, 393Delivery systems, 253, 254, 407 antiperspirants, 126–128Deodorants, 124, 127–128 benzoyl peroxide, 258, 259Depigmentation, 205–214, 219–232 cosmeceuticals formulation selection, 200Dermabrasion, 228 dimethylaminoethanol, 179Dermatitis, 314–315, 321 genistein, 387–390Dermatology kinetin, 179–180 peptides, 177–178 alpha-hydroxy acids, 242 personal cleansing products, 36–40 bionic acids, 242 topical nutritional antioxidants, 385 cosmeceuticals role, 187–202 triterpenoids, 180 polyhydroxy acids, 242 ubiquinone (coenzyme Q10), 181, 394–395 toners and astringents, 74–75 vitamin A, 168–170Dermis, 5 vitamin B3, 172–173Desmolytics, 237, 244–246 vitamin C, 174–175, 379Desquamation, 85–87, 98 vitamin E, 383Desquamatory enzymes, 85–87 EGF. See epidermal growth factorsDHEA-S. See dehydroepiandrosterone sulfate Elderly persons, See also aging; anti-agingDibenzoylmenthanes, 158, 159 Elegance of cosmetics, 118–119Digital imaging, 266, 267–268 Eleutherococcus senticosus (ginseng), 338–339Digitalis purpurea (foxglove), 297 ELISA. See enzyme linked immunosorbentDihydroacetone, 142–143Dihydrolipoic acid, 391–393 assayDihydrotestosterone, 274 Ellagic acid, 209, 214Dimethylaminoethanol (DMAE), Emollients, 69, 118–119 Emotional issues, 251, 273 178–179, 199

Index 415Endoscopic thoracic sympathectomy (ETS), [Extracts] surgery, 132–133 production goals, 300–301 quality issues, 303–304English plantain (Plantago lanceolata), safety and toxicology, 304 343 standardization, 302–303 topical botanicals, 300–304Environmental effects skin response, 188–189 Exuviating agents, 237, 240–244 stratum corneum, 92–94 Eyelids, 8–10 surfactant–skin interactions, 49 FaceEnvironmental Protection Agency (EPA), cleansers for acne, 279 147–148 formulation issues, 4–8 personal cleanser choice, 54–56Enzyme linked immunosorbent assay (ELISA)- relaxers, 405 based screening, 363–365 Farnesol activated receptor (FXR), 101–102Enzymes, 194–195 Fatty acids, 43–44, 81–84EPA. See Environmental Protection Agency Feel of sunscreens, 141Epidermal barrier issues, 115–117 Feet, 15–16Epidermal differentiation, 92–94, 101–102 Female genitalia, 24–25Epidermal growth factors (EGF), 195 Female skin, 27–28Epidermal lipogenesis, 102–107 Fenugreek (Trigonella foenum-graecum), 318,Epidermal turnover acceleration, 212–213Epidermis 343 Ferulic acid, 386 face, 5 Fibroblasts, 351–353 structure, 80–81 Filaggrin, 90, 91, 192–193Equisetum arvense (horsetail), 344 Film formers, 70Erbium:YAG lasers, 229 Fissures, 321Erbium resurfacing lasers, 228 Flavonoids, 181Erysipelas, 322 Flax (Linum usitatissimum), 318, 343–344Erythema, 137, 315, 372–373 Fluorescence images, 264, 265, 267Erythematous, 315 Flushing response, 174Erythroderma, 315 Flutamide, 286Erythromycin, 281, 284 Follicular epidermal hyperproliferation,Estrogens, 275, 287Ethanol, 68 273–274ETS. See endoscopic thoracic sympathectomy Follicular ostia, 4–5Eucommia ulmoides Oliver (EUOL), 338 Follicular predilection, 30Eupatorium cannabinum (hemp agrimony), 313, Folliculitis, 20 Formulation issues 314European Cosmetic Directive, 125 acne, 34European Society for Photobiology, 147 age/anti-aging, 28–29, 167–183European Union (EU), regulations, 125, alpha-lipoic acid, 393 antiperspirants, 123–134 191–192 astringents, 67–76Evening primrose, 318 basic cleansers, 120Excision of sweat glands, 133–134 best for cosmeceuticals, 199–200Exfoliation body, 22–23 contact dermatitis, 32–33 chemical, 237, 239–247 cuticles, 16–19 facial cleansing products, 55 dimethylaminoethanol, 179 microdermabrasion, 247 eyelids, 8–10 N-acetylglucosamine, 246–247 face, 4–8 physical, 237, 238–239 feet, 15–16 salicylic acid, 237, 244–246 female genitalia, 24–25 topical, 237–247 gender, 27–28Exogenous moisturization, 117–118Extracts cosmetic, 300–304 extraction processes, 301

416 Index[Formulation issues] Future trends, 403–407 genistein, 390–391 FXR. See farnesol activated receptor hair shaft architecture, 30–31 hands, 13–15 Galenic extracts, 310 hydroxy acids, 244 Garlic (Allium sativa), 331 kinetin, 180 Gels, 130, 255–256 lips, 10–13 Gender/formulation issues, 27–28 male genitalia, 25–26 Gene array analysis, 367–368 moisturizer components, 118–119 Genetic technology, 406 nails, 16–19 Genistein, 387–391 neck, 21–22 Genitalia, 24–26, 56 optimal skin care and product selection, Genital warts, 25 115–121 Gentle skin cleansing significance, 120 OTC acne medications, 253 Geriatrics, 29 peptides anti-aging formulations, 178 German chamomile (Matricaria recutita), 318, personal cleansing products, 35–59 salicylic acid, 246 332 scalp, 19–21 German Commission E approved herbs, 312, sensitive skin, 31–32 site-specific needs, 3–26 342–347 skin color, 29–30 Gingivitis, 324–325 skin lightening agents, 205–214 Gingko (Ginko biloba), 318, 332 special populations, 27–34 Ginko biloba, 318, 332 sunscreens, 143–144 Ginseng, 318 toners, 67–76 topical anti-inflammatories development, Eleutherococcus senticosus, 338–339 368–373 Panax ginseng, 338–339 triteroenoids, 180 Panax quinquefolius, 338–339 ubiquinone (coenzyme Q10), 181, 394 Glossodynia, 315 underarms, 23–24 Glucocorticoid receptor complex, 354–356 vitamin A, 170 Glucocorticoid-related steroids, 354, 356–357 vitamin B3, 174 Glutathionine peroxidase, 384 vitamin C, 175–176, 379 Glycerine, 53–54 vitamin E, 382 Glycerol, 91, 99, 107 Glycerol para-aminobenzoic acid, 157–158Foxglove (Digitalis purpurea), 297 Glycine soja (soy), 319, 335Fragile corneocyte envelopes, 88–90, 96 Glycolic acidFragrance allergy, 21 acne, 279Fragrance-free products, 54 anti-aging plus exfoliation, 240Fragrance oils, 70 cosmeceuticals, 190Fragrance/personal cleansing products, skin lightening, 227 structure, 240 54 See also alpha hydroxy acidsFranz diffusion cell, 370–371 Glycoprotein complexes, 84–87French maritime pinebark (Pinus pinaster), Glycosaminoglycans, 168 Glycyrrhiza glabra (licorice), 339 332–333 Glycyrrhiza uralensis (licorice), 339Fruit acids, 192–193 Grape seed (Vitis vinifera), 332–333Fungal infections Green tea, 318, 336–337 Growing conditions for botanicals, 310 botanicals, 322 Growth factors feet, 15 cosmeceuticals, 195–196 female genitalia, 25 future trends, 405 male genitalia, 26 Guidelines for safe sun practices, 146 nails and cuticles, 17–18 scalp, 19–20 Hair removal, 24N6-furfuryladenine. See kinetin Hair shaft architecture, 30–31Furunculosis, 321

Index 417Halitosis, 315, 321 Hyperkeratosis, 245, 321Hamamelis virginiana (witch hazel), 337 HyperpigmentationHands, 13–15Hand washes, 39–40, 41 botanicals, 321Harvesting plants, 299–300 causes, 219–221Heartsease (Viola tricolor), 344 formulation issues, 29Heavy metals, 304 medical and surgical approaches toHemorrhage, 317Hemp agrimony (Eupatorium cannabinum), skin lightening, 219–232 retinoids, 169 313, 314 therapeutic approaches, 223Herbs Hyperproliferation, 98, 273–274 Hyper-spectral imaging, 266–267, 268 herbal medicine, 309–310 Hypesthesia, 316 scientifically rational, 312, 337–342 Hypoallergenic products, 33Herpes, 11, 25, 321 Hypopigmentation, 29Hibiscus (Hibiscus sabdariffa), 339 Hyposalivation, 321Histamine antagonists, 106History Ichthyosis, 321 antiperspirants, 123–124 Idebenone (hydroxydecyl ubiquinone), 197, 226 cosmeceuticals, 187–188 Identification of plant species, 299Hormonal therapy, 286–287 IL-1. See interleukin-1Horse chestnut (Aesculus hippocastanum), 318, Imaging, 263–264, 265, 266, 268 Immunomodulators, 358–361 333–334 Impetigo, 322Horsetail (Equisetum arvense), 344 Induction phase of dry skin cycle, 97Humectants, 68–69, 99, 118–119 Infections, botanicals, 321–322Humidity, 92–94 InflammationHydroquinone, 205–206, 214, 2215-Hydroxy-2-hydroxymethyl-4H-pyrane-4-one acne, 275, 276 biology, 351–353 (kojic acid), 206–207, 214, 224, 227 botanicals, 322–323Hydroxy acids See also anti-inflammatories Inflammatory genes, 354–356, 359 acne, 279–280 Inflammatory mediators, 351–353 anti-aging formulations, 181 Ingrown hairs, 30–31 dry skin cycle, 101 Intense pulsed light (IPL), 230, 231 formulation factors, 244 Interleukin-1 (IL-1), 275 See also alpha hydroxy acids; Intertrigo, 24 Intrinsic aging, 188–189 polyhydroxy acids Invasive melanoma, 153Hydroxydecyl ubiquinone (idebenone), Iontophoresis, 132 IPL. See intense pulsed light 197, 226 Irritant contact dermatitis, 8, 9Hygiene needs Irritation personal cleanser pH, 50–51 body, 23 retinoids, 168–170 eyelids, 10 sunscreens, 140 face, 7 Isatis tinctoria (woad), 297 feet, 16 4-Isopropylcatechol, 224 female genitalia, 25 Isotretinoin (13-cis retinoic acid), 287–289, 290 hands, 14 lips, 12 Jambolan (Syzygium cumini), 344 male genitalia, 26 Japanese regulatory status of nails and cuticles, 18–19 neck, 21–22 antiperspirants, 125–126 scalp, 20 Jessner’s solution, 227 underarms, 24 Jock itch, 26Hyperforin, 303Hyperhidrosis, 14, 131–134, 321Hypericum perforatum (St John’s Wort), 302, 303, 319, 335–336

418 IndexJojoba (Simmondsia chinensis), 339 Loofahs, 238Juglans regia (walnut), 347 L-selenomethionine, 384–385, 386, 387 LXR. See liver activated receptorKeloid, 323 Lymphedema, 326Keratin, 90–91Keratinocytes, 273–274, 351–353 Macrolide antibiotics, 284Keratolytic exfoliants, 237, 244–246 Magnesium-L-ascorbyl-2-phosphateKeto acids, 181Kinetin (N6-furfuryladenine), 179–180, (VC-PMG), 210 Mahonia aquifolium (Oregon grape), 335 195–196 Makeup removal, 38–39Kojic acid (5-hydroxy-2-hydroxymethyl-4H- Malassezia globosa, 19–20 Male genitalia, 25–26 pyrane-4-one), 206–207, 214, 224, 227 Male grooming, 407 Male skin, 27–28Labeling OTC acne medications, 253 Malignant melanoma, 153Lacrimation, 321 Maltobionic acid, 241Lactic acid, 103–104, 240, 279–280. See also Malus domestica (apple), 338 Mandelic acid, 240 alpha hydroxy acids Manual exfoliation see physical exfoliationLactobionic acid, 241, 242 Marigold (Calendula officinalis), 345Lamium album (white nettle), 347 Market future trends, 407L-ascorbic acid. See vitamin C Marketing claims, 201Lasers, 228–231, 291 Marsh marigold (Caltha palustris), 313, 314,Latitude/skin cancer incidence, 154Lauric acid, 298–299 316, 327Lavender Mastitis, 323 Mastodynia, 323 Lavandula angustifolia, 344 Matricaria recutita (German chamomile), 318, Lavandula officinalis, 344Lemon balm (Melissa officinalis), 334 332Leprosy, 323 MED. See minimum erythema doseLicorice Medical mimics, 405 Glycyrrhiza glabra, 339 Medications Glycyrrhiza uralensis, 339 herb combination cautions, 318 hyperhidrosis, 133 skin lightening agents, 208–209, 226 hyperpigmentation induction, 221Lightening. See skin lightening Melaleuca alternifolia (tea tree), 336Linoleic acid, 102, 213, 225, 274–275 Melaleuca leucadendra (cajuput), 343Alpha-linolenic acid, 225 Melanoma incidence increase, 153Linum usitatissimum (flax), 318, 343–344 Melanosome transfer reduction, 211–212Lip balms, 12–13 Melilotus officinalis (sweet clover), 346–347Lipid-free liquid cleansers, 120 Melissa officinalis (lemon balm), 334Lipids Membrane permeability, 50 composition and dry skin, 94–96 Mentha spicata (spearmint), 341–342 delipidization, 45–47 Mesh puffs, 238 hyperproliferative disorders, 94–95 Metronidazole, 361 personal cleanser pH, 52 Microbial contamination, 303 stratum corneum, 81–84 Microdermabrasion, 228, 239, 247Lipogenesis, 102–107 Microflora, 53Alpha-lipoic acid, 196, 210, 225, 391–393 Microgel complexes, 256–257Liposuction, 133–134 Miliaria, 323Lips, 10–13 Milk thistle (Silybum marianum), 318, 334Liquid personal cleansers, 39–40, 56 Mimics, 405Liquiritigenin, 208–209, 214 Minimum erythema dose (MED), 137Liquiritin, 208–209, 214, 226 Minocycline, 284Liver activated receptor (LXR), 101–102 Moisturization and moisturizers, 14, 19, 23,Log P values, 369–370 115–120, 181

Index 419Monomethyl of hydroquinone, 221–222 Noncomedogenic claim, 34Morbidity, complication-causing Noni (Morinda citrifolia), 340 Noninflammatory acne, 276 botanicals, 315 Nonionic surfactants, 42Morinda citrifolia (noni), 340 Non-phenolic depigmenting agents, 224–225Mortality, complication-causing Non-steroidal anti-inflammatory drugs botanicals, 314 (NSAIDS), 357–358Morus alba (mulberry), 207 Nutraceuticals, 262, 405Mucocutaneous complications Nutritional antioxidants, 377–395 botanicals, 312, 313–317, 323 Oak (Quercus robur), 318, 345 isotretinoin, 287 Oat (Avena sativa), 345Mucocutaneous pruritus, 323 Occlusive agents, 118–119Mucositis, 316 Office dispensing, 189Mulberry (Morus alba), 207 Oily skin, 72Myroxylon balsamum (Peruvian balsam), Olea europaea (olive), 340 Oleic acid, 225 345–346 Oligomeric proanthocyanidins (OPCs), 332–333Myrtle (Myrtus communis), 339–340 Olive (Olea europaea), 340Myths/herbal medicine, 310 Onion (Allium cepa), 334–335 Onycholysis, 17N6-furfuryladenine. See kinetin Oolong tea, 336–337N-acetyl-4-S-cystalminylphenol (NA-CAP), OPCs. See oligomeric proanthocyanidins Optical technology future trends, 406 224 Optimal skin care product selection, 115–121N-acetylglucosamine (NAG), 243, 246–247 Opuntia ficus-indica (cactus pear), 338Nails, 16–19 Opuntia streptacantha (prickly pear), 340Nanofiltration, 302 Oral antibiotics, 281–286Nanotechnology, 407 Oral contraceptives, 285, 286, 287National Institutes of Health (NIH), 147–148 Oral supplements, 262Natural exfoliation, 237 Oregon grape (Mahonia aquifolium), 335Natural ingredients future trends, 404–405 Organic products, 404–405Natural moisturising factors (NMF), 90–92 Orthohydroxybenzoic acid. See salicylic acidNatural repair systems, 405 Over-the-counter drugs (OTD), 125Neck, 21–22 Over-the-counter (OTC), acneNecrosis, 317Neem (Antelaea azadirachta), 334 medications, 251–268New user future trends, 407 adjunctive acne products, 260–262NFAT activation, 359–360 advances, 254–268NF-kB transcription factor, 354–356 alpha hydroxy acids, 262Niacinamide benzoyl peroxide, 257–259 botanicals, 260 anti-aging formulations, 170–174, 182 capryloyl salicylic acid, 261 barrier augmentation, 104–106, 107 clinical considerations, 252 cosmeceuticals, 193–194 clinical imaging in product development/ moisturizer formulations, 119 skin lightening agents, 211 evaluation, 266–268 See also vitamin B3 combination therapy, 262–266Nicotinamide. See niacinamide formulations, 253Nicotinate esters, 170, 171, 174 monograph, 252–253Nicotinic acid, 170, 171, 174 nutraceuticals, 262Nigella sativa (black seed), 329 oral supplements, 262Night creams, 119 retinaldehydes, 260–261NIH. See National Institutes of Health salicylic acid, 254–257, 280, 281, 282NMF. See natural moisturising factors sulfur, 259–260Nomenclature sulfur/resorcinol combinations, 259–260 sunscreens, 156 toners and astringents, 67–68Nonacnegenic claim, 34

420 Index[Over-the-counter (OTC), acne medications] Pesticides, 303–304 tea tree oil, 260 Petrolatum, 39–40, 41, 54 trends, 254 Petroleum jelly, 100 Petroselinic acid, 102Over-the-counter (OTC), topical anti-inflam- PH matories, 353–361 cleansers, 279, 280Oxidation, 175 definition, 50 hydroxy acids formulation, 244PABA. See para-aminobenzoic acid personal cleansing products, 50–53Packing states, 82–83 stratum corneum, 91Pads, salicylic acid, 255 toners and astringents, 73Pal-KTTKS, 176–178, 182 PHAs. See polyhydroxy acidsPalmar hyperhidrosis, 14 Phenolic depigmenting agents, 221–224Palmar psoriasis, 14 Phoenix dactylifera (date palm), 330–331Palmitoyl-lysine-threonine-threonine-lysine- Photoaging features, 136 serine (pal-KTTKS), 176–178, 182 selenium, 385–386Panax ginseng (ginseng), 338–339 ubiquinone (coenzyme Q10),Panax quinquefolius (ginseng), 338–339Panthenol (vitamin B5), 194 394–395Papaya (Carica papaya), 318, 340 [Photoaging]Paper mulberry extract, 207Para-aminobenzoic acid (PABA), 157–158 vitamin C, 379Parallel-polarized light imaging, 263, 266 vitamin E, 383Paronychia, 18–19 Photocarcinogenesis prevention, 153–162Patented ingredients, 70–71 Photodamage, 21, 393Pathogenesis, acne, 273–276 Photodermatosis, 323Pathophysiology Photodynamic therapy, 291–292 Photography, 266 soap-induced dry skin, 94–96 Photoprotection, 119–120, 153–162, 381. winter-induced dry skin, 94–96PCR. See polymerase chain reaction See also sunscreensPediculosis, 324 Photoreactions, 316Peels, 227–228 Photostability of sunscreens, 156Penetration assessment, 368–370 Phototherapy, 291Penetration enhancers, 370 Physical conditions/personal cleanserPeppermint, 318Peptides, 176–178, 182 efficiency tests, 38Percutaneous absorption analysis, 370–372 Physical exfoliation, 237, 238–239Perleche, 12 Physical modalities, acne, 290–291Peroxisome proliferator activated receptor Physical sunscreens, 159 Physical therapies for skin lightening, (PPAR), 101–102Peroxyl free radicals, 380, 388 226–230, 231Personal cleansing products, 35–59 Physiology. See anatomy and physiology Phytoestrogens, 389 choice considerations, 54–59 Phytosphingosine, 106 cleansing efficiency tests, 36–40 Pigmentary disorders. See hyperpigmentation; delipidization, 45–47 effects on skin, 40–54 skin lightening fragrances, 54 Pigmentation, formulation issues, 29–30 pH effects, 50–53 Pigment dye lasers, 230 skin cleansing, 35–40 Pigment-specific lasers, 229–230, 231 soil removal, 35–36 Pimecrolimus, 358–360, 361 surfactant types, 40–42 Pimpinella anisum (anise), 328–329 surfactant–protein interactions, 47–49 Pineapple (Ananas comosus), 319, 346 surfactant–skin interactions, 42–53 Pinus pinaster (French maritime pinebark),Peruvian balsam (Myroxylon balsamum), 332–333 345–346 Plantago lanceolata (English plantain), 343 Plantar warts, 16

Index 421Plant growth factors, 195–196 Q-switched alexandrite lasers, 228–229Plants. See botanicals Q-switched Nd-Yag lasers, 229Poikiloderma, 21 Q-switched ruby lasers, 229Polarized light imaging, 263, 266 Quality issues, topical botanicals, 303–304Polyhydroxy acids (PHAs), 237, 241–244 Quality of life, acne, 251Polymerase chain reaction (PCR), Quasi-drugs, 125–126 Quercetin, 362–363 365–366 Quercus robur (oak), 318, 345Pomegranate (Punica granatum), 335Poplar (Populus spp.), 346 Race and body cleanser choice, 57–59Pores, 4–5 Radiation dermatitis, 324Postinflammatory hyperpigmentation, 29 Raptiva, 360Powder-based roll-on, 130 Razors, 24, 238–239PPAR. See peroxisome proliferator activated Reactive oxygen species, 209–211 Red-rooted sage (Salvia mittiorrhiza), 320 receptor Red sandalwood (Pterocarpus santalinus), 320,Prescription treatments 324 anti-inflammatories, 353–361 Regulatory issues hyperhidrosis, 133 skin lightening, 222 antiperspirants, 124–126Preventive measures in pigmentary botanicals, 311 cosmeceuticals, 191–192 disorders, 231 sunscreens, 144–145Prickly pear (Opuntia streptacantha), 340 Rejuvenation systems future trends, 405Processing of botanicals, 310–311 Repair of epidermal barrier, 117Product claims, 73–74 Residence time, 371–372Product reduction, 209–211 Resistance to antibiotics, 285–286Product selection for optimal skin care, Resorcinol, 259–260 Retinaldehydes, 167, 260–261 115–121 Trans-retinoic acid, 167, 168, 170Product stability, 73 13-Cis retinoic acid. See isotretinoinProfilaggrin catabolism, 91 Retinoid dermatitis, 278Progestins, 286–287 RetinoidsPropionibacterium acnes, 275–276 acne, 276–279, 287–288, 290Proteins, 47–49 anti-aging formulations, 167–170, 182Pruritus, 317, 323, 324 future trends, 404Pruritus ani, 324 isotretinoin, 287–290Pseudotumor cerebri, 284, 288 patient information, 278Psoriasis skin lightening agents, 225 Retinol, 167, 168–169 botanicals, 324 moisturizer formulations, 119 complication-causing botanicals, 317 Retinyl esters, 167–168, 169 hands, 14 Retinyl propionate, 167–169, 182 nails, 18 Reverse transcriptase-polymerase chain reaction scalp, 20 tazarotene, 277–278 (RT-PCR), 365–366Psychological impact of acne, 251, 273 Rigid corneocyte envelopes, 88–90, 96Pterocarpus santalinus (red sandalwood), 320, Rosacea, 32, 361 Rosemary (Rosmarinus officinalis), 341 324 Roughening, 37Puberty formulation issues, 28 RT-PCR. See reverse transcriptase-Puffs, 238Pulse-dye pigment lasers, 229 polymerase chain reactionPumpkin (Cucurbita pepo), 340 Rue (Ruta graveolens), 316, 319, 322, 324, 325Punica granatum (pomegranate), 335Purification techniques, 301–302 Ruta graveolens (rue), 316, 319, 322, 324, 325Purpura, 317 Ruta spp. (rue), 319Pustular, 317 Ruscus aculeatus (butcher’s broom), 343Pycnogenol (PYC), 332–333

422 IndexRWJ-50353 211–212 Severe complications of botanicals, 312, 313–317Safety benzoyl peroxide, 258 Shaving, 238–239 sun strategy, 135, 146–148 Shepherd’s purse (Capsella bursa-pastoris), 346 topical botanicals, 304 Sialorrhea, 317 Side effectsSage (Salvia officinalis), 346St. John’s Wort (Hypericum perforatum), 302, benzoyl peroxide, 258 biologic response modifiers, 360–361 303, 319, 335–336 botanicals, 311–319Sales growth of cosmeceuticals, 189 herbal medicine, 310Salicylates, sunscreens, 158–159 isotretinoin, 287–290Salicylic acid toners and astringents, 75 Signaling pathways, 354–355 acne, 279, 280, 282 Silybum marianum (milk thistle), exfoliation, 237, 244–246 OTC acne medications, 253, 254–257, 318, 334 Simmondsia chinensis (jojoba), 339 264–265 Single-nucleotide polymorphism (SNP), testing, over-the-counter acne medications, 201 279, 282, 283 Sjogren’s syndrome, 324 skin lightening, 227 Skin cancer, 154–155 See also beta hydroxy acids Skin Cancer Foundation, 147Salvia miltiorrhiza (red-rooted sage), 320 Skin color formulation issues, 29–30Salvia officinalis (sage), 346 Skin compatabilitySandalwood (Santalum album), 341Sandwich assay, 364 sunscreens, 140–141Sandwich model, 83 surfactants structural considerations,Sanguinaria canadendid (Bloodroot), 304Sanguinarin, 304 42–45Santalum album (sandalwood), 341 Skin feel of sunscreens, 141Sarsaparilla (Smilax medica), 341 Skin inflammation. See inflammationSaw palmetto (Serenoa repens), 319, 341 Skin lighteningScabies, 324Scaling, 98 astringents, 70Scalp, 19–21 botanicals, 226Scarlatina, 322 chemical peels, 227–228Scars, 383 cosmeceuticals, 222, 225–226SCCE. See stratum corneum chymotryptic cosmetic formulation, 205–214 dermabrasion, 228 enzyme future trends, 406Scientifically rational herbs, 312, 337–342 lasers, 228–230Screening assays, 363–368 medical and surgical approaches, 219–232Scrofulosis, 324 melanosome transfer reduction, 211–212SCTE. See stratum corneum tryptic enzymes microdermabrasion, 228SCTP. See stratum corneum thiaol physical therapies, 226–230, 231 prescription agents, 222 protease product reduction, 209–211Sebaceous glands, 5 reactive oxygen species, 209–211Seborrheic blepharitis, 9 skin turnover acceleration, 212–213Seborrheic dermatitis, 6–7, 19–20 therapeutic approach example, 230–231Sebum production, 275 toners, 70Selenium, 384–387 topical depigmenting agents, 221–226L-Selenomethionine, 384–385, 386, 387 traditional Chinese medicine, 213Self-tanning products, 141–143, 406 tyrosinase inhibition, 205–209Sensitive skin, 31–32, 71–72 Skin penetration assessment, 368–370Serenoa repens (saw palmetto), 319, 341 Skin roughening, 37Sesame (Sesamum orientale), 341 Skin tone alteration future trends, 406–407 Smilax medica (sarsaparilla), 341

Index 423Snakebites, 324 [Stratum corneum]SNP. See single-nucleotide polymorphism natural moisturising factors, 90–92Soap structure, 80–81 surfactant-protein interactions, 47–49 acne, 279 water holding mechanisms, 79–80 anionic surfactants, 41 basic cleanser formulations, 120 Stratum corneum chymotryptic enzyme body cleanser choice, 56 (SCCE), 85–87 facial cleanser choice, 55 surfactant–skin interactions, 43–44 Stratum corneum thiaol protease (SCTP), 85Soap-free synthetic detergent bars, 120, 279 Stratum corneum tryptic enzymes (SCTE),Soap-induced dry skin pathophysiology, 94–96Social impact of acne, 251, 273 85, 87SOD. See superoxide dismutase Styes, 325Sodium bicarbonate, 239 Sulfur, 259–260Sodium chloride, 239 Sulfur/resorcinol combinations, 259–260Sodium sulfacetamide, 281 Sulfur–sodium sulfacetamide, 281Soil removal, 35–36 Sunburn, 137, 358Solanum dulcamara (bittersweet Sunless tanning products, 141–143, 406 Sun protective factor (SPF), test, 136, nightshade), 342Solanum nigrum (black nightshade), 329 137–139, 156Solubility, 369–370 Sun safety, 146–148, 160, 231Solvent extraction, 301 Sunscreens, 8, 135–149Sophorcarpidine, 213–214Sorb apple (Sorbus domestica), 323 approved active ingredients, 156, 157Sorbus domestica (sorb apple), 323 chemical sunscreens, 157–159Soybean trypsin inhibitor (STI), 212 formulation challenges, 143–144Soy extract, 387–391 function, 136–139Soy (Glycine soja), 319, 335 hands, 15Spearmint (Mentha spicata), 341–342 hyperpigmentation therapeutic approaches,Species selection, 298SPF. See sun protective factor 223Spironolactone, 286 mechanisms of action, 156–159Stability moisturizer formulations, 119–120 photocarcinogenesis, 156–159 cosmeceuticals, 190 photostability, 156 cosmeceuticals formulation selection, physical, 159 products, 139–141 199–200 regulatory issues, 144–145 toners and astringents, 73 safe sun strategy, 146–148, 160 vitamin C, 175 types, 156–159Steam distillation, 301 UV filters active ingredients, 136–137, 139,Steroids, 353–357STI. See soybean trypsin inhibitor 145Sticks, 130 Superoxide dismutase (SOD), 194–195Stomatitis, 316, 317, 320, 324–325 SurfactantsStratum corneum barrier augmentation, 101–107 soil removal, 36 corneocytes envelope maturation, 87–90 types in personal cleansing products, 40–42 corneodesmolysis, 84–87, 107 Surfactant–protein interactions, 47–49 corneodesmosomes, 84–87 Surfactant–skin interactions dry skin cycle model, 96–99 delipidization, 45–47 dry skin management, 99–107 environmental effects, 49 face, 5 personal cleansing products, 42–53 lipid biophysics, 81–84 pH, 50 lipid chemistry, 81–84 stratum corneum lipids, 46–47 maturation, 107 surfactant structural considerations, 42–45 synthetic detergents, 44–45 temperature effects, 49 Sweat glands excision, 133–134 Sweating (hyperhidrosis), 14, 131–134, 321

424 IndexSweet clover (Melilotus officinalis), 346–347 [Topical therapies]Swelling response, 50, 51 botanicals, 297–305Symphytum officinale (comfrey), 328 comedolytics, 253Syndets, 120, 279 cosmeceuticals, 225–226Synergistic reactions, 190 desmolytics, 237, 244–246Synthetic detergents, 44–45. See also syndets exfoliation, 237–247Syphilis, 325 nutritional antioxidants, 377–395Syzygium cumini (jambolan), 344 pigmentary disorders, 221–226, 231 retinoids, 276–278Tacrolimus, 358–360, 361Tanning, 141–143, 406 Toxicology of topical botanicals, 304Tazarotene, 225, 277–279 Traditional Chinese medicine, 213Teas (Camellia sinensis), 336–337 Transcription factors, 354–356Tea tree (Melaleuca alternifolia), 260, 336 Transepidermal water loss (TEWL), 6, 53Temperature effects, surfactant–skin Transglutaminases, 87–90 Trans-retinoic acid, 167, 168, 170 interactions, 49 Treponema pallidum, 325Teratogens, 290 Tretinoin, 225, 227, 228, 277–279, 404Tests Triamcinolone, 291 Trichloroacetic acid peels, 227 cosmetic extracts safety, 304 Trigonella foenum-graecum (fenugreek), 318, personal cleanser efficiency, 36–40 sunscreens, 137–139 343 toners and astringents claims, 74, 75 Trimethoprim/sulfamethoxazole, 285Tetracyclines, 281–283 Tripeptide copper glycine-histidine-lysineTeucrium scorodonia (wood sage), 327TEWL. See transepidermal water loss (Cu-GHK), 176–178Therapeutic uses of botanicals, 312, 320–327 Triterpenoids, 180Thickening ingredients, 70 Triticum aestivum (wheat germ), 342Thioctic acid (alpha-lipoic acid), 196, Tumescent liposuction, 134 Turmeric (Curcuma domestica/longa), 330 210, 225, 391–393 Tyrosinase inhibition, 205–209Tightness, dry skin cycle, 99Tinea capitas, 20 Ubiquinone (coenzyme Q10), 181, 196,Tinea pedis, 15 393–395Tinea unguinum, 17Titanium oxide, 159 Ulcers, 317, 325T-lymphocytes, 353 Ultrafiltration, 302TNF-alpha inhibitors, 360, 361 Ultraviolet A (UVA), 154, 155, 157–159D-alpha-tocopherol, 382 Ultraviolet A (UVA) Protection Factor, 138Alpha-tocopherol, 210–211 Ultraviolet B (UVB), 154, 155, 157–159All-rac-alpha-tocopheryl acetate, 381 Ultraviolet (UV) radiationToners and astringents, 67–76 acne, 289 adverse reactions, 75 anti-inflammatories clinical study, 372–373 claims testing methods, 74, 75 approved filters, 136–137, 139, 145 dermatology uses, 74–75 erythema study, 372–373 facial cleansing, 55–56 genistein, 387–388 formulations, 68–73 -induced immunosuppression, 378, 379 functions, 68 -induced skin damage, 387–388 ingredients, 68–70 photocarcinogenesis, 153–162 new and patented ingredients, 70–71 skin cancer development relationship, product claims, 73–74 product forms, 68–70 154–155 skin types, 71–73 skin damage, 135–136Topical therapies spectral differences related to photo- antibiotics, 281 anti-inflammatories, 351–373 carcinogenesis, 155 UVA, 154, 155, 157–159 UVA-I, 136, 138, 148 UVA Protection Factor, 138

Index 425[Ultraviolet (UV) radiation] Vitex agnus-castus (chaste tree), 318, 343 UVB, 154, 155, 157–159 Vitis vinifera (grape seed), 332–333 Vitamin C, 378, 379 Walnut (Juglans regia), 347Underarms, 23–24 Warts, 326United States regulations, 125, 191 Washcloths, 238Unsaturated fatty acids, 225 WaterUrticaria, 317UV. See ultraviolet -based roll-on antiperspirants, 130 content of epidermal barrier, 116–117Valarian (Valeriana officinalis), 302–303 hardness and personal cleanser skinValue, cosmeceuticals formulation compatibility, 49 selection, 200 holding of stratum corneum, 79–80Varicosities, 326 skin cleansing, 36VC-PMG. See magnesium-L-ascorbyl-2- Western herbal mix (WHM), 337 Wheat germ (Triticum aestivum), 342 phosphate White birch (Betulae folium), 342Vehicles, 73, 253 Whiteheads. See codemosVenous insufficiency, 326 White nettle (Lamium album), 347Venous stasis, 326 Whitening agents. See skin lighteningVermillion, 11 White tea, 336–337Viola tricolor (heartsease), 344 White willow, 319Viral infections, 16, 322 WHM. See Western herbal mixVisible light, 263, 265, 291 Wildcrafting, 298Vitamin A, 119, 167–170, 182 Winter-induced dry skin, 94–96Vitamin B3, 170–174, 182, 193–194, 211. Witch hazel (Hamamelis virginiana), 337 Woad (Isatis tinctoria), 297 See also niacinamide Wood sage (Teucrium scorodonia), 327Vitamin B5 (panthenol), 194 Wound care, 326–327, 383Vitamin C, 174–176 Wrinkles, 168–169, 175 anti-aging formulations, 174–176 Xerosis, 96–99, 317, 327 antioxidants, 174 Xerostomia, 317 cosmeceuticals, 193 skin lightening agents, 209–210, 225 Yeasts, 11–12 topical nutritional antioxidants, 377–379, Zinc oxide, 159 386Vitamin D, 135, 160–161Vitamin E, 193, 210, 379–383, 386–387Vitamin K, 193