Supplement. Do Not Copy. Skin Through the Ages: of Acne, Photodamage, and Aging

Transcription

1 ISSN: February 2008 Volume 7 Issue 2 (Supplement) Supplement Skin Through the Ages: State-of-the-Art Penalties Options for the Apply Topical Treatment of Acne, Photodamage, and Aging

2 Intended Audience: This activity was developed for dermatologists and other physicians who treat patients with acne and/or photodamage. Statement of Need: Over an individual s lifetime, concerns surrounding skin health and appearance evolve. Common reasons for seeking a dermatologist s expertise include acne, photodamage, and aging. Acne is a primary complaint and often begins in adolescence, but it can endure throughout adulthood. Numerous therapeutic options are available, with topical antimicrobials being a mainstay, either alone or in combination with other agents. An important factor in achieving positive outcomes in acne treatment is providing patients with topical products that are easy to use and have an elegant feel. Both intrinsic and extrinsic factors promote skin aging. Dermal thinning and loss of collagen and elastin contribute to wrinkles, leathery texture, and discoloration. Products that minimize the effects of aging skin are growing in popularity, particularly given the increase in the aging population. Dermatologists could benefit from a review of the aging process, as well as an update of new products available to combat dermal aging. Learning Objectives: Upon completion of this activity, participants should be better able to: Discuss how advances in understanding the pathogenesis underlying mild-to-moderate acne are influencing therapeutic development/choices Describe the advantages and limitations of available and emerging topical antimicrobial therapies for mild-tomoderate acne in adolescents and adults Compare/contrast the physiology associated with intrinsic and extrinsic (photoexposure-related) dermal aging Recommend appropriate, individualized courses of treatment for the improvement of aged/photodamaged skin Disclosure: It is the policy of the Annenberg Center to ensure fair balance, independence, objectivity, and scientific rigor in all programming. All faculty and planners participating in sponsored programs are expected to identify and reference offlabel product use and disclose any significant relationship with those supporting the activity or any others whose products or services are discussed. In accordance with the Accreditation Council for Continuing Medical Education Standards, parallel documents from other accrediting bodies, and Annenberg Center policy, the following disclosures have been made: Dr Leyden has served as a consultant, participated on advisory boards, and/or participated in clinical trials for Allergan Inc, Anacor Pharmaceuticals Inc, CollaGenex, Galderma, Medicis Inc, Obagi Medical Products Inc, QLT, SkinMedica, Steifel Inc, and Warner-Chilcott. Dr Del Rosso has served as a speaker for Allergan Inc, Amgen, CollaGenex, Connetics, Coria, Dermik Laboratories, Doak, Galderma, GlaxoSmithKline, Graceway, Intendis, Medicis Inc, Novartis Pharmaceutical Corp, Obagi Medical Products Inc, Ortho-Neutrogena, Ranbaxy, SkinMedica, Stiefel Inc, Unilever, and Warner-Chilcott. He has served as a consultant for Allergan, Amgen, CollaGenex, Connetics, Coria, Doak, Galderma, Graceway, Intendis, Medicis Inc, Obagi Medical Products Inc, Ortho-Neutrogena, QLT, Ranbaxy, SkinMedica, Steifel Inc, Unilever, and Warner-Chilcott. He has received research support from Allergan, Amgen, CollaGenex, Connetics, Galderma, Graceway, Intendis, Obagi Medical Products Inc, Ortho-Neutrogena, QLT, and Stiefel Inc Dr Uitto has no relationships to disclose. Dr Bruce is a consultant/speaker for Allergan Inc, Dermik Laboratories, Medicis Inc, and Syneron Inc. She has received research support from 3M Pharmaceuticals, Allergan Inc, Altana, Anacor Pharmaceuticals Inc, Astellas Pharma US Inc, Contura International A/S, Dow Pharmaceutical Sciences, Dusa Pharmaceuticals Inc, Galderma R&D Inc, Hill Dermaceuticals Inc, Isolagen Technologies Inc, Medicis Inc, Novartis Pharmaceutical Corp, Obagi Medical Products Inc, Photocure ASA, QLT USA Inc, and Stiefel Inc. Each member of the Faculty has been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Dr Leyden will not provide any unapproved/off-label discussion. Dr Del Rosso will not provide any unapproved/off-label discussion. Dr Uitto will not provide any unapproved/off-label discussion. Dr Bruce will include unapproved/off-label discussion. The ideas and opinions presented in this educational activity are those of the faculty and do not necessarily reflect the Faculty: Guest Editor: James Leyden MD Emeritus Professor of Dermatology, Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA Suzanne Bruce MD views of the Annenberg Center and/or its agents. As in all President, Suzanne Bruce and Associates, PA educational activities, we encourage the practitioners to use The Center for Skin Research, Houston, TX their own judgment in treating and addressing the needs of each individual patient, taking into account that patient s James Del Rosso DO, FAOCD unique clinical situation. The Annenberg Center disclaims Clinical Assistant Professor of Dermatology, University of all liability and cannot be held responsible for any problems Nevada, School of Medicine, Las Vegas, NV that may arise from participating in this activity or following Jouni Uitto MD, PhD treatment recommendations presented. Professor and Chair, Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Philadelphia, PA grant from Obagi Medical This activity is supported by an independent educational Products. This activity is an enduring material and consists of a journal supplement. Successful completion is achieved by reading and viewing the material, reflecting on its implications in your practice, and completing the assessment component. The estimated time to complete the activity is 2.5 hours. This activity was originally released February 2008 and is el Journal of Drugs in Dermatology. igible All for Rights credit Reserved. through January 2009.

3 February 2008 Volume 7 Issue 2 (Supplement) Original Articles s2 Emerging Topical Antimicrobial Options for Mild-to-Moderate Acne: A Review of the Clinical Evidence James Del Rosso DO, FAOCD s8 s12 s17 s23 s29 New Developments in Topical Antimicrobial Therapy for Acne James Leyden MD The Role of Elastin and Collagen in Cutaneous Aging: Intrinsic Aging versus Photoexposure Jouni Uitto MD, PhD Cosmeceuticals for the Attenuation of Extrinsic and Intrinsic Dermal Aging Suzanne Bruce MD Complementary Effects of Topical Antiaging Treatments in Conjunction with Aesthetic Procedures Suzanne Bruce MD CME Materials Journal of Drugs in Dermatology: New Methods and Techniques is published monthly by Journal of Drugs in Dermatology (JDD) 377 Park Avenue South, 6th Floor New York, NY telephone: fax: No part of this publication may be reproduced, stored in a retrieval system, or transmitted in electrical or other forms or by any means without prior written permission from JDD. This publication has been registered with the Library of Congress (ISSN: ). The publisher and the organizations appearing This activity is supported by an independent educational grant from herein assume no responsibility for any injury and/or damage to persons or property as a matter of product liability, negligence, or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. No suggested test or procedure should be carried out unless, in the reader s judgment, its risk is justified. Because of the rapid advances in the medical sciences, we recommend that independent verification of diagnoses and drug dosages should be made. Discussions, views, and recommendations as to medical procedures, choice of drugs, and drug dosages are the responsibility of the authors. Statements and opinions expressed in the articles and communications herein are those of the author(s) and not necessarily those of the editors, publisher, or staff. The editors, publisher, and staff disclaim any responsibility for such material and do not guarantee, warrant, or endorse any product or service advertised in this publication nor do they guarantee any claim made by the manufacturer of such product or service. Accreditation and Certification: This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Annenberg Center for Health Sciences at Eisenhower and Precept Educational Sciences. The Annenberg Center is accredited by the ACCME to provide continuing medical education for physicians. The Annenberg Center designates this educational activity for a maximum of 2.5 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. There is no charge for this activity. Statements of Credit will be provided by mail following activity participation, and upon completion and return of the evaluation form and post-test to the Annenberg Center for Health Sciences at Eisenhower (#4622), Bob Hope Drive, Rancho Mirage, CA or by FAX to Please allow 4-6 weeks for the delivery of your statement. This activity is an enduring material and consists of a journal supplement. Successful completion is achieved by reading and viewing the material, reflecting on its implications in your practice, and completing the assessment component. The estimated time to complete the activity is 2.5 hours. The paper used in this publication meets the minimum requirements of the American National Standard for Information Sciences Permanence of Paper for Printed Library Materials, ANSI Z Journal of Drugs in Dermatology This activity was originally released February 2008 and 2008-Journal is eligible for of credit Drugs through in Dermatology. January All Rights Reserved.

4 s2 COPYRIGHT 2008 JOURNAL OF DRUGS IN DERMATOLOGY EMERGING TOPICAL ANTIMICROBIAL OPTIONS FOR MILD-TO-MODERATE ACNE: A REVIEW OF THE CLINICAL EVIDENCE James Del Rosso DO, FAOCD Dermatology Residency Director, Valley Hospital Medical Center, Las Vegas, NV Abstract Topical antimicrobial agents are commonly used as first-line agents for the management of mild to moderate acne vulgaris. Agents with antibacterial activity (eg, benzoyl peroxide and clindamycin), reduce counts of Propionibacterium acnes, while also decreasing the numbers of inflammatory and noninflammatory lesions. In order to optimize efficacy, topical antibiotics are most commonly used in combination with benzoyl peroxide, an approach which also reduces the emergence of strains of P acnes that are less sensitive to antibiotics. Other topical antiacne options include retinoids (with or without an antimicrobial agent), sulfacetamide, sulfacetamide-sulfur, and azelaic acid. Certain formulations of benzoyl peroxide offer improved tolerability, while a new micronized form may enhance efficacy by optimizing follicular penetration. This wide array of options allows dermatologists to tailor topical treatments to the needs of individual patients. Introduction The pathogenesis and chronic course of acne vulgaris are multifactorial and Propionibacterium acnes are understood to play a key role in the promotion of inflammation in acne. While normally colonizing areas of the face and trunk, P acnes overgrowth in acne vulgaris may encourage comedo formation, and its exoproducts have been shown to promote inflammation through stimulation of the innate immune response. A host of topical antimicrobial options, most of which reduce the P acnes population, are currently available and are considered first-line treatments for mild to moderate acne vulgaris. To improve and expand our armamentarium, new topical antimicrobial formulations and treatment strategies continue to be investigated. lations containing erythromycin, clindamycin, benzoyl peroxide (BPO), sodium sulfacetamide, and azelaic acid; topical retinoids are frequently used in combination with certain antimicrobial agents. Among dermatologists, clindamycin is the favored prescribed topical antibiotic agent based on analysis of the prescribing patterns of dermatologists (IMS Health Incorporated, unpublished data, 2006). Products containing sulfacetamide, sulfur, and azelaic acid are also prescribed, often in combination with other agents. Benzoyl Peroxide Available for over 50 years, BPO, a nonspecific antibacterial agent, continues to be one of the pivotal therapies in the treatment of acne vulgaris. As shown in Figure 1, the ability of BPO to reduce P acnes counts typically exceeds that achieved with topical clindamycin or erythromycin Range of Topical Antimicrobial Therapies Table 1 summarizes the topical antimicrobial agents available monotherapy. 1 This effect is a result of the direct toxic effect for treatment of acne vulgaris. These include various formu- of BPO on the organism. Today, BPO can be found in a wide Penalties variety Apply of formulations, ranging from cleansers to the more Table 1. Topical antimicrobial options for the treatment of acne conventional and widely used leave-on products. Several vulgaris. newer formulations contain various additions intended to reduce the irritation sometimes encountered with BPO use, for Topical antibiotics: example, glycolic acid, zinc, or combinations of humectants Clindamycin (eg, glycerin) and emollients (eg, dimethicone). Microsphere formulations, designed to deliver drug more slowly Erythromycin over time and thus reduce irritancy, have become available Benzoyl peroxide (BPO) in recent years. More recently, a micronized BPO formulation Combination products: has been developed that appears to optimize follicular penetration relative to other commercially available BPO formulations. This enhanced penetration may correlate with Clindamycin/BPO Erythromycin/BPO improved efficacy when compared with some traditional Clindamycin/tretinoin formulas. 2 Thus, innovations aimed at improving tolerability BPO/adapalene (under investigation) and efficacy of BPO continue to emerge. Sulfacetamide Sulfacetamide-sulfur Azelaic acid Topical Antibiotics A number of clinical trials have examined the antimicrobial efficacy of clindamycin or erythromycin monotherapy for acne vulgaris. A meta-analysis of such trials published between 1966 and 2003, 3 revealed comparable levels of efficacy

5 s3 TOPICAL ANTIMICROBIAL OPTIONS FOR ACNE tween these compounds in the earliest studies, based on inflammatory lesion counts. The efficacy of erythromycin in terms of total lesion count reductions, however, dropped from its initial high of 40% to 60% in trials conducted in the 1970s to a low of approximately 20% during the 1990s. Conversely, the efficacy of clindamycin was unchanged in this regard in trials conducted over the past 3 decades. Such findings suggest that erythromycin-resistant strains of P acnes have emerged substantially over the past 20 years, compromising the efficacy of topical erythromycin for acne vulgaris. Regardless of the topical antibiotic chosen when treating acne vulgaris, decreased sensitivity of P acnes to the antibiotic is important to address by avoiding antibiotic use as monotherapy and by combining antibiotic use with BPO therapy. Compared with topical antibiotic monotherapy, combination topical antibiotic/bpo offers greater clinical benefits over the long term. First, evidence indicates that combination products that include BPO lead to greater reductions in P acnes counts 1,4 (Figure 1). Such products were also associated with greater reductions in inflammatory lesion counts (Figure 2a). 5 Second, compared with single-agent formulas, combination products appear to better suppress the development of P acnes strains that are less sensitive to antibiotics, thus helping to maintain efficacy with continued, long-term use. 6 One recent investigation compared the emergence of antibiotic-resistant P acnes strains in patients treated with either clindamycin 1% gel monotherapy or combination therapy with clindamycin 1%/BPO 5% gel. 6 As illustrated in Figure 2b, beginning at Figure 1. Reduction in P acnes with common topical antimicrobial agents. BPO=benzoyl peroxide. Adapted with permission from Leyden JJ. Semin Cutan Med Surg. 2001;20: Figure 2a. Reduction in inflammatory Penalties lesion count with combination clindamycin/benzoyl Apply peroxide gel vs. antimicrobial monotherapy. Data shown are mean percentage decreases from baseline in inflammatory lesion counts after 11 weeks of treatment. 4 BPO=benzoyl peroxide. * P<.05 vs. BPO 5%, clindamycin 1%, vehicle; P<.05 vs. vehicle.

6 s4 TOPICAL ANTIMICROBIAL OPTIONS FOR ACNE week 8, the number of resistant P acnes counts increased dramatically from baseline in the clindamycin 1%-monotherapy treatment arm, while in the combination-therapy arm the number of resistant counts remained near baseline levels throughout the study. 6 These findings indicate that it is preferable to begin with a topical antibiotic regimen that includes BPO from the outset. Combinations with Topical Retinoids Topical retinoids are an important treatment option for acne vulgaris, as these compounds exert a number of significant biologic effects. First, they play a role in blocking the inflammatory cascade triggered by the presence of P acnes exoproducts via downregulation of toll-like receptor 2. 7 Moreover, activation of retinoic acid receptors decreases activity of transglutaminase, 8 which in turn decreases hyperproliferation of keratins in the follicle; this plays a significant role in reducing comedo formation. Finally, retinoids stimulate dermal collagen production while also inhibiting activator protein-1-mediated formation of matrix metalloproteinases, 9 which may help to prevent acne scarring. Compound stability is a challenge with topical retinoid therapy. Tretinoin in conventional vehicle formulations is not stable in the presence of sunlight or in the presence of certain other agents such as BPO. To address this problem, newer formulations of tretinoin have been designed to be less labile. The microsphere formulation of tretinoin has greater stability in the presence of light or BPO. Moreover, other recently developed retinoids, including adapalene 10 and tazarotene, are stable in the presence of light, topical antibiotics, and BPO. As seen with use of a topical antibiotic, efficacy of topical retinoid therapy is increased when paired with BPO and/or an antibiotic. In one study from Shalita and colleagues, 11 patients were randomized to receive tretinoin 0.1% microsphere applied at bedtime, paired with either a gentle, nontherapeutic cleanser or 6% BPO cleanser in the morning. There was a 2-fold greater reduction in inflammatory lesion counts in the combination tretinoin/bpo group compared with the retinoid monotherapy group. Combining a retinoid with BPO and an antibiotic also yields enhanced therapeutic effects. 12,13 For instance, with 12 weeks of topical adapalene 1% gel, along with BPO and clindamycin, reduction in the number of total lesions was greater (71%) than that seen among patients given adapalene 1% monotherapy (58%). 12 Similarly, clindamycin 1.2%/tretinoin 0.025%, formulated as an aqueous gel combination product, appears to offer advantages over retinoid monotherapy. With this product, the tretinoin is present in both solubilized and suspended crystalline forms, which allows for the slower release and skin penetration of tretinoin, thus enhancing tolerability. With 12 weeks of therapy, patients who applied clindamycin 1.2%/tretinoin 0.025% gel once daily in the evening exhibited significantly fewer inflammatory and noninflammatory lesions, compared with those given tretinoin or clindamycin alone. 13 BPO may be used in combination with clindamycin 1.2% plus tretinoin 0.025% gel to reduce emergence of clindamycin-resistant P acnes strains. Figure 2b. Emergence of antibiotic resistance: combination therapy versus monotherapy. Least squares mean percentage reduction of baseline clindamycin-resistant P acnes counts during 16 weeks of treatment with the combination of clindamycin/bpo versus clindamycin alone. BPO=benzoyl peroxide. * P=.018 clindamycin 1% vs. clindamycin 1%/BPO 5%. Reproduced with permission from Cunliffe WJ, Holland KT, Bojar R, et al. Clin Ther. 2002;24:

7 s5 TOPICAL ANTIMICROBIAL OPTIONS FOR ACNE BPO is generally applied in the morning, while clindamycin 1.2% plus tretinoin 0.025% gel is applied at bedtime. Sulfacetamide and Sulfacetamide-Sulfur Sodium sulfacetamide is believed to exert its antibacterial activity at least partially via competitive antagonism of paraaminobenzoic acid, which bacteria rely on for growth. Sulfur is used for acne vulgaris due to its purported antiinflammatory properties. While no pivotal trials for sulfacetamide-sulfur have been published for acne treatment, the long history of its use with apparent efficacy and favorable safety warranted its grandfathered acceptance by the FDA for the clinical treatment of acne. 14 A wide array of combination sulfacetamide-sulfur cleansers and leave-on formulations have recently been introduced for topical therapy of acne vulgaris, rosacea, and seborrheic dermatitis. 14,15 Emerging Benzoyl Peroxide Formulations Given its over-the-counter availability, BPO is perhaps the most widely used topical antimicrobial agent for the treatment of acne vulgaris. Researchers are continuing to study ways to improve the tolerability and efficacy of BPO. Most of these efforts concern altering the vehicle or manner in which BPO is delivered to the affected skin area. Some of the more recent innovations in BPO formulations include microsphere technology, aqueous-based gels, liposomal delivery, and microemulsions. The latest innovation involves the use of micronization to produce solubilized BPO particles, which allows the smaller-sized particles to penetrate down into the follicle. Efficacy with 3 different dosing schedules of the solubilized BPO 5% formula has been examined: 19 1 pump of gel applied Azelaic Acid once daily; 2 pumps of gel once daily; or 1 or 2 pumps applied once daily for 1 week, then increased to twice daily. In Topical azelaic acid 15% gel is FDA approved for the treatment addition, all patients were provided with a cleanser and of rosacea; a 20% cream formulation is FDA approved toner containing salicylic acid to use twice daily. After 21 for the treatment of acne. 16 The difference in terms of skin days, regardless of the dosing schedule, the numbers of noninflammatory penetration between formulations is substantial based on (comedonal) lesions and inflammatory lesions in vitro analysis: the 15% gel skin penetration of azelaic acid were significantly reduced using the micronized BPO formula. is 8-fold greater compared with the 20% cream formulation. As shown in Figure 3, all treatment groups improved significantly In clinical studies, azelaic acid 15% gel reduces papules and from baseline, but there was a trend toward greater pustules approximately 70%, which was comparable to that improvement at week 3 among patients who started with the observed with clindamycin gel or BPO 5% gel. However, at once-daily regimen with the increase to twice daily. The this time the azelaic acid 15% gel formulation is not approved differences between the dosing groups were not statistically in the US for the treatment of acne vulgaris. significant, and it may be that some patients will show results Figure 3. Mean percentage change in inflammatory lesion count, by dose of micronized BPO formulation. A=1 pump, once daily; B=2 pumps, once daily; C=1 or 2 pumps once daily, increasing to twice daily. * P.001 vs. baseline. Reproduced with permission from Wilson DC. Poster presented at: Winter Clinical Dermatology Conference Hawaii; January 13-17, 2007; Kohala Coast, Hawaii.

8 s6 TOPICAL ANTIMICROBIAL OPTIONS FOR ACNE on a once-daily regimen without the need to increase to a twice daily regimen. The Problem of Truncal Acne Vulgaris Few data have been published on truncal acne vulgaris, and most of what is known in this regard is based on personal clinical impressions and experience. One recent study sought to describe the frequency of truncal acne vulgaris, as well as its clinical presentation and severity. Among 696 patients with acne vulgaris, 364 (50.0%) had concurrent facial and truncal disease. 20 Notably, 22.4% of the patients who mentioned facial acne as their chief complaint made no mention of their truncal acne, which was detected only by clinical examination. When truncal acne was detected, the majority of patients (78.2%) were interested in topical treatment of their truncal acne. This shows that examination of the trunk, regardless of patient complaint, is important for detection of truncal acne. Treatment strategies for truncal acne are also not well defined. Use of topical therapy is challenging, mainly because these areas are hard to reach and topical medications are not dispensed in quantities large enough to cover the involved surface area. As a result, truncal acne is likely to be treated with an oral antibiotic such as doxycycline or minocycline. However, when a systemic antibiotic unopposed by BPO is prescribed, some antibiotic-resistant P acnes strains may emerge. Mild to moderate truncal acne may in fact respond well to topical therapy. Overcoming the pragmatic challenges of application of the products demands Table 2. Optimizing compliance and adherence to topical antiacne therapy. Choose an effective and well-tolerated regimen Combination of agents with different mechanisms of action Vehicles containing emollients and/or humectants Vehicles with advanced technology (eg, microsphere) some effort, but may not be insurmountable. Recruiting a family member to apply medication or using an application device that can target the back may resolve the problem. Managing Topical Antimicrobial Tolerability and Adherence Regimen effectiveness, tolerability, simplicity, and safety are perhaps the most important factors influencing patient compliance and long-term adherence. Other variables include type of adjunctive products used, level of patient motivation, and expectations about treatment outcome. Table 2 summarizes steps dermatologists may consider to optimize adherence to therapy in patients with acne vulgaris. The therapeutic regimen chosen should attempt to maximize efficacy as well as tolerability; an early rapid improvement in symptoms may provide the encouragement patients need to adhere with therapy over the long term. Some combination products that incorporate 2 active agents with differing mechanisms of action also employ vehicles that include humectants and emollients designed to improve tolerability. Upon treatment initiation, dermatologists should also define the adjunctive products to be used. Certain cleansers and moisturizers may improve tolerability and boost adherence; on the other hand, harsh or otherwise irritating products may only heighten treatment-related side effects or sabotage treatment efficacy by causing skin irritation. For these reasons, dermatologists or their designated staff members are encouraged to provide clearly written instructions about use of both prescription and adjunctive skin-care products. Finally, patient expectations can be unrealistically optimistic. During office visits, dermatologists must be sure to help patients understand what realistically to expect with their therapy (ie, slowly progressive improvements and partial lesion clearing). Given that improvements may gradually progress over several months, serial photographs from each visit may help dermatologists and patients more clearly observe the effects of therapy over time. Conclusions Identify adjunctive products to be used with regimen A broad array of effective topical antimicrobial agents are available for the treatment of mild-to-moderate acne vulgaris. (ie, designated skin care products) BPO, topical antibiotics, and topical retinoids continue to be Provide written instructions on both prescribed and mainstays of therapy. Products that combine agents with adjunctive product regimens. differing mechanisms of action tend to be most effective. Tolerability has been improved in recent years as vehicles now Help patient to form realistic expectations about often contain emollients and humectants, acting to reduce therapy: common side effects such as erythema, dryness, and peeling. How rapidly improvement will emerge Advances in formulation technology continue to improve How improvement will be determined the tolerability and efficacy of topical antimicrobial regimens. Differentiate new lesions from both resolving References lesions and residual postinflammatory 1. Leyden JJ. The evolving role of Propionibacterium acnes in acne. hyperpigmentation and erythema Semin Cutan Med Surg. 2001;20: How to handle treatment-emergent irritation 2. Erianne J, Prince DL, Ramirez J, Wilson D, Zeichner J. The pharmacologic science of a novel benzoyl peroxide formulation and the Length of therapy course Likely long-term outcome implications for clinical effects. Poster presented at: 25th Anniversary Fall Clinical Dermatology Conference ; October 6-9, Consider serial photography to track progress 2006; Las Vegas, NV.

9 s7 TOPICAL ANTIMICROBIAL OPTIONS FOR ACNE 3. Simonart T, Dramaix M. Treatment of acne with topical antibiotics: lessons from clinical studies. Br J Dermatol. 2005;153: Leyden JJ. Effect of topical benzoyl peroxide/clindamycin versus topical clindamycin and vehicle in the reduction of Propionibacterium acnes. Cutis. 2002;69: 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: Cunliffe WJ, Holland KT, Bojar R, et al. A randomized, doubleblind comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topical treatment of acne vulgaris. Clin Ther. 2002;24: Liu PT, Krutzik SR, Kim J, Modlin RL. Cutting edge: All-trans retinoic acid down-regulates TLR2 expression and function. J Immunol. 2005;174: Nagpal S, Chandraratna RA. Recent developments in receptorselective retinoids. Curr Pharm Des. 2000;6: Thacher SM, Vasudevan J, Chandraratna RA. Therapeutic applications for ligands of retinoid receptors. Curr Pharm Des. 2000;6: 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(suppl 52): 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: Del Rosso JQ. Study results of benzoyl peroxide 5%/clindamycin 1% topical gel, adapalene 0.1% gel, and use in combination for acne vulgaris. J Drugs Dermatol. 2007;6: Schlessinger J, Menter A, Gold M, et al. Clinical safety and efficacy studies of a novel formulation combining 1.2% clindamycin phosphate and 0.025% tretinoin for the treatment of acne vulgaris. J Drugs Dermatol. 2007;6: Gupta AK, Nichol K. The use of sulfur in dermatology. J Drugs Dermatol. 2004;3: Abramovits W, Kennedy AJ. Sulfur/sodium sulfacetamide preparations. SkinMed: Dermatol Clin. 2004;3: Azelex (azelaic acid 20% cream) [package insert]. Irvine, CA: Allergan, Inc; Draelos ZD. The rationale for advancing the formulation of azelaic acid vehicles. Cutis. 2006;77(suppl): Thiboutot DM. Versatility of azelaic acid (AzA) 15% gel in treatment of acne vulgaris: a review of clinical literature. Poster presented at: American Academy of Dermatology 65th Annual Meeting; February 2-6, 2007; Washington DC. 19. Wilson DC. Evaluation of a novel acne treatment system (CLENZIderm MD ) designed to enhance the efficacy of benzoyl peroxide treatment: an investigator-blind, randomized study. Poster presented at: Winter Clinical Dermatology Conference Hawaii ; January 13-17, 2007; Kohala Coast, Hawaii. 20. Del Rosso JQ, Bikowski JB, Baum E, et al. A closer look at truncal acne vulgaris: prevalence, severity, and clinical significance. J Drugs Dermatol. 2007;6: ADDRESS FOR CORRESPONDENCE James Del Rosso DO, FAOCD PMB E. Flamingo Rd. #8 Las Vegas, NV Phone:

10 s8 COPYRIGHT 2008 JOURNAL OF DRUGS IN DERMATOLOGY NEW DEVELOPMENTS IN TOPICAL ANTIMICROBIAL THERAPY FOR ACNE James Leyden MD Professor Emeritus, Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA Abstract Benzoyl peroxide (BPO) has been an important component of the acne treatment armamentarium for decades. A number of characteristics contribute to its success in acne, including its lipophilicity, potent antibacterial activity, and ability to suppress antibiotic-resistant strains of Propionibacterium acnes. With some commercially available products in which BPO comprises crystals in suspension, aggregation of BPO can occur on the skin surface in large clumps, resulting in poor penetration of sebaceous follicles. In addition, the poor water solubility of BPO, coupled with its chemical instability in other solvents, presents challenges with respect to formulating topical products with optimal bioavailability, stability, and tolerability. Several products and vehicle systems have evolved in attempts to improve on the benefits of BPO in treating acne. A new acne treatment has been developed that contains 5% solubilized BPO consisting of small-size particles. This new product exhibits enhanced follicular penetration of BPO, improved P acnes kill rates and clinical efficacy, and good consumer acceptance relative to existing formulations. Introduction Numerous intertwined factors contribute to the pathophysiology of acne and include excess sebum production, abnormal follicular desquamation of corneocytes that leads to comedogenesis, Propionibacterium acnes proliferation, and inflammation. Excess sebum production and abnormal desquamation of follicular corneocytes provide an ideal environment for P acnes proliferation, which subsequently triggers inflammatory cytokine responses via activation of toll-like receptors. 1,2 While the primary effect of P acnes is inflammation, it also aggravates the development of noninflammatory lesions (comedones). Thus, the importance of P acnes as an etiologic factor warrants its reduction or eradication as a primary therapeutic target in acne. water, BPO is highly lipophilic, a favorable characteristic for penetration into sebaceous follicles. Topically applied BPO penetrates unchanged through the stratum corneum or into the follicles, but ultimately is converted to benzoic acid and many other mostly unidentified compounds. 5 Currently marketed formulations of BPO tend to be suspensions consisting of crystalline clumps of molecules of varying sizes that are deposited on the surface of the skin. In clumps, the ability of BPO to penetrate the sebaceous follicles where it can interact with P acnes may not be optimal. Previous attempts to improve the solubilization of BPO using various solvents foundered when enhanced solubility occurred at the cost of adversely impacting the stability of BPO, with premature decomposition to benzoic acid and other degradation products. 6-8 Physicochemical Characteristics of Benzoyl Peroxide Benzoyl peroxide (BPO) has been used in the treatment of acne for several decades. In addition to its mild anticomedo- Penalties Solubilized Apply Benzoyl Peroxide While the concept that solubilization may lead to better bioavailability and the potentially improved efficacy of BPO genic properties, it is a highly effective antibacterial to which antimicrobial resistance has not been documented; moreover, BPO can actually reverse antibiotic resistance among P acnes. 3,4 The BPO molecule is relatively small, with a low molecular weight (Figure 1). Although it is poorly soluble in Figure 1. Molecular structure of benzoyl peroxide. is not new, it has only been achieved recently. A solubilized formulation of BPO 5% gel has been developed (Clenziderm MD, Obagi Medical Products, Inc.), and several analyses have been conducted to determine its bioavailability, efficacy, and tolerability relative to currently marketed formulations of BPO The pattern of deposition of the solubilized BPO 5% gel was compared with that of a commercially available generic formulation of BPO 5% gel. 9 Silicone replicas were created from the skin on cleansed faces of healthy volunteers before and 30 minutes after the application of equal aliquots of either the solubilized or generic BPO gel. The pretreatment skin replicas showed intact superficial squamous cells on both sides of the face, with no particulate matter on the skin surface or in the follicles. Following application of the generic BPO 5% gel, a crystal residue remained on the skin surface squamous cells, suggesting that the material had not penetrated the follicles (Figure 2a). In contrast, following application of the solubi-

11 s9 NEW DEVELOPMENTS IN TOPICAL ANTIMICROBIAL THERAPY FOR ACNE lized BPO gel, no residue was visible on the skin surface although globular material was evident in the follicular ostia (Figure 2b) suggesting the material penetrated the sebaceous follicles better than the comparator. Clinical Efficacy in Acne To confirm whether the enhanced penetration of the solubilized BPO formulation translated into improved microbiological efficacy, additional studies were conducted. One evaluation was a split-face study 10 designed to assess the intrafollicular bactericidal activity of solubilized BPO 5% gel using a modified scrub technique that was found to be very reliable and reproducible for examining the contents of sebaceous follicles. 12 In the present study, 24 healthy volunteers had 0.2 ml of solubilized BPO gel applied to 1 side of their uncleansed forehead and 0.2 ml of either generic prescription BPO 5% or a BPO 5%/antibiotic combination product applied to the other side. 10 Follicular plugs were extracted using cyanoacrylate glue, plated onto agar, and anaerobically incubated. All treatments resulted in a reduction from baseline in the number of P acnes colony-forming units at 8 hours posttreatment, with the greatest reductions by the solubilized BPO product versus comparators (2.5 log 10 reduction with solubilized BPO vs 1.7 log 10 reduction for BPO/antibiotic combination, and 1.9 log 10 reduction with solubilized BPO vs 1.7 log 10 reduction with the generic BPO product). These results further suggest that the solubilized BPO product has enhanced bioavailability relative to other marketed formulations. A second study using traditional measures of efficacy was performed to prove the concept of improved efficacy of solubilized BPO 5% gel in acne. 11 This was a split-face study in which 34 patients with mild-to-moderate facial acne (17 to 40 inflammatory lesions and 10 to 100 noninflammatory lesions) were randomized to receive treatment with solubilized BPO 5% gel plus a salicylic acid-based toner or prescription BPO 5%/antibiotic combination product plus a salicylic acid-based toner. Both treatments were applied twice daily for 2 weeks. Noninflammatory Penalties lesion counts were reduced 34% Apply with the solubilized BPO 5% gel treatment and 21% with the prescription BPO/antibiotic combination product treatment. Reductions in inflammatory lesion counts were similar between groups (52% and 50%, respectively). In a 12-week study of similar design in 38 patients with acne vulgaris, reductions in noninflammatory and inflammatory lesion counts were similar between groups (at least 65% reduction in each type of lesion in each treatment group), indicating that the solubilized 5% BPO product was as effective as a BPO/antibiotic combination product. 10 Tolerability Benzoyl peroxide formulations can be irritating, causing erythema, scaling, burning, and stinging in some patients, particularly during treatment initiation. Indeed, there have been numerous attempts to minimize irritation associated with BPO with various vehicle technologies. 13,14 Because there appears to be an inverse correlation between efficacy and tolerability, a formulation with increased bioavailability of BPO may, in theory, be associated with an increased risk for irritation. To assess this specifically, a blinded, split-face study was conducted to compare the tolerability of the solubilized BPO lotion against a BPO/clindamycin combination product (J Leyden, unpublished data). A total of 50 female subjects applied the following treatments: a 3-step acne system consisting of a mild cleanser, solubilized 5% BPO lotion, and a moisturizer containing 20% glycerin and 2% dimethicone to 1 side of the face; and an over-the-counter cleanser and BPO/clindamycin combination product containing 2 emollients to the other side of the face. Patients used the topical agents twice daily for 3 weeks in a laboratory setting. Erythema and dryness, assessed by this author, occurred as expected; very mild to mild erythema was present on both sides of the face in ~50% of subjects over the course of the study (Figure 3a). Cases of dryness were slight or very slight in all cases. Compared with the BPO/clindamycin system, the solubilized BPO acne system resulted in lower mean levels of dryness (P.05 at week 2 and.055 at week 3; Figure 3b). These differences may be attributed to the high glycerin content in the solubilized acne system moisturizer (J Leyden, unpublished data). Figure 2. Magnification (300x) of skin 30 minutes following application of a) generic BPO 5% gel product and b) a new formulation of solubilized BPO 5% gel. a. b.

12 s10 NEW DEVELOPMENTS IN TOPICAL ANTIMICROBIAL THERAPY FOR ACNE Figure 3. Percentage of patients (N = 50; 47 patients reporting results) reporting tolerability-related outcomes in a split-face clinical trial evaluating a novel solubilized BPO acne treatment system with those of a commercial BPO/clindamycin combination prescription. a) Erythema, b) dryness ( * P<.05, P=.055 for means between groups), c) burning or stinging ( * P.05 for means between groups), and d) comfort of treatment ( * P.05 for means between groups) (J Leyden, unpublished data). a. b. c. d. Subjects reported burning and stinging much more frequently lized BPO product and acne system has demonstrated enhanced on the solubilized BPO treated side Do of the face than Not on the Copy penetration of BPO into the sebaceous follicles and as BPO/clindamycin-treated side (P.05 for differences between groups in mean scores at weeks 1, 2, and 3; Figure 3c). combination of BPO and clindamycin with respect to efficacy part of a specific regimen appears to offer advantages over the This was reported most frequently in the first week of treatment. Increased burning and stinging relative to a nonsolu- needed to confirm and extend these findings. and comfort. Further studies in larger numbers of patients are bilized 5% BPO product appears Penalties to further confirm that the Apply enhanced solubilization of BPO is resulting in biologic consequences (ie, increased follicular penetration). Most interesting is that when subjects were asked to rate the overall 1. Kim J, Ochoa MT, Krutzik SR, et al. Activation of toll-like recep- References degree of comfort with the acne treatments, there was a tor 2 in acne triggers inflammatory cytokine responses. J Immunol. clear preference for the solubilized 5% BPO treatment system 2002;169: (Figure 3d). At weeks 2 and 3, more subjects reported that 2. Jugeau S, Tenaud I, Knol AC, et al. Induction of toll-like receptors the solubilized BPO treatment system was very comfortable by Propionibacterium acnes. Br J Dermatol. 2005;153: compared with the BPO/clindamycin product (P.05 for 3. Taylor GA, Shalita AR. Benzoyl peroxide-based combination therapies for acne vulgaris: a comparative review. Am J Clin Dermatol. means between groups). Thus, burning and stinging did not appear to affect consumer acceptance of the treatment system (J Leyden, unpublished 2004;5: data). Summary Benzoyl peroxide, alone or in combination with an antibiotic, is a very effective acne agent with a long history of use. One of the most important benefits as an antibacterial is that it curtails and even reverses P acnes resistance. Therefore, it will remain an important component in the acne treatment armamentarium, and any improvements that enhance its tolerability and efficacy will be welcomed by dermatologists. The new solubi- 4. Cunliffe WJ, Holland KT, Bojar R, Levy SF. A randomized, double-blind comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topical treatment of acne vulgaris. Clin Ther. 2002;24: Nacht S, Yeung D, Beasley JN, Anjo MD, Maibach HI. Benzoyl peroxide: percutaneous penetration and metabolic disposition. J Am Acad Dermatol. 1981;4: Chellquist EM, Gorman WG. Benzoyl peroxide solubility and stability in hydric solvents. Pharm Res. 1992;9:

13 s11 NEW DEVELOPMENTS IN TOPICAL ANTIMICROBIAL THERAPY FOR ACNE 7. Das Gupta V. Effect of some formulation adjuncts on the stability of benzoyl peroxide. J Pharm Sci. 1982;71: Hongo T, Hikage S, Sato A. Stability of benzoyl peroxide in methyl alcohol. Dent Mater J. 2006;25: Spellman MC, Ramirez J. A comparison of patterns of deposition of two formulations of benzoyl peroxide on the skin and in the follicular ostia as visualized by scanning electron microscopy. Poster presented at: American Academy of Dermatology 65th Annual Meeting; February 2-6, 2007; Washington, DC. 10. Erianne J, Prince DL, Ramirez J, Wilson D, Zeichner J. The pharmacologic science of a novel benzoyl peroxide formulation and the implications for clinical effects. Poster presented at: 25th Anniversary Fall Clinical Dermatology Conference; October 6-9, 2006; Las Vegas, NV. 11. Wilson DC, Meadows KP, Ramirez J. A comparison of a novel benzoyl peroxide system with a combination benzoyl peroxide and clindamycin product: a 2-week split face study of effectiveness and tolerability. Poster presented at: American Academy of Dermatology 65th Annual Meeting; February 2-6, 2007; Washington, DC. 12. Holland KT, Roberts CD. A technique for sampling micro-organisms from the pilo-sebaceous ducts. J Appl Bacteriol. 1974;37: Jelvahgari M, Siahi-Shadbad MR, Azarmi S, Martin GP, Nokhodchi A. The microsponge delivery system of benzoyl peroxide: preparation, characterization, and release studies. Int J Pharm. 2006;308: Weinberg JM. The utility of benzoyl peroxide in hydrophase base (Brevoxyl ) in the treatment of acne vulgaris. J Drugs Dermatol. 2006;5: ADDRESS FOR CORRESPONDENCE James Leyden MD Skin Study Center KGL, Inc. 505 Parkway Broomall, PA Phone:

14 s12 COPYRIGHT 2008 JOURNAL OF DRUGS IN DERMATOLOGY THE ROLE OF ELASTIN AND COLLAGEN IN CUTANEOUS AGING: INTRINSIC AGING VERSUS PHOTOEXPOSURE Jouni Uitto MD, PhD Professor and Chair, Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Philadelphia, PA Abstract Cutaneous aging occurs through 2 biologically distinct processes: intrinsic and extrinsic aging. The first is a naturally occurring process that results from slow tissue degeneration. In human dermis, intrinsic aging is characterized by 3 features: atrophy of the dermis due to loss of collagen, degeneration in the elastic fiber network, and loss of hydration. In contrast to intrinsic aging, extrinsic aging is due to environmental factors. Since ultraviolet (UV) exposure is the principal cause of extrinsic aging, it is often referred to as photoaging. At the microscopic level, the distinguishing feature of photoaging is a massive accumulation of elastotic material in the upper and middle dermis, a process termed solar elastosis. Using recombinant DNA technology, it has become possible to demonstrate that UV radiation can activate the human elastin promoter. This provides a mechanism for enhanced elastin biosynthesis, which contributes to the clinical and morphologic changes observed in photoaged skin. Introduction Cutaneous aging is a complex biological process associated with disruption of the physical integrity of the skin. The process has 2 components intrinsic and extrinsic aging that act independently. Intrinsic aging, sometimes called innate aging, is a natural process that is the result of an accumulation of irreversible age-associated degenerative changes. The effect of intrinsic aging on the skin is probably not unlike the effect of aging on the internal organs. Superimposed on this intrinsic component is extrinsic aging, which is primarily due to photodamage caused by ultraviolet (UV) irradiation of unprotected skin. From a clinical standpoint, the 2 forms of cutaneous aging can be distinguished by comparing the sun-damaged face with another part of the body that has not been chronically exposed to the sun (eg, the underside of the arm) (Figure 1). Innate aging of the skin is typically characterized by very fine wrinkling, atrophy of the dermis, and a loss of subcutaneous adipose tissue. This is in sharp contrast to sun-damaged skin, which shows coarse wrinkling and furrowing along with an apparent thickening of the skin. These features are largely due to a phenomenon known as solar elastosis, in which elastotic material accumulates in the dermis. A number of mechanisms have been proposed for the degenerative changes of innate aging in skin and other tissues. Figure 1. Examples of extrinsic aging due to sun damage (left), and innate aging in sunprotected skin (right). Note the sun-damaged skin is characterized by coarse wrinkling and furrowing and apparent skin thickening. The sun-protected skin features fine wrinkling, dermal atrophy, and a loss of subcutaneous adipose tissue with age.

15 s13 ELASTIN AND COLLAGEN IN CUTANEOUS AGING One theory holds that as tissues and cells become older, changes occur in their gene expression profile. Not only do the amounts of protein change, but aging cells also begin to manufacture abnormal proteins. In this context, the cutaneous proteins that appear to be most affected by the process of intrinsic aging are extracellular matrix proteins, primarily collagen and elastin. There are at least 4 groups of extracellular matrix macromolecules required for normal skin physiology. Collagen and the fibers formed from it impart tensile properties to skin, allowing skin to serve as a protective organ against external trauma. Collagen is the most abundant of the extracellular matrix proteins; type I collagen accounts for approximately 80% of the dry weight of the dermis. 1 Fibers formed from the protein elastin provide elasticity and resilience, and they confer the snap-back properties to normal skin. A third category of cutaneous extracellular matrix proteins are noncollagenous glycoproteins. These are less abundant than collagen and elastin, but they play an important role in cellular adhesion, cellular motility, and other biological functions needed to maintain the physiology of human skin. Finally, there are the glycosaminoglycan/proteoglycan complexes. These macromolecules, which include hyaluronic acid, are a minor component of normal human skin, making up only 0.1% to 0.3% of total dry weight, yet they play a critical role by providing hydration. 1 Approximately 60% of the total weight of the dermis is water, retained largely as a result of the water-absorbing capacity of these macromolecules, as glycosaminoglycans can bind up to 1000 times their volume in water. 1 As skin naturally matures from that of the newborn to that of an elderly person, it undergoes a number Do of structural Not changes. Copy Newborn skin has an abundant collagen meshwork, accompanied by an intact elastic fiber network, and significant amounts of hyaluronic acid which provides a high degree of hydration. By contrast, naturally aged skin shows signs of dermal atrophy, primarily due Penalties to a loss of collagen. There is Apply clear degeneration of the elastic fiber network, so that the resilience of the skin is lost, 2 and there is a loss of hydration due to changes in the glycosaminoglycan macromolecules. 3 Collagen Metabolism in Aging Skin Intrinsic aging has a dramatic effect on the network of collagen fibers of human skin. The quantitative changes are reflected by changes in collagen biosynthesis, which shows a steady decline up to about the third or fourth decade of life (Figure 2). 4 After that, collagen biosynthesis remains at a level that is too low to allow mature skin to repair and replace the collagen that has been lost as part of the degradative, ageassociated process. A number of factors combine to disrupt normal collagen maintenance and production in aging skin fibroblasts. In addition to a decrease in collagen gene expression there is simultaneous overexpression of collagenase. 5 The expression of collagen and collagen-degrading enzymes in innately aged cells appears to be unresponsive to extracellular signals that regulate these genes in young fibroblasts. 6 Underexpression of collagenase inhibitors such as tissue inhibitor of metalloproteinase-1 further enhances the activity of collagendegrading enzymes. 7 The net result of these changes is the conversion of fibroblasts, which manufacture and maintain Figure 2. Age-associated changes in synthesis of human skin collagen. The synthesis of hydroxyproline (A), solubility of collagen (B), and activity of prolyl hydroxylase (C) decrease with advancing age. Reproduced with permission from Uitto J. Ann Clin Res. 1971;3:

16 s14 ELASTIN AND COLLAGEN IN CUTANEOUS AGING the collagen meshwork in young skin, to fibroclasts, which degrade and disrupt the extracellular matrix in aged skin. Elastic Fibers in Human Skin Elastic fibers are a relatively minor component of normal, sun-protected human skin, contributing only 2% to 4% of total dry weight. 8 The fibers, which are composed of a core containing elastin and an outer microfibrillar covering, form a fine interconnecting network throughout the dermis, providing skin with elasticity and resilience. A number of cutaneous diseases reveal the important structural role played by the elastic fibers. Many of them are heritable single-gene disorders in which elastic structures are selectively destroyed. Individuals affected by these disorders share symptoms of cutaneous sagging and loss of skin resilience as seen in cutis laxa, a disorder caused by a specific defect in elastin or in microfibril proteins of the elastic fiber network. 9,10 globular elastotic structures (Figure 4). In Figure 5, solar elastotic structures are shown by confocal microscopy to replace almost all of the dermal collagen, which is the dominant component of healthy skin. 12 Gene Studies Clinical observations provide strong evidence that sun exposure causes photoaging. It is not easy to determine by observation alone whether UV irradiation is the actual cause of the aberrant changes in elastic fibers and which spectrum of UV may be responsible. Figure 3. Cutaneous aging. Protected a), sun-exposed b), and sundamaged c) skin. Because elastin is highly insoluble, its rate of biosynthesis is difficult to measure directly; however, molecular biology techniques allow measurement of the messenger RNA (mrna) levels of elastin, which correlate well with the rate of biosynthesis in the skin. In 1988, Fazio examined the mrna levels in fibroblasts from the skin of individuals of various ages, ranging from 3 to 61 years of age, and data demonstrated that the rate of elastin biosynthesis is found to remain relatively stable up to about the third or fourth decade of life, after which it declines precipitously. 11 Elderly individuals have a diminished capacity to replace elastic fibers lost through naturally occurring degradative processes. This occurs at the same time that the capacity is lost to restore the framework of collagen fibers and that levels of glycosaminoglycans decline, b. which results in reduced hydration; overall, these losses result in dermal atrophy. Extrinsic Aging Extrinsic aging is due to environmental causes. The process is often called photoaging, since almost all extrinsic aging results from sun exposure of Penalties unprotected skin and radiation Apply from the UV region of the spectrum is the major culprit. Photoaging, which is superimposed on the process of innate aging, is a major health hazard in terms of increased risk for skin cancer development. While the risk of photoaging varies with the amount of exposure, a number of factors, including genetic ones, clearly c. influence the rate of its development. These include the degree of skin pigmentation, which alters the amount of UV that penetrates the skin, as well as lifestyle factors that affect the degree of sun and UV exposure. At the microscopic level, sun damage is characterized by the accumulation of abnormal elastotic material, a process called solar elastosis. As the damage advances, pleiomorphic elastotic structures predominate. Although these structures are composed of elastotic material, they do not have a normal fibrous appearance (Figure 3). Confocal laser scanning microscopy using elastin-specific antibodies shows how the normal morphology of dermal elastic fibers changes to one of a.

17 s15 ELASTIN AND COLLAGEN IN CUTANEOUS AGING To address these questions, a mouse model was developed in which the 5' promoter regions of the human elastin gene was linked to a reporter gene coding for the bacterial enzyme chloramphenicol acetyl transferase (CAT). After this DNA construct was transferred into mice, the activity of CAT in the transgenic animals was measured under a variety of conditions. 13 Since CAT is not normally made by mice, any enzyme activity could only come from the transgenic enzyme under the control of the human elastin promoter. A tissuespecific survey found that under basal conditions the promoter in transgenic mice was most active in the lungs and in the aorta, which represents the mouse tissues containing the highest amounts of elastin. Under these baseline conditions, skin showed barely detectable levels of CAT, indicating that the elastin promoter was less active in this tissue. A number of manipulations were carried out to determine under which conditions the elastin promoter in skin became activated. One of these manipulations involved looking at the response of the promoter to various wavelengths within the UV spectrum. The animals, or cells cultured from them, were irradiated with light sources that emitted UVB or UVA. When mouse skin was irradiated with UVB, a progressive increase in CAT activity due to elastin promoter activation was observed. At the highest levels of UVB exposure, there was an 8-fold increase in promoter activity. When skin cells were cultured from transgenic mice cells and exposed in vitro, up to a 30-fold enhancement in enzyme activity was observed, suggesting that UVB can have direct effects on cells by activating the elastin promoter and causing them to overproduce elastin. A series of experiments similar to those using UVB was carried out with UVA-irradiated animals and skin cells derived from them. In vivo exposure resulted in an approximately 2-fold sustained enhancement of elastin promoter activity, Type I Collagen while the activity of the elastin promoter was essentially unchanged when cells were irradiated in vitro. Because there was little effect in the cultured cells, the enhancement of promoter activity by UVA probably occurs through secondary mechanisms; UVA may elicit cytokines or other mediators in the epidermis, which are then able to increase elastin fibrillogenesis in skin. Conclusion Cutaneous age-associated alterations are the result of a combination of intrinsic and extrinsic aging, the latter primarily due to sun exposure. Substantial perturbations in the major extracellular matrix components of skin, collagen, and elastin, occur in both types of aging. During extrinsic aging, UVA and UVB spectra both produce changes in elastin metabolism and probably changes in collagen as well. Novel strategies are needed for the treatment and prevention of the degenerative processes that occur during aging. Among approaches currently available are pharmacologic interventions, such as retinoic acid and alpha-hydroxy acids, and surgical approaches. Based on our understanding of the molecular processes that underlie cutaneous aging, new pharmacologic agents, such as elastase inhibitors and elastin and collagen boosters, may prove to be effective treatments for aging skin in the future. Figure 5. Confocal laser scanning microscopy of extracellular matrix components of protected and sun-damaged skin. 12 Figure 4. Confocal microscopy of elastic fibers in protected a) and sun-damaged b) skin. 12 a. b. Elastin Protected Sun-damaged Merged Reproduced with permission from Bernstein EF, et al. J Am Acad Reproduced with permission from Bernstein EF, et al. J Am Acad Dermatol. 1996;34: Dermatol. 1996;34:

18 s16 ELASTIN AND COLLAGEN IN CUTANEOUS AGING References 1. Bernstein EF, Uitto J. The effect of photodamage on dermal extracellular matrix. Clin Dermatol. 1996;14: Escoffier C, de Rigal J, Rochefort A, Vasselet R, Leveque JL, Agache PG. Age-related mechanical properties of human skin: an in vivo study. J Invest Dermatol. 1989;93: Meyer LJ, Stern R. Age-dependent changes of hyaluronan in human skin. J Invest Dermatol. 1994;102: Uitto J. Collagen biosynthesis in human skin. A review with emphasis on scleroderma. Ann Clin Res. 1971;3: Varani J, Warner RL, Gharaee-Kermani M, et al. Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin. J Invest Dermatol. 2000;114: Chen YQ, Mauviel A, Ryynanen J, Sollberg S, Uitto J. Type VII collagen gene expression by human skin fibroblasts and keratinocytes in culture: influence of donor age and cytokine responses. J Invest Dermatol. 1994;102: Hornebeck W. Down-regulation of tissue inhibitor of matrix metalloprotease-1 (TIMP-1) in aged human skin contributes to matrix degradation and impaired cell growth and survival. Pathol Biol (Paris). 2003;51: Uitto J. Molecular pathology of collagen in cutaneous diseases. In: Callen JP, Dahl MV, Golitz LE, Greenway HT, Schachner LA, eds. Advances in Dermatology. St. Louis: Mosby Year-Book; 1991: Rodriguez-Revenga L, Iranzo P, Badenas C, Puig S, Carrio A, Mila M. A novel elastin gene mutation resulting in an autosomal dominant form of cutis laxa. Arch Dermatol. 2004;140: Lebwohl MG, Schwartz E, Jacobs L, Lebwohl M, Sakai L, Fleischmajer R. Abnormalities of fibrillin in acquired cutis laxa. J Am Acad Dermatol. 1994;30: Fazio MJ, Olsen DR, Kuivaniemi H, et al. Isolation and characterization of human elastin cdnas, and age-associated variation in elastin gene expression in cultured skin fibroblasts. Lab Invest. 1988;58: Bernstein EF, Chen YQ, Kopp JB, et al. Long-term sun exposure alters the collagen of the papillary dermis. J Am Acad Dermatol. 1996; 34: Bernstein EF, Brown DB, Urbach F, et al. Ultraviolet radiation activates the human elastin promoter in transgenic mice: a novel in vivo and in vitro model of cutaneous photoaging. J Invest Dermatol. 1995;105: ADDRESS FOR CORRESPONDENCE Jouni Uitto MD, PhD Bluemle Life Sciences Building 233 South 10th St., Ste. 450 Philadelphia, PA Phone:

19 s17 COPYRIGHT 2008 JOURNAL OF DRUGS IN DERMATOLOGY COSMECEUTICALS FOR THE ATTENUATION OF EXTRINSIC AND INTRINSIC DERMAL AGING Suzanne Bruce MD President, Suzanne Bruce and Associates, PA; The Center for Skin Research, Houston, TX Abstract Since the term cosmeceutical was coined over 2 decades ago, the number of products in this category that claim to combat dermal aging has grown dramatically. Topical retinoids remain the mainstay for treating photoaging given their proven efficacy in both clinical and histologic outcomes. In addition to retinoids, many other cosmeceutical agents are now available. The proliferation of products can cause confusion among consumers, who often ask their dermatologist for advice as to which antiaging products they should choose. Ideally, the antiaging claims of cosmeceutical formulations and their components should be demonstrated in controlled clinical trials. In order to provide appropriate recommendations to their patients, dermatologists must become familiar with the available data on currently marketed products and gain experience with antiaging regimens. This review discusses the efficacy of a number of currently marketed drug products with proven photoaging benefits and cosmeceutical products that claim similar benefits. Among the agents discussed are single-entity and combination products containing hydroquinones, retinoids, topical antioxidants, and minerals. Introduction The Food, Drug, and Cosmetic Act of 1938 clearly defines and distinguishes between drugs and cosmetics. 1 A drug is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and is intended to affect the structure or any function of the body... 1 A cosmetic is a product intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance of the skin. 1 While for the most part products in these categories are mutually exclusive, in dermatology a group of products has evolved that has characteristics of both. First called cosmeceuticals by Albert Kligman, MD, 2 decades ago, 2 these topical products contain biologically active ingredients, but are sold to improve appearance, not for therapeutic purposes. Some drug products and many cosmeceuticals are marketed as agents that attenuate the effects of aging on the skin. Topical Drugs with Demonstrated Activity against Dermal Aging The efficacy of several chemical agents for the prevention and treatment of dermal aging is well established. Among preventive therapies, sunscreens are recognized as the most important drug-product class. In addition to reducing erythema associated with acute ultraviolet B (UVB) exposure, sunscreens with adequate UVA and UVB protection can also prevent melanin production and collagen and elastin degradation. After sunscreens, topical retinoids are the second most important drug class to combat and reverse dermal aging. With over 2 decades of experience, there is a vast amount of evidence that regular retinoid use over several months results in clinical improvement in skin texture, wrinkles, and pigmentation. 3 The main drawback to retinoid use is local irritation and erythema; however, this usually subsides after several weeks of use or by reducing the frequency of application from once daily to every other day. Hydroquinones and related compounds are also used to reverse dermal aging. Hydroquinones suppress melanocyte metabolic processes, including pigment production. These agents primarily address dyspigmentation related to photoaging and lighten skin and even out skin tone. They are often used as adjuncts to topical retinoids and other treatments. 4-7 Compared with retinoids there are very few data substantiating the efficacy of hydroquinones for dermal aging. Recently, as part of their ongoing review of over-the-counter drug (OTC) products, the US Food and Drug Administration (FDA) proposed a ban on OTC hydroquinones that would reverse their generally regarded status as safe and effective and require any marketed hydroquinone product to submit a New Drug Application (NDA) for continued marketing. 8 The change in rulemaking stems from new toxicology and carcinogenesis data on orally administered hydroquinone. However, some dermatologists 9 consider the proposed ban and NDA requirements for topical OTC hydroquinones to be excessive. Cosmeceuticals for Dermal Aging The aging of the baby boomer population has given rise to increased consumer interest in maintaining a youthful appearance throughout middle age. The cosmetic and pharmaceutical companies have responded with a broad array of products containing active ingredients that claim to improve the appearance of lines and wrinkles (Figure 1). Given the number of products available, it can be difficult for consumers and even dermatologists to distinguish those products that genuinely produce benefits from those that do not. As physicians, dermatologists have been trained to select treatments for their patients based on evidence gained through adequate and well-controlled trials. With drug products and devices, the FDA ensures that such trials are performed before new drugs can be approved or devices can be marketed; however, cosmeceuticals are not required to undergo the same rigorous testing prior to marketing. When

20 s18 COSMECEUTICALS FOR DERMAL AGING conducted at all, clinical trials for most of these agents have been very small, open-label evaluations, often lacking an appropriate comparator. Another main concern is that, while the active ingredients may have been shown to provide an antiaging benefit in vitro or in vivo, often they are not evaluated in the final formulation. 10 This is a serious omission, since factors such as concentration, vehicle and other formulation components, and skin penetration may affect product performance. Thornfeldt 11 has recommended some basic tenets for evaluating cosmeceuticals. First, a biologically sound rationale should exist for the cutaneous effects claimed by the ingredient. Second, the therapeutic concentration range of the ingredient should be known, and the cosmeceutical product should contain an amount of the ingredient that is known to be therapeutically meaningful. Third, formulation science should produce a final product in which the active ingredients are stable. Similarly, formulation science should ensure that the active ingredient(s) penetrate the stratum corneum. With respect to clinical trials of cosmeceuticals, such trials should have the following characteristics: have a doubleblind, a prospective design, use the final marketed product, use visible end points for evaluation, enroll a sufficient number of subjects to determine clinical and statistical significance, and be performed by third-party researchers. More recently, companies appear to be responding to dermatologists insistence for evidence backing their claims, and there is a trend toward improved clinical trial data for cosmeceutical products. Following is a discussion of some studies conducted with final marketed cosmeceutical products. Figure 1. Some topical cosmeceutical ingredients touting antiaging claims. Figure 2. Percentage increase/decrease from baseline in photodamage parameters after 6 weeks of idebenone applied twice daily. Reproduced with permission from McDaniel DH, et al. J Cosmet Dermatol. 2005;4:

21 s19 COSMECEUTICALS FOR DERMAL AGING Idebenone Idebenone is an antioxidant that is structurally related to coenzyme Q Its safety and efficacy for improving photodamaged skin was evaluated in a clinical trial in which 50 female subjects aged 30 to 65 years with moderate photoaging were randomized to receive double-blind commercial lotions containing either 0.5% or 1% idebenone. 12 Subjects were instructed to apply the product twice daily for 6 weeks. Assessments were performed by an experienced blinded investigator evaluating before and after photographs using a 5-point scale (0=no improvement to 4=100% improvement). Results are shown in Figure 2. While both concentrations resulted in improvements from baseline, no statistical significance was reported. A placebo arm might have better demonstrated the meaningfulness of the reported percentage improvements. Copper Zinc Malonate The clinical effects of a physician-dispensed bimineral product containing copper zinc malonate were evaluated in a trial in which 32 female subjects aged 45 to 69 years applied a controlled amount of product (~0.25 g) to the periorbital areas twice daily for 8 weeks. 13 Except for cleanser, the use of other facial products in the areas treated was not permitted. In addition to patient assessments and photography, this study used more objective measures to evaluate outcomes. To assess skin elasticity, a Cutometer was used to measure the speed of recoil of the skin after being pulled into a vacuum. A Corneometer was used to assess the dielectric constant in the stratum corneum, in order to determine the moisture content of the skin. Silicone replicas were created to measure the number and depth of the wrinkles in the periorbital areas. Over time, the speed of skin recoil increased steadily from baseline, from a 20% increase at week 2 to a 46% increase at week 9 (P.01 at week 2 and.001 at weeks 4, 6, 8, and 9). to the study treatment. The dielectric constant in the stratum corneum increased 6% to 7% at weeks 2 through 6, but then returned to baseline by week 8. The normalization of moisturization suggests that other improvements were independent of skin hydration. By week 9, the mean percentage reduction from baseline in wrinkles was 16% (P.05). Serial photography demonstrated the improvements in wrinkles over time (Figure 3). In a separate evaluation of the same copper zinc malonate eye cream in 23 subjects who applied it either once or twice daily, biopsy evaluation showed that twice-daily application was more beneficial than once-daily application in terms of increased levels of elastin and collagen. 14 Twice-daily treatment resulted in the replacement of clumped and relatively thick elastic fibers by finer, more discrete fibers; once-daily treatment was minimally effective in inducing histologic changes. Data regarding once- or twice-daily use are particularly meaningful, as proper administration will ensure the best possible outcomes and likely result in greater patient satisfaction. Tretinoin/Hydroquinone-based System Because hydroquinones are primarily active against skin dyspigmentation, their combination with a retinoid potentially offers a product that also treats the fine lines and wrinkles of photoaging. A large scale, 4-arm study evaluated the efficacy of a proprietary 4-step skin treatment system (cleanser, toner, and day and night creams) containing 0.1% tretinoin and 4% hydroquinone with that of regimens consisting of tretinoin plus an OTC cleanser and daily moisturizer with sunscreen, 4% hydroquinone plus the same OTC products, and the OTC products alone. 15 A total of 387 female subjects aged 38 to 65 years (at least 50% had fine perioral wrinkles) were randomized to receive one of the 4 treatments on a twice-daily regimen for 24 weeks. With the proprietary 4-step system, hydroquinone was applied twice daily and tretinoin once daily;, and with the other arms that contained these ingredients, hydroquinone and tretinoin were applied once daily. Assessments using an 11-point scale (0=no damage to 10=extensive damage) were conducted by an investigator who was blinded A total of 301 subjects completed the study. At 12 and 24 weeks, the 3 treatment arms containing tretinoin and/or hydroquinone produced numeric improvements from the Figure 3. Improvement in appearance of periorbital lines in a 56-year-old female with a bimineral complex eye cream applied twice daily. Reproduced with permission from Miller TF, Batra RS, Ramirez J. Poster presented at: American Academy of Dermatology 65th Annual Meeting; February 2-6, 2007; Washington, DC.

22 s20 COSMECEUTICALS FOR DERMAL AGING baseline in investigator-assessed parameters, although improvements from the baseline were only significant with the tretinoin/hydroquinone combination system (Figure 4). 15 Improvements were more pronounced at 24 weeks than at 12 weeks. As might be expected, subjects randomized to the hydroquinone regimens reported more erythema, scaling, burning, and stinging, although mean change from baseline scores were still in the mild range. Hydroquinone/Stabilized Retinol Combination Product Since tretinoin can cause some unwanted dermal effects, a less irritating retinoid such as retinol has been evaluated in combination with hydroquinone. In a 16-week study, a cosmeceutical formulation containing 4% hydroquinone and 0.3% stabilized retinol in an emollient vehicle was found to be more effective in diminishing dyspigmentation, fine wrinkles, and tactile roughness in sun-damaged skin than a 0.05% tretinoin single-component emollient cream. 16 Topical Antioxidant Formulations Cosmeceutical formulations of the antioxidant vitamins C and E have proven to be of value in the treatment of photoaging. Interest in vitamin C to treat photoaged skin has increased based on preclinical studies demonstrating their ability to block UV-induced erythema. In addition, in vitro studies have shown that vitamin C stimulates collagen production by fibroblasts, and further studies indicate that it has anti-inflammatory activity and suppresses melanin formation. Figure 4. Improvement in skin parameters after a) 12 weeks and b) 24 weeks of 4 different topical treatment regimens. a. b. * P.05 versus other regimens. Reprinted with permission from Cosmetic Dermatology. 2006;19(4): , Quadrant HealthCom Inc.

23 s21 COSMECEUTICALS FOR DERMAL AGING Together, these functions of vitamin C contribute to its ability to reverse the appearance of photoaging. Vitamin E also exhibits activity that suggests it may be of value for the treatment of photoaging. In animal studies, topical vitamin E, in the form of D-α-tocopherol, was found to protect against acute and chronic UV-induced damage, based on inhibition of tumor formation. In clinical studies, topical vitamin E decreased wrinkles and solar lentigoes of photoaging; these benefits were confirmed by a histologic examination in mice. When used in combination, topical L-ascorbic acid (15%) with α-tocopherol (1%) gave 4-fold greater protection against UV-induced erythema, compared to 2-fold greater protection with either vitamin alone. 17 Increasing the lipid solubility of vitamin C appears to improve its effectiveness. A double-blind, half-face study compared a vitamin C-complex formulation consisting of 10% ascorbic acid (water soluble) and 7% tetrahexyldecyl ascorbate (a lipid form of provitamin C) to vehicle. The anhydrous base allowed for a time-released delivery of the vitamin C and prevented its rapid degradation, while the lipid form of provitamin C was used for its ability to penetrate into the dermis, where it is converted to vitamin C. After 12 weeks, results showed significant improvements in photoaging scores, with biopsies indicating an increase in collagen production. The formulation of vitamin C produced a clinically visible and statistically significant improvement in wrinkling when used topically for 12 weeks. 18 Green tea extracts contain antioxidant polyphenols and have been promoted as a treatment for improving the appearance of photoaged skin. The efficacy of green tea extracts was evaluated in a study of 40 women with moderate photoaging who were randomized to either a combination regimen of 10% green tea cream and 300 mg twice-daily 3. Stratigos AJ, Katsambas AD. The role of topical retinoids in the green tea oral supplementation or a placebo regimen for 8 treatment of photoaging. Drugs. 2005;65: weeks. No significant differences in clinical grading were 4. Lowe N, Horwitz S, Tanghetti E, Draelos Z, Menter A. Tazarotene found between the green tea and placebo-treated groups; versus tazarotene plus hydroquinone in the treatment of photodamaged facial skin: a multicenter, double-blind, randomized study. however, an improvement in the elastic tissue content of J Cosmet Laser Ther. 2006;8: treated specimens (P<.05) was observed upon histologic Clinical Evaluations of Cosmeceuticals in Everyday Practice In the absence of clinical trial data, how can a dermatologist determine if a particular cosmeceutical is beneficial? One means of assessment is through individual split-face trials. Although this is not a common clinical practice, it may be of benefit for a dermatologist self-assessment of a new product or when suggesting a product to skeptical patients (by using it on one side of the face and not the other, patients can see the changes for themselves). The most important tool for assessing dermal changes is serial photography. Commonly used to assess the effect of lasers, it is helpful to show patients the effects of prescription or OTC cosmeceutical dermal antiaging regimens. The documented changes can serve as motivation for the patient to continue using the product(s). A more sophisticated photographic tool is the VISIA Complexion Analysis System (Canfield Imaging Systems), which uses multispectral imaging and analysis to capture and measure key visual information for areas affecting complexion health and appearance, such as wrinkles, skin evenness, pores, and spots. This is a useful method for educating patients about the state of their skin and the existence of subclinical sun damage, rating it against the database of their age- and sex-matched peers. As with serial photography, the VISIA system can assess changes produced via use of cosmeceutical/topical antiaging products. Summary The market for antiaging dermatologic products is growing at a fast pace with cosmeceuticals leading the way. Dermatologists are a key point of contact for patients who are seeking to look younger; they are experts who can guide patients through the confusing barrage of antiaging claims by directing them to the most proven products. Clearly, cosmeceuticals can be of benefit in combating the signs of aging. An assessment of the available data to substantiate efficacy and safety is warranted, and more data are available for some products than others. Antiaging claims associated with cosmeceuticals should be substantiated with demonstrated efficacy of these ingredients in the final marketed product. Dermatologists should press companies to provide appropriate evidence, in the form of adequately designed clinical trials, to substantiate antiaging claims for their products. References 1. Food, Drug, and Cosmetic Act of USC 301 (1938). Available at: Accessed September 14, The future of cosmeceuticals: an interview with Albert Kligman, MD. Dermatol Surg. 2005;31: examination of skin biopsies Draelos ZD. Novel approach to the treatment of hyperpigmented photodamaged skin: 4% hydroquinone/0.3% retinol versus tretinoin 0.05% emollient cream. Dermatol Surg. 2005;31: Gladstone HB, Nguyen SL, Williams R, et al. Efficacy of hydroquinone cream (USP 4%) used alone or in combination with salicylic acid peels in improving photodamage on the neck and upper chest. Dermatol Surg. 2000;26: Fleischer AB, Schwartael EH, Colby SI, Altman DJ. The combination of 2% 4-hydroxyanisole (Mequinol) and 0.01% tretinoin is effective in improving the appearance of solar lentigines and related hyperpigmented lesions in two double-blind multicenter clinical studies. J Am Acad Dermatol. 2000;42: US Department of Health and Human Services, Food and Drug Administration (21 CFR Part 310). Skin bleaching products for over-the-counter human use: proposed rule. Fed Regist. 2006;71: Levitt J. The safety of hydroquinone: a dermatologist s response to the 2006 Federal Register. J Am Acad Dermatol. 2007;26. [Epub ahead of print.]

24 s22 COSMECEUTICALS FOR DERMAL AGING 10. Thornfeldt CR. Cosmeceuticals: separating fact from voodoo science. Skinmed. 2005;4: Thornfeldt CR. Science or spin? Healthy Aging. 2006;2: McDaniel DH, Neudecker BA, DiNardo JC, Lewis II JA, Maiback HI. Clinical efficacy assessment in photodamaged skin of 0.5% and 1% idebenone. J Cosmet Dermatol. 2005;4: Miller TF, Batra RS, Ramirez J. Evaluation of the effect of a novel bi-mineral complex on photoexposed periorbital skin. Poster presented at: American Academy of Dermatology 65th Annual Meeting; February 2-6, 2007; Washington, DC. 14. Smith S, Bruce S, Batra RS, Ramirez J. Clinical evaluation of the effect of a novel bi-mineral complex on periorbital skin. Poster presented at: American Academy of Dermatology 65th Annual Meeting; February 2-6, 2007; Washington, DC. 15. Herndon JH, Stephens TJ, Sigler ML. Efficacy of a tretinoin/hydroquinone-based skin health system in the treatment of facial photodamage. Cosmet Dermatol. 2006;19: Draelos ZD. Novel approach to the treatment of hyperpigmented photodamaged skin: 4% hydroquinone/0.3% retinol versus tretinoin 0.05% emollient cream. Dermatol Surg. 2005;31: Burke KE. Interaction of vitamins C and E as better cosmeceuticals. Dermatol Ther. 2007;20: Fitzpatrick RE, Rostan EF. Double-blind, half-face study comparing topical vitamin C and vehicle for rejuvenation of photodamage. Dermatol Surg. 2002;28: Chiu AE, Chan JL, Kern DG, Kohler S, Rehmus WE, Kimball AB. Double-blinded, placebo-controlled trial of green tea extracts in the clinical and histologic appearance of photoaging skin. Dermatol Surg. 2005;31: ADDRESS FOR CORRESPONDENCE Suzanne Bruce MD The Center for Skin Research 1900 St. James Pl, Ste. 650 Houston, TX Phone:

25 s23 COPYRIGHT 2008 JOURNAL OF DRUGS IN DERMATOLOGY COMPLEMENTARY EFFECTS OF TOPICAL ANTIAGING TREATMENTS IN CONJUNCTION WITH AESTHETIC PROCEDURES Suzanne Bruce MD President, Suzanne Bruce and Associates, PA; The Center for Skin Research, Houston, TX Abstract The dermatologist has a variety of tools for improving the appearance of aging skin. These include injectable botulinum toxins and dermal fillers, laser treatments, chemical peels, and various topical agents, including cosmeceuticals. A combined approach using more than one facial rejuvenation tool is considered ideal for many patients, as it targets the various areas of the face and numerous dynamic and static changes associated with aging. A topical cosmeceutical regimen, such as one containing tretinoin and hydroquinone, can enhance the effects of facial rejuvenation procedures and encourage patients to adopt a daily cleansing and rejuvenation regimen that they can continue after the procedure to help maintain the aesthetic effects. Introduction Aging of the face involves both dynamic and static changes in the skin, musculature, bone, and fat, and the dermatologist has numerous tools to assist patients in enhancing facial appearance (Table 1). Given that virtually all of the aging changes are multifactorial in origin, a combined approach is considered ideal for many patients. Patients concerns regarding their aging are not usually related to one particular area, but rather the aging face in general. Treatment can be individualized and directed toward the most pronounced changes, which are unique to each person. Furthermore, use of multiple treatments may prolong responses and prevent further changes, particularly when the combination includes a topical regimen. Benefits of Combining Aesthetic Procedures Although it is intuitive that combination treatments will yield better results than a single aesthetic procedure, several studies have attempted to quantify these benefits. In a study in which 38 subjects were randomized to receive botulinum neurotoxin type A (BoNTA) plus hyaluronic acid (HA) versus HA alone for moderate-to-severe glabellar lines, not only was there a greater aesthetic effect with a combination versus a single-product treatment at measured time points, but the longevity of treatment was substantially prolonged with combination treatment. The median time to return to preinjection glabellar furrows was 32 weeks with BoNTA plus HA versus 18 weeks with HA alone. 1 In another recently presented analysis of pooled data from 6 clinical studies, Carruthers et al 2 observed that a larger proportion of patients (62%) reported looking younger following BoNTA treatment of multiple upper facial areas (glabella, forehead, and crow s feet) than did patients receiving BoNTA for single areas of the face (crow s feet, 45%; or glabella, 40%). Thus, the multiple treatment produced a greater benefit in terms of self-perceived youthfulness. Carruthers and Carruthers 3 compared the results of full-face broadband light (BBL) with that of full-face BBL combined with BoNTA treatment of moderate-to-severe crow s feet in 30 female subjects. While BBL alone produced remarkable improvements in telangiectasias, lentigines, and skin texture, the BoNTA cotreatment increased these results by 15%. These observations led the investigators to postulate a possible synergistic, as well as complementary, effect. 3 Topical retinoid and/or hydroquinone regimens have been used prior to ablative and nonablative skin resurfacing procedures for many years. 4-7 In a survey of 339 dermatologists and plastic surgeons performing laser resurfacing, tretinoin was recommended for pretreatment skin care by 80% of respondents, and hydroquinone was recommended by 69%. 5 In Table 1. The toolbox for nonsurgical facial rejuvenation. Penalties Botulinum Apply toxins Dermal fillers: Replacement Combination Stimulatory Permanent Chemical peels Microdermabrasion Lasers Topical products: Retinoids Hydroquinones Sunscreens Moisturizers Cosmeceuticals

26 s24 EFFECTS OF TOPICAL ANTIAGING TREATMENTS a comparative study among 40 Indian women with melasma, the combination of a modified Kligman s cream formula (tretinoin 0.05%, hydroquinone 5%, and hydrocortisone 1%) plus glycolic acid peels was significantly more effective in improving melasma than was with a modified Kligman s formula alone. 6 For treating acquired dermal melanocytosis with Q-switched ruby laser, pretreatment with tretinoin 0.1% and hydroquinone 5% was associated with lower rates of postinflammatory hyperpigmentation compared with earlier experiences with laser alone. 7 The adjunctive use of topical tretinoin and hydroquinone preparations may be beneficial with other types of facial rejuvenation procedures. A recently completed large-scale experience trial evaluated the combined effect of facial rejuvenation procedures with maintenance use of a 4-step proprietary skin care regimen containing 0.1% tretinoin and 4% hydroquinone as active ingredients along with a cleanser, toner, exfoliant, sunscreen, and moisturizer. 8 This 4-step system has been previously shown to be superior to regimens containing tretinoin 0.1% cream plus over-the-counter (OTC) products, hydroquinone plus OTC products, and OTC products alone in terms of improving attributes of photodamaged skin such as periocular and perioral fine wrinkles, mottled hyperpigmentation, clarity, sallowness, laxity, and tactile roughness. 9 postprocedure. Patient demographics were typical of those who comprise the antiaging target market: 95% were female, 76% were between 35 and 65 years of age, and 89% had Fitzpatrick skin types II to IV. Approximately half of patients underwent ablative procedures, and half underwent nonablative, nonsurgical procedures. Physicians evaluated various attributes of skin quality of patients using a 4-point scale (0=none to 3=severe/prominent) before and after patients used the hydroquinone/tretinoin system in conjunction with a facial rejuvenation procedure. As expected, patients exhibited an improvement in skin texture attributes such as fine wrinkles, sallowness, tactile roughness, and hyperpigmentation (Figure 1). 8 Results were similar among patients who underwent ablative and nonablative treatments. Among patients who received BoNTA and the tretinoin/hydroquinone-based system (n=239), improvements of at least 1 grade in sallowness, tactile roughness, hyperpigmentation, and fine periocular wrinkles were observed in 80% of patients (Figure 2). Thus, for patients seeking wrinkle reduction with BoNTA treatment, the complementary use of a tretinoin/hydroquinone-based treatment system is an effective adjunct, as it results in an additional improvement across multiple parameters of skin quality that would not be attributable to BoNTA alone. Optimizing Combined Antiaging Regimens In this recent study, patients from numerous study Preprocedure centers across the US who received various procedures such as BoNTA, dermal filler injections, laser treatment, microdermabrasion, chemical peels, or ablative surgery (lasers or facelift) also applied the 4-step tretinoin/hydroquinone treatment system for a mean of 4 weeks preprocedure and 6 weeks The use of a tretinoin/hydroquinone-based system may produce several benefits when used to prepare the skin prior to chemical peels, microdermabrasion, and nonablative and ablative laser treatments. Retinoids thin the stratum corneum, allowing for better penetration of laser light and Figure 1. Percentage of patients exhibiting at least a 1-grade improvement on a 4-point scale (0=none to 3=prominent/severe) in skin attributes following the use of a 4-step tretinoin 0.1%/hydroquinone 4%-based skin care system in conjunction with facial rejuvenation procedures. 8

27 s25 EFFECTS OF TOPICAL ANTIAGING TREATMENTS agents such as aminolevulinic acid, if used. Pretreatment with retinoids prior to dermabrasion, deep chemical peeling, or laser resurfacing can accelerate re-epithelialization. 7,10-12 It has been suggested that pretreatment with hydroquinone may suppress the production of new melanin and accelerate the return of skin to normal pigment should postprocedure hyperpigmentation occur. 5,7 The lightening of background skin color with tretinoin and hydroquinone allows for the safer and more aggressive use of higher energy treatment parameters. This may be especially useful when treating the chest, hands, or arms with intense pulsed light (IPL), as these areas tend to have greater degrees of actinic bronzing than the face. If the same light setting is used on the chest/hands/arms as the face, there is a greater risk of burning the chest/neck/arms due to the increased melanin in those areas. An additional advantage regarding the use of any cosmeceutical pretreatment is that patients begin observing a daily cleansing and rejuvenation regimen that, it is hoped, the patient will continue after the procedure. Given that many of the actions that have been documented with tretinoin (ie, reinvigoration of cellular function, enhanced collagen synthesis, reduced expression of matrix metalloproteinases, normalization of follicular keratinization, and enhanced wound healing) 13,14 are similar to those sought with use of laser and light therapies, it seems prudent to initiate treatment with topical preparations like tretinoin and hydroquinone to jump-start these targeted processes in patients for whom laser or light treatments are planned. In some cases, topical treatment may obviate the need for laser resurfacing. Indeed, results have been obtained with a topical tretinoin/hydroquinone-based skin care system that are arguably similar to those that can be expected from a laser or IPL treatment (Figures 3 and 4). In general, treatment with a tretinoin/hydroquinone-based system should be discontinued several days to weeks prior to microdermabrasions, chemical peels, and fractionated resurfacing. Discontinuation of pretreatment is not necessary prior to IPL or pulsed dye therapy; a more robust reaction is often observed when using topical pretreatment prior to photodynamic therapy due to increased absorption of the aminolevulinic acid. Postprocedure Patients can be instructed to reinitiate the topical tretinoin/hydroquinone-based regimen at their own discretion, when they feel both the procedure-related skin irritation and sensitivity have subsided. For patients in whom a series of procedures is planned (ie, chemical peels, photodynamic therapy, or fractionated resurfacing), it may be best to wait until the series is complete before reinitiating a topical cosmeceutical regimen. Once tolerated, topical cosmeceutical regimens can be continued indefinitely. Barriers to Use The 2 most common barriers to using topical antiaging products are local irritation induced by both retinoids and hydroquinone, and lack of patient motivation. In an open-label trial in which 120 patients with moderate-to-severe photodamaged facial skin received tretinoin cream 0.02% for 52 weeks, skin irritation (erythema, peeling, burning/stinging) was reported as an adverse event by 43% of patients. 15 Most cases were mild to moderate, and only 6% discontinued therapy as a result. Irritation tended to peak during the first 2 weeks of tretinoin therapy, and skin sensitivity returned to baseline by week 8. Among patients who had previously administered the tretinoin 0.02% cream for 24 weeks, then stopped for 12 weeks and restarted therapy, irritation peaked later (4 weeks) during tretinoin restart, but also returned to Figure 2. Percentage of patients exhibiting at least a 1-grade improvement on a 4-point scale (0=none to 3=prominent/severe) in skin attributes following the use of a 4-step tretinoin 0.1%/hydroquinone 4%-based skin care system in conjunction with botulinum neurotoxin type A for facial rejuvenation. Penalties 8 Apply

28 s26 EFFECTS OF TOPICAL ANTIAGING TREATMENTS Figure 3. Patient photographs before and 6 weeks after the daily use of a 4-step tretinoin 0.1%/hydroquinone 4%-based skin-care system. Photos courtesy of Suzanne Bruce MD. Figure 4. Patient photographs before and 6 weeks after the daily use of a 4-step tretinoin 0.1%/hydroquinone 4%-based skin-care system. Photos courtesy of Suzanne Bruce MD. noticeable to the untrained eye. This is particularly important because results often occur gradually, so patients may not notice subtle improvements, especially in the first few weeks of treatment. Indeed, in a 24-week, double-blind, randomized, placebo-controlled trial evaluating once-daily application of tretinoin 0.02% cream, 15 patient self-assessment scores of individual features of photodamage (small wrinkles, tone, color, texture, tightness, and pores) and overall appearance at 24 weeks were similar in the treatment group and the vehicle group, even though investigator assessments demonstrated statistically significant improvements in the tretinoin arm. These results are of interest given that noticeable improvements would be expected and did occur according to blinded-investigator assessments by 6 months, yet the patients did not perceive them. At 24 weeks, 62% of patients receiving tretinoin and 57% receiving the vehicle reported baseline by week 8. Thus, tretinoin-naive patients and tretinoin restarters should be advised that skin irritation (eg, erythema and dryness) can be expected to subside within 2 months of treatment initiation. Some of the more practical means for attaining patient compliance with topical rejuvenation programs focus on proper patient education. For example, if the dermatologist and his or her staff are enthusiastic about the products and the results obtained, patients will be more likely to be motivated to try them. In our practice new patients are shown serial photographs from the practice s own patient base showing improvements over time, and these are routinely reviewed with practice staff so they are familiar with them. Thorough explanations should be provided on how to use the products, what to expect in terms of results, and how to manage any irritation; these instructions also should be given in written for- mat to reinforce verbal discussions. Last, serial photography overall improvement (P=.34). However, patients perceptions is invaluable for showing patients how their skin has improved over time and can be a powerful motivation to con- in which 77% of patients receiving tretinoin 0.02% cream for of improvements changed in the long-term follow-up study, tinue to use the regimen. Patients will appreciate the extra 52 weeks reported improvement. 15 care and interest shown them through the use of serial pho- tographs. Staff members should be trained to point out specific areas of improvement that may not be Summary immediately Table 2. How does a dermatologic practice benefit from offering effective skin rejuvenation regimens? Builds trust and credibility when regimens are recommended that deliver great results. Increases referrals when patients tell their friends about their great results. Offers opportunities for patients to come back to the practice. Helps patients advance to trying procedure-based solutions to their skin-aging problems in addition to topical treatments. Topical antiaging regimens are an essential component of a comprehensive approach to skin rejuvenation. From a practice-building perspective, successful results with skin rejuvenation procedures offer several advantages (Table 2). All patients who seek aesthetic advice should be urged to initiate and maintain a daily topical rejuvenation program. Proper education of office staff and patients is a key component to attainment of the best results and highest possible levels of patient satisfaction with proven regimens. References 1. Carruthers J, Carruthers A. A prospective, randomized, parallel group study analyzing the effect of BTX-A (Botox) and nonanimal sourced hyaluronic acid (NASHA, Restylane) in combination compared with NASHA (Restylane) alone in severe glabellar rhytides in adult female subjects: treatment of severe glabellar rhytides with a hyaluronic acid derivative compared with the derivative and BTX-A. Dermatol Surg. 2003;29: