40 Years of Topical Tretinoin Use in Review

June 2013 | Volume 12 | Issue 6 | Original Article | 638 | Copyright © 2013

Hilary E. Baldwin MD,a Marge Nighland BS,b Clare Kendall MA,c David A. Mays PharmD MBA,c Rachel Grossman MD,b,c and Joan Newburger PhDc

aSUNY Downstate Medical Center, Brooklyn, NY bValeant Dermatology, a subsidiary of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ cJohnson & Johnson Consumer & Personal Products Worldwide, Skillman, NJ

Abstract

Topical tretinoin has been approved for use in dermatology for 40 years and is currently approved for the treatment of acne vulgaris and photodamage. During this time, topical tretinoin has accumulated significant efficacy and safety data in the treatment of acne and photodamaged skin and demonstrated clinical potential for treating a range of other dermatologic conditions. The diverse effects may be due to complex underlying mechanisms of action associated with tretinoin, including keratolytic activity, collagenesis, and other mechanisms associated with the activation of nuclear retinoic acid receptors (RARα, RARβ, and RARγ). In this article, we review the history of topical tretinoin use to date and outline emerging research suggesting that topical tretinoin may have potential clinical use for treating a multitude of other dermatological conditions when used either as monotherapy or in combination with other agents. We also describe newer formulations of topical tretinoin that have been designed to reduce irritation potential. In light of the substantial history of safety and efficacy of topical tretinoin in acne and photodamage, we speculate that it holds promise in treating many additional dermatological conditions, which may be explored in future research.

J Drugs Dermatol. 2013;12(6):638-642, e94-e105.

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INTRODUCTION

As early as the 1960s, topical tretinoin demonstrated clinical potential in a variety of skin disorders, including acne, actinic keratoses, other hyperkeratotic conditions, and antitumor effects in a number of basal cell cancers. Since then, other uses have been described, including the treatment of lesions of the oral mucosa and the ocular surface epithelia, hypertrophic scarring, various infections, and pigmentation disorders.1,2

Kligman and colleagues3 at the University of Pennsylvania reported on the effectiveness of topical tretinoin in treating acne in 1969. In 1971, tretinoin became the first retinoid to be approved by the US Food and Drug Administration (FDA) as a topical treatment for acne vulgaris (AV).4,5

Soon after topical tretinoin became available to the public, elderly patients using it to treat acne reported noticing a general improvement in the condition of their skin.6 Considering this, Kligman and colleagues began trials to study the use of topical tretinoin in treating photodamaged skin. Beneficial results were subsequently verified by large multicenter trials and clinical experience supporting the efficacy and safety of topical tretinoin to treat photodamaged skin.6 In 1995, topical tretinoin was approved by the FDA for the palliation of fine wrinkles, mottled hyperpigmentation, and tactile roughness of facial photodamage.7

The aim of this review is to provide an overview of the history and current uses of topical tretinoin, including likely mechanisms of action, approved indications and dosing, and associated safety and tolerability issues, as well as to speculate on potential therapeutic areas that may be targets for further research and future clinical applications.

Clinical Chemistry, Pharmacology, and Mechanisms of Action

Tretinoin (all-trans retinoic acid) is a retinoid metabolite of naturally occurring vitamin A that activates 3 nuclear retinoic acid receptors (RARα, RARβ, and RARγ). These receptors can act to modify gene expression, protein synthesis, and epithelial cell growth and differentiation.8,9 Tretinoin may exert its clinical effects, at least in part, through activation of retinoid receptors; however, its exact mechanisms of action are unknown.8,10 The binding profile of tretinoin differs from that of synthetic retinoids, such as adapalene, which binds preferentially to RARβ and RARγ, and tazarotene, which binds to all 3 RARs but appears to lead to an effective gene expression only via RARβ and RARγ.11

Topical tretinoin has the ability to modify abnormal follicular keratinization and promote comedolysis, modulate the proliferation and differentiation of epidermal cells, stimulate the formation of new collagen, reduce inflammation, stimulate fibroblasts, prevent collagen loss, and inhibit the induction of skin metalloproteinases (ie, collagenase, 92-kd gelatinase, and stromelysin, which are induced by ultraviolet [UV] irradiation and may degrade skin collagen).8,10,12-15 In addition, tretinoin decreases epidermal melanin, as measured by Fontana Masson staining,15,16 and may

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