220 JOURNAL OF COSMETIC SCIENCE RETINOIDS AND ACNE...A PERSPECTIVE Braham Shroot, Ph.D. DFB Pharmaceuticals, Inc., San Antonio, Texas Vitamin A is so named because it was the first lipid fraction isolated in the extraction of plasma constituents. In 1926, the observation was made in Vitamin A- deprived mice that their skin was scaly and inflamed, and when the mice were fed Vitamin A, these effects were reversed. This Vitamin A deficiency resulted in an intense episode of nutritional research into the metabolism and biochemistry of the precursor to Vitamin A, beta-carotene and its metabolites containing the beta ionone motif, collectively referred to as retinoids. The first report of treatment for acne with oral Vitamin A, a disease of the pilo- sebaceous unit of unknown etiology, appeared in ! 949 by Straumfjord. In 1969, Kligman reported the successful use of topical Vitamin A for acne. Lack of significant efficacy led the same team to study the more potent metabolite, Vitamin A acid, the active ingredient in the current marketed product family, Retin A©. In parallel to these discoveries in dermatology, retinoids became the focus of research in developmental biology. It was discovered that retinoic acid was found to play a key role in the signaling pathway in embryonic development of skeleto, cardiovascular and neuronal systems. For some years it was thought that retinoic acid was a morphogen and that limb development was controlled by a tissue gradient concentration of retinoic acid and its precursors in a space-temporal relationship. Although the retinoids have been fount to play a key role in limb development, they are no longer considered a morphogens, but these findings do relate to the teratology issues that surround this group of compounds and present a major drawback to a wider pharmaceutical usage of these versatile molecules. In the early 90's, even more attention focused on this family as a result of the identification of nuclear receptors called Retinoic Acid Receptors (RAR's). These receptors are related by homology in their DNA binding region to a super family of ligand activated transcription factors comprising, among others, estrogen, Vitamin D, and steroid hormones. Following this discovery, came the finding that these hormones acted through a common mechanism related to a second receptor, RXR, which formed heterodimers with the receptors (PAR's) recognizing all the other hormones in this super- family. This discovery unified much research at the time and, in turn, led to the identification of another natural retinoid, isomer 9-cis retinoic acid. As research progressed, new transcription dimer partners were discovered, notably the Peroxisome Proliferating Activating Receptors (PPARS). Ligands binding to PPARS are now the focus of research in adult onset diabetes. Further this field has benefited from cancer research, which produced some very encouraging clinical observations with another natural retinoid, 13-cis retinoic acid. Drawing upon this fertile scientific environment, investigators in dermatology were able to study the mode of action ofretinoids in skin-related models. Using these

2002 ANNUAL SCIENTIFIC MEETING 221 models calibrated with the parent substances, researchers saw the creation of synthetic analogues with improved clinical performance in acne. In particular, the models developed in the NIH cancer program, based on the action to induce differentiation in a mouse teratocarcinoma cell line F9 and the reversal of keratinocytes differentiation in a Vitamin-A deprived hamster tracheal organ culture, were replaced by test systems assaying the formation of terminally differentiated human skin derived keratinocytes and the rhino mouse as an in vivo model of the comedone. The major line of research has focused on modulating cell proliferation and differentiation by retinoids. The primary lesion in acne is the micro-comedone, which forms at the orifice of the pilo-sebaceous unit by the formation of a cellular plug formed from debris which obstructs this unit. This plug consisting of corneocytes, skin lipids, and proteins rapidly build up through accelerated proliferation of the keratinocytes located at the orifice of the sebaceous unit. Bacterial colonization follows, creating, in turn, a chronic inflammatory state. Although the cause of acne is unknown, and may be related to an enhanced sebum production through hormonal imbalance, the retinoid target has been primarily viewed as an action to reverse the comedogenesis. Interestingly enough, topical retinoids have no effect on sebum production. In contrast, when 13-cis retinoic acid is given by mouth, sebum production is rapidly reduced. However, through research at the molecular level, retinoids were found to inhibit the formation of gene products regulated by AP 1, a transcription factor controlling the expression ofmetallo-proteases and strongly linked to inflammatory mechanisms and dermal matrix architecture. The anti-inflammatory pathway was also invoked to explain the action of topical retinoids in moderate acne and psoriasis. This mechanism was also related to another observation from the Kligman group in 1986 that topical application of tretinoin could diminish fine lines and wrinkles and reduce mottled hyper-pigrnentation, which are signs of photo-induced skin damage. Pharmaceutical research has produced many different dosage forms of retinoids including micro-sphere, vesicular and host -guest complexes. The retinoid armamentarium, as a group of drug products, have a combined a market value of around $700 million annually, and if the oral forms of these drugs were included, this figure would approach $1 billion annually. The combination of serendipity, rational science and astute marketing has given rise to a family of drug products that treat not only acne but may prevent skin cancer, enhance therapeutic control of type II diabetes, and benefit life- style skin disorders such as photo-induced skin damage.