Retinoids

Topically used retinoids are comprised of a class of compounds built around the core structure of naturally occurring retinol (vitamin A), which itself is derived from the dietary hydrolysis of ^-carotene. Several varying retinoids have been sold as cosmetics and as prescription drugs to treat chronologically aged and photodamaged skin. More relevant to this chapter, nearly all of them when formulated into moisturizers have been shown to con­sistently improve the appearance of fine lines and wrinkles, both in terms of potency and breadth of response. The commonly used retinoids in the cosmetic market include retinol and esters such as retinyl acetate, retinyl propionate, and retinyl palmitate. Less common but still used is retinal, the oxidized product of retinol. Metabolically, all these retinoids can be converted intracellularly to the true active form, rans-retinoic acid (tRA) (Fig. 15.1). This product has been on the market for some time as a topical prescription drug that was originally approved for treating acne (Retin-A), and subsequently approved for treating photodamaged skin, including fine lines and wrinkles (Renova). Since most formulations containing retinoids applied topically can elicit negative effects such as dryness, redness, burning, and irritation [1], there have been extensive research efforts to identify retinoid analogues that have reduced side effects when formulated into moisturizers [2]. While

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Figure 15.1 Metabolism of retinoids to all-trans retinoic acid.

products have been successfully developed and are marketed, it is not apparent that there is a clear reduction in the negative side effects.

Topical retinoids are capable of eliciting robust changes in skin biological systems and this is most evident at the molecular level by changes in gene expression patterns, which ultimately lead to the various biochemical and cellular responses observed [3,4]. The pri­mary point of regulation for gene expression changes occur via binding of tRA (and iso­forms) as a ligand to select heterodimer nuclear receptor complexes, which then bind to retinoic acid-response elements in the promoter region of select genes, and turn on gene expression. The receptor complexes are comprised of members from the retinoic acid receptor (RAR) and retinoid X receptor (RXR) family of proteins, both of which are further comprised of а, p, and у isoforms. The availability of various combinations between the
representative isoforms from each family into a heterodimeric complex provides a key regulatory point for regulating diverse gene expression profiles.

While topically delivered retinoids have the ability to elicit profound changes in skin [5,6], the basic premise for these changes can be ascribed to a normalization of skin that has undergone morphological and molecular changes due to aging and environmental insults (primarily UV damage from chronic sun exposure). On a macro level, this includes thickening of the skin to diminish the appearance of fine lines and wrinkles via increased epidermal proliferation and differentiation (net increase in epidermal thickness), increased production of epidermal glycosaminoglycans (GAG), and increased net content of collagen in the dermis (net increase in dermal thickness). From a kinetics response perspective, the significant changes in skin from topical retinoids are observed after continued usage for two months or longer, even though some minor effects can be observed within a few weeks of usage (Fig. 15.2).

It is established that formulations containing topical retinoids besides tRA can improve the appearance of fine lines and wrinkles in chronologically photodamaged skin, particularly retinol [7,8], retinal [9,10], and both retinyl acetate and retinyl propionate (Fig 15.2) [11]. Numerous publications have examined the structural, biochemical, and gene expression changes associated with tRA treatment of photodamaged and aged facial skin [3,12,13].

Two synthetic retinoid analogues, adapalene and tazarotene, have been approved as pre­scription drugs for the treatment of acne. Of these, only 0.1% tazarotene (Avage) has been approved by the FDA for the treatment of fine lines, wrinkles, and hypo – and hyperpigmen­tation. The side effects from tazarotene are the typical retinoid-mediated ones but are con­sidered to be more irritating than both adapalene and tretinoin. In addition, it appears that the kinetics of skin response to tazarotene is much quicker than other retinoids, both in efficacy and irritation.