Journal of Dermatological Treatment (2000) 11, 47±52 2000 Journal of Dermatological Treatment. All rights reserved. ISSN 0954-6634 47 Re-emergence of topical retinol in dermatology LH Kligman 1 and EH Gans2 All-trans-retinol was the first vitamin to be 1 synthesized in the laboratory. University of Pennsylvania, School of Dermatologic research with this Medicine, Department of Dermatology, agent, first begun in the 1960s, Philadelphia, PA, USA; 2 Medicis Pharmaceuticals, Inc., Phoenix, was discontinued because of its instability. Investigations since AZ, USA then have focused primarily on a metabolite of vitamin A, alltrans-retinoic acid, for the treatment of various dermatological disorders. TREATMENT: While topically applied retinoic acid is effective in reducing the signs of intrinsic aging and repairing photodamaged skin, depending on the concentration it causes a number of irritant effects, including Received 7th February 1999 Accepted 21st September 1999 BACKGROUND: erythema, peeling, dryness, and pruritus in some patients. This drawback stimulated renewed efforts to find a less irritating retinoid. ADVANCES: As a result of advances in the cosmetic industry, retinol is now being produced in a stable formulation, and is again commanding the attention of investigators. CONCLUSION: Clinical trials conducted so far indicate that, like retinoic acid, retinol can induce changes that have a beneficial effect on the epidermis but with decreased irritation. (J Dermatol Treat (2000) 11: 47–52) Keywords: Retinol Ð Photodamage Ð Tretinoin Introduction Vitamin A and its natural metabolites and synthetic analogues comprise a class of biologically active compounds known as retinoids.1 These agents play a vital role in certain biologic functions, such as vision, embryogenesis, growth, tissue maintenance and differentiation. In normal epidermis, retinoids increase cell proliferation, while in hyperproliferative epithelia they may have a normalizing effect.2 Early investigations described the clinical use of all-trans-retinol (ROL), the first vitamin to be synthesized in the laboratory, in the treatment of skin diseases due to abnormal keratinization3; 4 and in acne.5; 6 These studies used high doses of ROL and produced multiple disagreeable side effects.7 In the early 1960s, two researchers, AM Kligman in the USA and G Stuttgen in Germany, attempted to study the effect of topical ROL in the treatment of acne. However, these early unpublished trials were Correspondence: Lorraine H Kligman, PhD, University of Pennsylvania, School of Medicine, Department of Dermatology, Rm. 227 CRB ± 415 Curie Blvd, Philadelphia, PA 19104, USA. Fax: ‡1 215 573 2116 unsuccessful because of the inherent light sensitivity and instability of ROL. Investigators then turned their attention to a more stable metabolite of vitamin A, all-trans-retinoic acid (RA).8; 9 Topical RA, also known as tretinoin, was shown to be effective in the treatment of acne.10 Later, because retinoids had been shown to enhance wound healing in animal models by increasing deposition of granulation tissue11 and to stimulate fibroblast mitogenesis,12 it was thought that retinoids might induce repair of the dermal changes characteristic of photoaging. Studies in humans and hairless mice proved this to be true.13; 14 Characteristics of aged and photoaged skin Skin that is chronically overexposed to sunlight undergoes slow but cumulative damage in the epidermis and in the connective tissues of the dermis.15; 16 While the use of sunscreens is strongly advised, it may not always provide complete protection against photodamage. Approximately 7% of solar radiation is able to penetrate a sunscreen with 48 LH Kligman and EH Gans a sun protection factor of 15. Therefore, during longterm chronic sun exposure, photodamage may occur despite the use of sunscreens. Such damage has been shown to occur in mice and in humans17; 18 even in the absence of erythema. Although it was once thought that only UVB radiation was harmful to skin, recent research has shown that UVA also can cause severe damage.18¡20 Both wavebands can produce erythema, inflammation, increased levels of proteoglycans and glycosaminoglycans, collagen damage, elastosis and, ultimately, an increasing occurrence of skin cancer. Photoaged skin, clinically called dermatoheliosis,21 has the following visible expressions: substantial coarseness, yellowing, laxness, sagging, dyspigmentation and wrinkles. Few of these changes are seen in skin that is intrinsically aged but has been protected from chronic solar radiation. Innately aged but otherwise healthy skin may be thin, dry and scaly with mild sagging and fine lines. Moreover, innately aged skin does not exhibit the striking histologic degradation that occurs, particularly in the dermis, in response to photodamage.16 Treatment of photoaging Hairless mice Since hairless mice respond to UV exposure in a manner that is accelerated but similar to that of humans,22 this species has been used as a model for human photoaging and its treatment with RA.23¡25 RA, applied topically to photoaged mice, has ameliorated UV-induced wrinkles25 and has induced the synthesis of new, normal appearing collagen in the upper dermis.13; 23; 25 Furthermore, RA reduced the level of the UV-induced glycosaminoglycans and encouraged the synthesis of new elastic fibers.24 Clinical Numerous controlled clinical studies have assessed the effect of RA on human photoaged skin.14; 26¡28 One of these26 evaluated the efficacy of 0.1% RA cream applied to photodamaged skin for 16 weeks. Two studies, one of which was multicentered,27; 28 evaluated 0.05% RA in a more emollient cream in more than 250 patients for 24 weeks. Features of substantial photodamage, such as coarse wrinkling and extensive dyspigmentation, were reduced. There were also cosmetic improvements, such as production of smoother skin texture, more uniform color and reduction in fine lines. With even longer treatment (10–22 months) improvements continued.29 The formation of type I collagen, which is significantly decreased in the papillary dermis of Re-emerge nce of topical retinol in dermatology photodamaged human skin, was found to become partly restored by topical treatment with 0.1% RA cream with long-term use.30 These studies also demonstrated that RA can produce irritancy and scaling in some patients depending on concentration, skin type and age. Therefore, various delivery systems have been developed to improve the acceptability of RA in patients undergoing treatment of moderate to severe acne and dermal photodamage. Attention refocused on ROL The UV-induced visible epidermal changes result in an unacceptable feel and appearance of the skin such as dryness, coarseness, uneven tone, fine lines and wrinkling. These conditions are treated every day by many people, but particularly by women, with a wide range of skin types who desire effective cosmetic products that will ameliorate these conditions without irritation. As a result, ROL, long used at very low concentrations in cosmetic products, is again of interest. Once abandoned because of its instability, ROL can now be sequestered in Microsponge polymers (Advanced Polymer Systems, Inc., Redwood City, CA, USA) with low irritancy and cosmetic acceptability for treating the visible signs of aging and photoaging. Protected from oxidation by antioxidants such as vitamins C and E, it remains stable with a shelf life of at least 2 years. By obviating the rapid degradation that ROL would otherwise undergo, the new formulation has permitted the resumption of research with this agent. Metabolism of ROL The metabolism and biological activity of ROL have been investigated in vitro in cultured human keratinocytes. 31 It was found that ROL was metabolized primarily to retinyl esters and to relatively small amounts of RA which activated nuclear RA receptors and RA-receptor-dependent gene transcription. However, these findings were not supported by a 1995 in vivo study by Kang et al32 in which ROL was applied in increasing doses to human skin under occlusion for periods ranging from 6 hours to 4 days. Some ROL remained as free ROL whereas some was metabolized to retinyl ester, retro-retinoids and didehydroretinol. However, RA levels were undetectable or detectable only in trace amounts even though RA-like effects on the epidermis were noted. In a later paper from the same laboratory, the penetration into human skin of occluded and unoccluded ROL versus occluded and unoccluded RA was studied.33 RA levels within the skin were not measured but, instead, activity of the enzyme retinoic LH Kligman and EH Gans acid-4 hydroxylase (RA-4-OHase) was assayed. Although several retinoids induce the enzyme, its only substrate is all-trans-RA, which it metabolizes to 4-hydroxyretinoic acid.34 Occluded ROL induced similar amounts of RA-4-OHase as did occluded RA, whereas in unoccluded tests ROL was a more effective inducer than was RA. These authors suggest that the inability to find, even at the detection level of one nanogram of RA, measurable amounts of RA when ROL is applied to human skin may be due to the induction of RA-4-OHase, which prevents the accumulation of RA.35 Safety Because orally administered high doses of retinoids have caused congenital deformities in both animals and humans, studies have been conducted to investigate their safety when administered topically. In studies with RA, using amounts that are usually applied to normal skin once or repeatedly36 or to inflamed skin with a damaged barrier,37 the systemic absorption was either non-existent or nonsignificant. In another study, subtotal body inunction with 0.025% RA twice daily or total inunction with 1% RA resulted in undetectable levels of RA in the blood using a sensitive gas chromatographicmass spectrometric assay.38 Thus, teratogenesis as a result of topical application of RA to skin is highly unlikely. Finally, using standardized risk assessment methods for developmental toxicity,39 Johnson analyzed topical RA compared with known toxic agents such as oral 13-cis-RA and methotrexate.40 A safety margin of more than 100 for RA contrasted sharply with values close to 1 for the other drugs examined, thus supporting the epidemiologic and animal data that topical RA is not a human developmental toxicant. With regard to retinol, the results of the Ames test, both with and without metabolic activation, showed that vitamin A, like RA is non-mutagenic.41 It also appears to be non-carcinogenic, inhibiting the development of malignant phenotypes in vitro and carcinogenesis in laboratory animals.42 Furthermore, studies have demonstrated that ROL, whether under occlusion or not, does not produce the irritation caused by RA under occlusion.32; 33 Ef®cacy of ROL Recent basic scientific studies have demonstrated that ROL can be effective in inducing beneficial epidermal changes with less irritation than RA.32; 33 On buttock skin occluded for 4 days and compared with the vehicle, 1.6% ROL induced significant epidermal thickening similar to that of 0.025% RA.32 Re-emergence of topical retinol in dermatology 49 Trace erythema, not significantly different from vehicle, occurred with ROL whereas RA induced measurable erythema. A second study tested skin penetration of ROL and RA with 4-day occlusion versus once-daily application for 4 days on unoccluded sites.33 Under occlusion both retinoids penetrated the skin similarly as judged by the induction of RA-4-OHase. In the unoccluded mode, which corresponds with actual usage conditions, ROL penetration was more effective than that of RA, but required a 10-fold higher concentration than RA. As in the first study,32 ROL increased epidermal thickness without the erythema induced by RA. These studies demonstrated that ROL has lower potency than RA, requiring higher concentrations than RA to produce similar epidermal effects. Despite this, ROL is more effectively delivered into skin, inducing retinoid changes in the epidermis without irritation. A number of clinical trials of ROL have been completed and others are in progress. In one coded but uncontrolled study two topical preparations containing either ROL or vitamin E were applied on opposite forearms of 14 women between 33 and 47 years old who described their skin as sensitive.43 Application was for 3 months, but in the final month the sites were exposed twice a week to UV radiation equal to 1.5 times each subject’s minimal erythemal dose as previously determined. A measurement of the looseness/adhesiveness of the stratum corneum showed a significant decrease in the ratio indicating a reduction in scaliness with ROL compared with the vitamin E-treated arm. Additionally, there was a reduction in the UV-induced shallow wrinkling with the ROL cream. An open, uncontrolled pilot study was conducted in which 0.15% ROL was sequestered in Microsponges (Kligman AM, Kligman D. A pilot clinical assessment study of an 0.15% Retinol delivery system. Clinical Research Dept., Advanced Polymer System, Inc., Redwood City, CA). Ten caucasian women, aged 37–53 years were treated on the face once daily for 3 months. At the beginning of the study, all subjects displayed mottling, fine wrinkling, skin laxity and dry, rough skin texture. These features were clinically evaluated using a 0–9 ordinal scale. In addition, a desquamation index was determined with a D’Squames test kit (Cuderm, Inc., Dallas, TX, USA). Evaluations were made at baseline and after 3 months of treatment. The results were expressed as percentage improvement over baseline (Figure 1). All parameters evaluated exhibited significant improvement with the retinol treatment. Before and after photographs from one of the subjects are shown in Figure 2. Improvement in skin texture and in the fine lines around the eye is seen. 50 LH Kligman and EH Gans Re-emerge nce of topical retinol in dermatology 80 70 Figure 1 Clinical improvement (§SD) after 3 months of application of a 0.15% retinol cream. The percentage improvement over baseline for five parameters is shown. Improvement in all clinical features examined was highly significant (P < 1%) as determined by non-parametric statistics (Wilcoxon’s signed rank test). % improvement 60 Figure 2 Improvement in fine lines in the eye area as a result of treatment. (A) Before treatment; (B) after 3 months of 0.15% retinol cream treatment. 50 40 30 20 10 0 Desquamation (dryness) Smoothness Dyspigmentation (mottling/age spots) Fine lines Texture & laxity LH Kligman and EH Gans Treatment Re-emergence of topical retinol in dermatology Increase in epidermal thickness Increase in Decrease in keratinocyte melanin orderliness Epidermal biopsies showing a change Retinola 0.15% ‡ – 0.15% ‡‡ ‡‡ 0.30% ‡‡ ‡‡ 0.30% ‡‡ – 0.30% – ‡‡ 0.60% ‡ – 0.60% ‡‡ – 0.60% ‡‡ ‡‡ No treatment No treatment No treatment ‡‡ ‡‡ ‡ – ‡ – ‡‡ ‡‡ ‡‡ ‡ ‡‡ ‡ ‡‡ – – – – Epidermal biopsies with essentially no change 0.15% ROL 3 specimens Vitamin C 3 specimens No treatment 9 specimens – ˆ No change; ‡ ˆ small to moderate change; ‡‡ ˆ moderate to substantial change. a Retinol – AFIRM. Table I Effect of retinol, vitamin C cream and no treatment on forearm epidermis In a third study, ROL was evaluated over a longer period. Female subjects, aged 35–55 years, with clinical signs of photodamage, applied one of the test creams to one dorsal forearm twice daily for 9 months (Leyden JJ et al. Clinical safety and efficacy assessment of 0.15%, 0.30% and 0.60% Retinol Delivery Systems (AFIRM). Clinical Research Dept., Medicis Pharmaceutical Corp., Phoenix, AZ). The contralateral forearm served as an untreated control. The creams tested were as follows: ROL cream at 0.15%, 0.30% and 0.60% (AFIRM 1X, 2X and 3X, respectively: Medicis Pharmaceutical, Corp., Phoenix, AZ) and 10% vitamin C serum (Cellex C). Epidermal shave biopsies were taken from both arms after 9 months and compared with baseline biopsies. These were assessed for changes in epidermal thickness, orderliness of keratinocytes, decrease in melanin and the presence of inflammation. After 9 months, 15 subjects yielded five biopsies from 0.15% ROL treatment, three from 0.30% ROL, three from 0.60% ROL, three from Cellex C and 12 from untreated arms. One biopsy was lost in processing and three were inadequate for study. The results are shown in Table I. With the exception of three biopsies from 0.15% ROL-treated skin, all ROL-treated biopsies showed significant epidermal improvement without signs of inflammation. This is compared with no improvement seen in nine of the untreated and in all Cellex C biopsies. Conclusions Taken together, findings from basic scientific and clinical studies indicate that ROL, like RA, can reverse some of the changes that occur in the epidermis as a result of photoaging and chronologic aging. These changes produce an improved visible or cosmetic appearance of the skin. ROL, although requiring higher doses than RA, is delivered into the skin more effectively and with significantly less irritation. The stabilization of ROL in a new vehicle system permits topical application in a range of useful concentrations. References 1. Sporn MB, Roberts AG, Goodman DS, The retinoids. 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