James A. Mezick

Topical all-trans-retinoic acid prevents corticosteroid-induced skin atrophy without abrogating the anti-inflammatory effect.

We tested the ability of all-trans-retinoic acid to prevent corticosteroid-induced skin atrophy without lessening the anti-inflammatory effect of the steroids. Histologic study and skin-fold thickness in hairless mice treated topically with various steroids, followed by topical all-trans-retinoic acid, were used to measure prevention of atrophy. By both assessments, all-trans-retinoic acid prevented atrophy. Noninterference with the anti-inflammatory property of steroids was tested in a phorbol ester-induced mouse ear edema model and by histologic assessment of croton oil-induced inflammation of mouse dermis. We found that all-trans-retinoic acid did not interfere with steroid suppression of either edema or dermal inflammation. Thus all-trans-retinoic acid was effective in preventing steroid-induced atrophy without affecting the steroids anti-inflammatory property.

Pharmacological Effects of Retinoids on Skin Cells

Retinoids exert profound pleiotropic effects in skin, affecting many aspects of cell differentiation and proliferation. For this reason, retinoids have prominent pharmacological effects on major skin cells (keratinocytes, dermal fibroblasts, melanocytes, sebocytes) and have shown great potential as therapeutic agents in dermatology. In keratinocytes, retinoids induce proliferation, resulting in epidermal hyperplasia. Retinoids also modulate epidermal differentiation, however, many of the suppressive effects of retinoids observed in vitro do not occur in vivo. Dermal fibroblasts are important target cells of retinoids and are stimulated to produce extracellular matrix proteins, particularly when skin is damaged by wounding, ultraviolet radiation or glucocorticoids. Retinoids regulate pigmentation and can lighten hyperpigmented skin in animals and humans. Studies with cultured melanocytic cells show that tyrosinase activity is reduced by retinoids. The powerful sebosuppressive effect of some retinoids, such as 13-cis-retinoic acid, demonstrates that sebocyte differentiation is altered by retinoids. Retinoids inhibit proliferation and lipid synthesis in cultured human sebocytes and alter their keratin expression.

A Direct Comparison of Pharmacologic Effects of Retinoids on Skin Cells in vitro and in vivo

The purpose of these studies was to directly compare the pharmacologic effects of retinoids on cutaneous cells in vitro and in vivo. Previously, it was demonstrated that all-trans-retinoic acid stimulates the proliferation of growth-arrested human keratinocytes and fibroblasts in culture. In the present studies, all-trans-retinoic acid was compared to three other retinoids--13-cis-retinoic acid, P-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl-1-p ropenyl] benzoic acid (TTNPB) and M-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl-1-p ropenyl] benzoic acid (meta-carboxy-TTNPB]--for growth stimulation using a cultured human squamous epithelial cell line (UM-SCC-1) and human dermal fibroblasts. These four retinoids were also evaluated for their effects on reduction of horn-filled utriculi when topically applied to the skin of rhino mice. All-trans-retinoic acid stimulated proliferation of both fibroblasts and epithelial cells over concentrations ranging from 0.01 to 1.0 micrograms/ml. In fibroblasts, 13-cis-retinoic acid was less potent than all-trans-retinoic acid, whereas, in epithelial cells these two retinoids were equipotent. In contrast, TTNPB was more potent than all-trans-retinoic acid at stimulating the growth of both fibroblasts and epithelial cells. The analog, meta-carboxy-TTNPB was essentially inactive as a growth stimulator of both cell types. In the rhino mouse utriculus reduction model, the rank order of potency for the retinoids was the same as that for in vitro cell growth stimulation (TTNPB greater than all-trans-retinoic acid greater than 13-cis-retinoic acid). Meta-carboxy-TTNPB was inactive at reducing utriculi at a dose of 5,000 times the ED50 of TTNPB.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of topical retinoids for cutaneous pharmacological activity in Yucatan microswine

The pharmacological effects of retinoids on skin have been studied primarily in test systems using small animals, such as mice and rabbits. Because of potentially significant differences in skin permeation and metabolism between small animals and humans, we have used Yucatan microswine as an alternative model for testing topical retinoids. Microswine skin resembles human skin, functionally and anatomically, more closely than most other species. In these studies, microswine skin was treated topically with retinoids for 5 consecutive days per week for 5 weeks. We found microswine epidermis to be functionally responsive to retinoids in that it undergoes hyperplasia and shows an increase in transepidermal water loss (TEWL). All-trans-retinoic acid, and its analogs, 13-cis-retinoic acid, 4-hydroxy-retinoic acid and 4-oxo-retinoic acid all caused epidermal thickening and increased TEWL. The three analogs were less potent than all-trans-retinoic acid. A synthetic retinoid, TTNPB, potently induced epidermal hyperplasia and increased TEWL, but a close stuctural analog, m-carboxy-TTNPB, which is also inactive on nuclear retinoic acid receptors, was without effects on microswine epidermis. These findings show that microswine are useful for evaluating the cutaneous effects of topical retinoids. This model could be of value in identifying retinoids with potential clinical activity.

Retinoid modulation of phorbol ester effects in skin

Publisher Summary This chapter reviews convenient assay methods for retinoids against phorbol ester-induced effects in the skin. The chapter describes methods for measuring 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced edema, ornithine decarboxylase (ODC) activity, and DNA synthesis. Measurements of TPA-induced ear edema, ODC activity, and DNA synthesis provide convenient methods to assess the effects of retinoids on phorbol ester-mediated events in the skin. The antiinflammatory effects of retinoids in the TPA ear edema model may be due to their action as inhibitors of arachidonic acid metabolism, all-trans-Retinoic acid and 13-cis-retinoic acid are reported to act as inhibitors of snake venom phospholipase A 2 and to inhibit the release and metabolism of arachidonic acid in calcium ionophore-stimulated rat peritoneal macrophages. In TPAtreated mouse skin, phospholipase A 2 activity is elevated and would provide a source of free arachidonic acid for metabolism into prostaglandin E 2 (PGE 2 )and 15-hydroxyeicosatetraenoic acids (HETE).

EFFECTS OF TOPICAL ANTIINFLAMMATORY AGENTS ON FREUND'S ADJUVANT-INDUCED SKIN LESIONS IN RATS

Freunds adjuvant, when administered intradermally to rats, causes polyarthritis as well as inflammation of the skin, eye, gastrointestinal and genitourinary tracts. We assessed the effects of antiinflammatory drugs on ear skin lesions to determine if this might be a useful skin inflammation model. The hind paw of male Lewis rats was injected withMycobacterium butyricum in paraffin oil. Lesions appeared between days 13 and 15 after adjuvant injection. Each ear exhibited on average 1 to 3 highly erythematous, elevated lesions, 2 to 3 mm in diameter. By histology, the lesions consisted of epidermal hyperplasia, with a prominent accumulation of inflammatory cells in the dermis. Ears were treated topically with glucocorticoids, cyclosporine and indomethacin on days 15 through 21 after adjuvant injection. By day 22, dexamethasone, fluocinolone acetonide, and cyclosporine caused near-complete clearing of lesions whereas indomethacin exacerbated the inflammation by causing increased numbers of skin lesions. These results show the potential usefulness of adjuvant-induced skin lesions in rats as a novel subchronic inflammation model.

Chapter 19. Pharmacological Developments in Dermatology

Publisher Summary The most common dermatological diseases are the diseases of the sebaceous glands, such as acne, dermatophyte infections, malignant and benign tumors, seborrheic dermatitis, atopic dermatitis, and psoriasis. Dermatology has had to be content to use drugs initially developed for other diseases, although the new discipline of dermatopharmacology has emerged to optimize the delivery of existing drugs and, more importantly, to develop the animal models of skin diseases and use them to identify new dermatologic agents. The field of immunodermatology has also been discussed in the chapter stressing the importance of immunologic derangement in many skin disorders. This chapter includes specific developments made concerning psoriasis, atopic dermatitis, acne, and more general sections on inflammatory mediators likely to play a role in skin inflammation, topical anti-inflammatories, and vehicles of current use in topical therapy. Psoriasis is a common, multifactorial, genetically determined disease of unknown etiology that is characterized by a benign, unrestricted epithelial growth of skin. It produces recurrent lesions that are often emotionally and physically debilitating to the patient. Atopic dermatitis is a chronic inflammatory skin disease that occurs most frequently in people with a personal or family history of allergies (for example, asthma or allergic rhinitis). Acne vulgaris is the most common disease of the skin. It is characterized by a variety of lesions that may be noninflammatory (open and closed comedones) or inflammatory (papules, pustules, nodules).