Robert J. Capetola

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.

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)

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).

Protein kinase c independent restoration of specific immune responsiveness in common variable immunodeficiency

7,8-Disubstituted guanine ribonucleosides represent a class of B lymphocyte agonists that utilize a protein kinase C-independent signaling pathway. These compounds provide an alternate T helper signal for B cells and enhance antigen-specific humoral responses in the murine model and in an IL-2-dependent human model in vitro. They effectively restore high level immune responses in a variety of murine models of immunodeficiency both in vivo and in vitro. In this study we examined the potential of these compounds to improve antibody responses generated by cultured cells from patients with common variable immunodeficiency (CVI). The inability to mount normal humoral responses to antigen was confirmed in nine patients with diagnosed CVI (CVI: 37 +/- 16, normal 653 +/- 116 plaque-forming cells (PFC)/culture; P less than 0.001). In cultured lymphocytes from eight of the nine patients studied, a normal level or greater responses to nominal antigen could be elicited by antigen in the presence of the immunostimulatory nucleoside 7-methyl-8-oxoguanosine (7m8oGuo). The average response to antigen increased from 37 +/- 16 without nucleoside to 1733 +/- 488 PFC/culture in its presence (P less than 0.002). Restoration of specific immune responses was an antigen-dependent and nucleoside dose-dependent event. Signaling by 7m8oGuo rendered the response to antigen protein kinase C independent in cultures of cells from normal donors as well as from CVI patients. These data substantiate (i) that a non-C-kinase signaling pathway for antigen-dependent differentiation exists, (ii) that this pathway can function normally in B cells from patients with CVI when triggered appropriately, and (iii) that 7,8-disubstituted guanine ribonucleosides can convert a C-kinase-dependent signaling event to a C-kinase-independent signaling event. Substituted guanine ribonucleosides may have potential as immunotherapeutic agents for patients with CVI.

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).