A Macrolactam Inhibitor of T Helper Type 1 and T Helper Type 2 Cytokine Biosynthesis for Topical Treatment of Inflammatory Skin Diseases1

Abstract

T lymphocytes play a critical part in inflammatory skin diseases but are targeted by available therapies that have only partial efficacy, significant side-effects, or both. Because psoriasis, atopic dermatitis, and allergic contact hypersensitivity are associated with T helper type 1 (Th1), T helper type 2 (Th2), or mixed Th1-Th2 cell subsets and cytokine types, respectively, there is a need for a better broad-based inhibitor. The macrolactam ascomycin analog, ABT-281, was found to inhibit potently T cell function across species and to inhibit expression of multiple cytokines in human peripheral blood leukocytes which have been found in human skin disease cells and tissues. These included immunoregulatory Th1 (interleukin-2 and interferon-gamma) and Th2 (interleukin-4 and interleukin-5) cytokines. ABT-281 was shown to have potent topical activity (ED50 = 0.6% in acetone/olive oil) in a stringent swine model of allergic contact hypersensitivity, but its potency was markedly reduced compared with ascomycin when administered systemically due to more rapid clearance. Topical application of 3% ABT-281 in acetone/olive oil over 25% of the body surface in swine resulted in undetectable blood levels. Compared with a wide potency range of topical corticosteroids in clinical formulations, 0.3% and 1% ABT-281 ointments profoundly inhibited dinitrochlorobenzene-induced contact hypersensitivity in the pig by 78% and 90%, respectively, whereas super-potent steroids such as clobetasol propionate only inhibited in the 50% range and mild to moderate potency steroids such as fluocinolone acetonide were inactive. The potent topical activity of ABT-281 in swine, its superior efficacy, its rapid systemic clearance following uptake into the bloodstream, and its ability to inhibit cytokine biosynthesis of both Th1 and Th2 cell subsets, suggests that it will have a broad therapeutic value in inflammatory skin diseases, including psoriasis, atopic dermatitis, and allergic contact dermatitis.

Hydrating Effects of a Corticoid Oil Formulation and Its Vehicle on Human Skin

“…We present the first objective controlled demonstration of the validity of this approach and also support most dermatologists' recommendation of applying lubrication when the skin is wet. However, this study only tested hydrating effects; its clinical effects have been reported elsewhere [7,8].…”

New drugs in the treatment of psoriasis

“…It was synthesised in a search for compounds that are topically effective, but exhibit weak systemic activities following absorption. A-86281 and FK-506 showed similar topical potency in swine contact hypersensitivity assays, yet A-86281 was cleared more rapidly and was less potent when given systemically [91,92].…”

Regulatory Mechanisms of Calcineurin Phosphatase Activity

“…Their key difference is the presence of an allyl group in TRL where the ascomycins feature an ethyl group. The ascomycins have been subject to extensive clinical testing in the past decade [109][110][111]. Notable members of this group are, beside the parent molecule ascomycin (FK520), pimecrolimus (SDZ ASM-981), ABT-281, and SDZ 281-240.…”