l-683590 and Skin-Diseases

Controlled trials and clinical experience indicate that systemic cyclosporin A and tacrolimus are effective treatments for psoriasis, and that cyclosporin A also improves atopic eczema. A variety of other inflammatory and non-inflammatory skin diseases are probably also responsive to these drugs. However, the widespread and longer-term use of cyclosporin A and tacrolimus are limited by side effects. The molecular mechanisms of action of cyclosporin A, tacrolimus and a related drug, sirolimus, have been well defined in T cells and involve inhibition of critical signalling pathways that regulate T cell activation. For example cyclosporin and tacrolimus inhibit calcineurin phosphatase activity and thereby inhibit activation of the transcription factor NFAT. The therapeutic efficacy of topical calcineurin inhibitors in atopic eczema have restimulated interest in the mechanism of action of these drugs in skin disease. Recently the expression pattern of calcineurin and NFAT has been defined in non-immune tissues including the akin. The relevance of this to the mechanism of action of systemic and topical calcineurin inhibitors and sirolimus in skin disorders is discussed.

Topics: Administration, Topical; Calcineurin Inhibitors; Cyclosporins; Humans; Immunosuppressive Agents; Lymphocyte Activation; Sirolimus; Skin Diseases; Tacrolimus

Ascomycin derivatives represent a novel class of anti-inflammatory macrolactams currently under development for the treatment of skin diseases. The main biological effect of ascomycins is an inhibition of the synthesis of both Th1 and Th2-type cytokines in target cells. Several compounds are being developed with SDZ ASM 981 being at the most advanced stage. It has high anti-inflammatory activity in animal models of skin inflammation and does not induce skin atrophy. Topical application of SDZ ASM 981 was shown to be effective in atopic dermatitis (AD), allergic contact dermatitis and also in psoriasis under semi-occlusive conditions. In patients with AD, SDZ ASM 981 cream led to consistently low systemic exposure even when applied on large areas of skin. SDZ ASM 981 overcomes the drawbacks of current topical therapies of inflammatory skin diseases as its safety profile is better than that of topical corticosteroids. Studies continue to investigate its efficacy and safety in the treatment of inflammatory skin diseases.

Topics: Adult; Animals; Anti-Inflammatory Agents; Child; Clinical Trials as Topic; Dermatitis, Atopic; Dermatitis, Contact; Dermatologic Agents; Drug Evaluation, Preclinical; Humans; Models, Animal; Rats; Skin Diseases; Tacrolimus

Topics: Adjuvants, Immunologic; Humans; Mycophenolic Acid; Skin Diseases; Tacrolimus; Thalidomide

Ascomycin derivatives represent a novel class of anti-inflammatory macrolactams that are under development for the treatment of skin diseases. The main biological effect of ascomycins is a blockage of the synthesis of both Th1- and Th2-type cytokines in target cells. SDZ ASM 981 is the most advanced ascomycin derivative under development. It has high antiinflammatory activity in animal models of allergic contact dermatitis and does not induce skin atrophy. Topical application of SDZ ASM 981 has been shown to be effective in atopic dermatitis (AD) and allergic contact dermatitis. Clinical studies using semi-occlusive conditions have also shown effectiveness in psoriasis. SDZ ASM 981 holds promise in overcoming the drawbacks of topical corticosteroids and studies are ongoing to further investigate its efficacy and safety in the treatment of inflammatory skin diseases.

Topics: Animals; Anti-Inflammatory Agents; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Immunosuppressive Agents; Skin Diseases; Tacrolimus

Drug therapy for the major inflammatory skin diseases, which include atopic dermatitis, psoriasis and allergic contact dermatitis, is often inadequate due to poor efficacy, toxicity, or both. Much research has focused on the macrolactam T cell inhibitors as a promising new class of agents for immunotherapy, and medicinal chemistry efforts to design novel ascomycin analogs have produced clinically promising agents. A synthetic program to modify the ascomycin nucleus to alter its physicochemical properties and promote systemic clearance is described. A biologic screening strategy to identify analogs with reduced systemic activity and rapid pharmacokinetic elimination led to identification of the clinical candidate, ABT-281. A swine contact hypersensitivity model was used as a stringent indicator of skin penetration as human doses of topical corticosteroids produced inhibition only in the 50% range and ED50 values were 100-fold less potent than in rat. Also, cyclosporine was confirmed to be topically inactive in swine, as seen in human. ABT-281 had topical potency equal to tacrolimus (FK506) despite a severalfold lower potency for inhibiting swine T cells in vitro, consistent with superior skin penetration. ABT-281 was found to have a shorter duration of action after i.v. dosing in monkeys using an ex vivo whole blood IL-2 production assay. Systemic potency was reduced by 30-fold or more in rat popliteal lymph node hyperplasia and contact hypersensitivity assays. Following i.v. or i.p. administration in the swine contact hypersensitivity model, ABT-281 was 19- and 61-fold less potent, respectively, than FK506. Pharmacokinetic studies showed that ABT-281 had a shorter half life and higher rate of clearance than FK506 in all three species. The potent topical activity and reduced systemic exposure of ABT-281 may thus provide both efficacy and a greater margin of safety for topical therapy of skin diseases.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Cyclosporine; Dermatitis; Drug Design; Humans; Immunosuppressive Agents; Inflammation; Interleukin-2; Skin Diseases; T-Lymphocytes; Tacrolimus