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Discovery of topical calcineurin inhibitors and pharmacological profile of pimecrolimus.

Stuetz, Anton and Baumann, Karl and Grassberger, Max and Wolff, Klaus and Meingassner, Josef (2006) Discovery of topical calcineurin inhibitors and pharmacological profile of pimecrolimus. International Archives of Allergy and Immunology, 141 (3). pp. 199-212. ISSN 1018-2438

Abstract

Using a newly developed model of allergic contact dermatitis in pigs, calcineurin inhibitors of the tacrolimus and ascomycin type were shown to have a highly anti-inflammatory action after topical application. These findings provided the first pharmacological evidence of the efficacy of this novel class of topical agents in the treatment of inflammatory skin diseases, and, thus, their potential to become the first alternative to corticosteroids in more than 40 years. As a result of a large research program into ascomycins, pimecrolimus (Elidel(R), SDZ ASM 981) was selected for development due to its favorable pharmacology and safety profile, alongside tacrolimus (Protopic(R), FK 506). In vitro, pimecrolimus inhibits the transcription and release of pro-inflammatory cytokines in T cells. Similar to the corticosteroids, betamethasone-17-valerate and dexamethasone, pimecrolimus is effective at nanomolar concentrations. Targeting mainly T cells, pimecrolimus has, however, a more specific mode of action. Moreover, in contrast to corticosteroids, pimecrolimus has no effect on Langerhans' cells, the professional antigen- presenting dendritic cells of the skin that are crucial for local immunosurveillance. When applied topically, pimecrolimus exerts a high and selective anti-inflammatory activity in the skin, shows minimal percutaneous absorption, and has a low potential to affect systemic immunoreactions. Pimecrolimus cream 1% has proven to be well tolerated, safe, and highly effective in clinical studies in patients with atopic dermatitis.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); On author or institutional server; Publisher's version/PDF cannot be used
Keywords: Atopic dermatitis; Calcineurin inhibitors; Inflammatory skin diseases; Pharmacological profile; Pimecrolimus; Tacrolimus
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Date Deposited: 14 Dec 2009 13:57
Last Modified: 31 Jan 2013 01:12
URI: https://oak.novartis.com/id/eprint/609

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