Macrolactam immunomodulators for topical treatment of inflammatory skin diseases

The immunomodulatory macrolactams provide an alternative to glucocorticoste roids for the topical treatment of atopic dermatitis and other inflammatory dermatoses. Tacrolimus (FK506), as well as the newer ascomycin derivative ASM 981 (pimecrolimus), penetrate the inflamed epidermis and are suitable f or topical therapy. Both substances inhibit the transcription of proinflamm atory cytokine genes such as interleukin 2, which are dependent on the nucl ear factor NF-AT. They block the catalytic function of calcineurin, which l eads to the inhibition of the transport of the cytoplasmic component of NF- AT to the cell nucleus. Multicenter, randomized, double-blind clinical tria ls with topical formulations have shown the efficacy of both substances in moderate to severe atopic dermatitis. A review is presented of the biochemi cal and cell biologic properties, mode of action, pharmacokinetic data, sid e effects, results of the clinical trials, and further indications for tacr olimus and ASM 981, along with an overview of the related substances cyclos porine and sirolimus (rapamycin).