Discovery of Topical Calcineurin Inhibitors and Pharmacological Profile of Pimecrolimus

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®, SDZ ASM 981) was selected for development due to its favorable pharmacology and safety profile, alongside tacrolimus (Protopic®, 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.

Binding of Pimecrolimus and Tacrolimus to Skin and Plasma Proteins: Implications for Systemic Exposure after Topical Application

“…Pimecrolimus (Elidel) and tacrolimus (Protopic) are calcineurin inhibitors used for the topical treatment of atopic dermatitis (Stuetz et al, 2006). The compounds bind to cytoplasmic proteins of the immunophilin family, in particular to macrophilin12 (Kissinger et al, 1995;Grassberger et al, 1999), which is highly and ubiquitously expressed (Galat, 2003); inhibition of calcineurin occurs in a ternary calcineurinimmunophilin-drug complex.…”

Randomized Trial of Pimecrolimus Cream plus Colchicine Tablets versus Colchicine Tablets in the Treatment of Genital Ulcers in Behçet’s Disease

“…T cell activation, both in the peripheral blood and tissue specimens, is present in this disease [2]. PIM has a more specific mode of action targeting mainly T cells [12]. T lymphocytes rather than plasma cells or other B cells are supposed to be the primary target of PIM.…”

“…Therefore, treatment with topical PIM represents a promising therapeutic option for plasmacytosis and non-specific inflammatory recurrent balanitis [15, 16]. Topically applied PIM specifically inhibits the transcription and release of pro-inflammatory cytokines and mediators from T cells and mast cells in the skin [11, 12]. When applied topically, PIM exerts a high and selective anti-inflammatory activity in the skin [12].…”

“…Colchicine (COL) has been used for mucocutaneous BD for a long time [10]. Pimecrolimus (PIM) cream 1% is a non-steroidal anti-inflammatory topical calcineurin inhibitor developed for the treatment of chronic topical skin disorders, such as atopic dermatitis [11, 12]. However, it has been proven to be effective in various inflammatory skin diseases, e.g.…”

Origin of the Allyl Group in FK506 Biosynthesis

“…They are currently registered for use as immunosuppressants after organ transplantation as well as for treatment of inflammatory skin diseases and eczema (1)(2)(3). In recent clinical studies, these compounds have also shown great promise for treatment of various forms of cancer, as well as for neurological disorders (4,5).…”