Elidel
[Development and pre-clinical aspects of pimecrolimus]

[Article in German]

Stutz A, Grassberger M, Meingassner JG.

Novartis Forschungsinstitut, Vienna, Austria. anton.stuetz pharma.novartis.com

Pimecrolimus (SDZ ASM 981), an ascomycin derivative, inhibits the phosphatase calcineurin and blocks the production of inflammatory cytokines in T cells. In contrast to corticosteroids, pimecrolimus has a cell selective mode of action, exerting e.g. no effect on dendritic cells, which have a central function in the skin-associated immune system. Pimecrolimus shows less permeation through skin than corticosteroids and tacrolimus which indicates a lower potential for systemic side effects after topical application. In animal models pimecrolimus has a marked dose-dependent anti-inflammatory activity. However, treatment with pimecrolimus does not induce skin atrophy in contrast to corticosteroids. In contrast to tacrolimus, pimecrolimus does not impair the primary immune reaction in the sensitization phase of allergic contact dermatitis and has generally less effect on systemic immune reactions. In summary, the pharmacological profile of pimecrolimus suggests high clinical efficacy together with excellent safety.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12719859&dopt=Abstract pimecrolimus Elidel



Elidel
[Antipruritic effects of pimecrolimus and tacrolimus]

[Article in German]

Stander S, Luger TA.

Klinik und Poliklinik fur Hautkrankheiten, Universitatsklinikum Munster. sonja.staender uni-muenster.de

The development of topical calcineurin inhibitors resulted in a significant improvement in the treatment of inflammatory skin diseases such as atopic dermatitis. In addition, an excellent amelioration of pruritus could be observed. Other itchy dermatoses such as chronic irritative hand dermatitis, rosacea, graft-versus-host-disease, renal pruritus, lichen sclerosus, prurigo simplex, prurigo nodularis, scrotal eczema, and inverse psoriasis also have been treated successfully with pimecrolimus and tacrolimus. The antipruritic effect currently is believed to be related to the inhibition of inflammatory cytokines. Furthermore, recent investigations indicate a release of neuropeptides from sensory nerve fibers and degranulation of mast cells mediated by pimecrolimus and tacrolimus. Similar effects have been observed during capsaicin treatment. These findings may provide a possible explanation for initially observed calcineurin inhibitors related side-effects such as burning and pruritus. Moreover, the antipruritic potency may be related to a direct effect on nerve fibers leading to suppression of itch mediated by unknown mechanisms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12719860&dopt=Abstract pimecrolimus Elidel



Elidel
Pimecrolimus inhibits the elicitation phase but does not suppress the sensitization phase in murine contact hypersensitivity, in contrast to tacrolimus and cyclosporine A.

Meingassner JG, Fahrngruber H, Bavandi A.

Novartis Research Institute, Vienna, Austria. josef.meingassner pharma.novartis.com

Pimecrolimus (SDZ ASM 981, Elidel) is a nonsteroid inflammatory cytokine inhibitor specifically developed for the treatment of inflammatory skin diseases. Its effect on the elicitation and sensitization phases of oxazolone-induced contact hypersensitivity was compared with tacrolimus and cyclosporine A (CyA) in BALB/c mice using the ear swelling assay. The compounds were administered orally. Elicitation was dose-dependently inhibited by all three compounds. The minimal effective doses were 30 mg per kg (pimecrolimus, tacrolimus) and 90 mg per kg (CyA), respectively. There was no impairment of sensitization by pimecrolimus up to the highest dose tested (120 mg per kg), in contrast to CyA (60% inhibition at 60 mg per kg) and tacrolimus (71% inhibition at 30 mg per kg). Weight and cellularity of the draining lymph nodes in mice treated with tacrolimus or CyA during sensitization were reduced. In addition, proliferation of T cells after secondary stimulation was inhibited in cell cultures from lymph nodes of mice treated with tacrolimus or CyA. Thus, in contrast to tacrolimus and CyA, pimecrolimus exerts a more selective immunomodulatory effect. It does not impair the primary immune response (sensitization phase) but effectively inhibits the secondary phase, the elicitation phase that is the clinical manifestation of contact hypersensitivity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12839566&dopt=Abstract pimecrolimus Elidel



Elidel
Pimecrolimus does not affect the differentiation, maturation and function of human monocyte-derived dendritic cells, in contrast to corticosteroids.

Kalthoff FS, Chung J, Musser P, Stuetz A.

Novartis Research Institute, A-1235 Vienna, Austria. frank.kalthoff pharma.novartis.com

Clinically, corticosteroids (CS) are among the first line drugs in the therapy of autoimmune and allergic diseases and potently inhibit the activation of immune cells. However, due to their pleiotropic mode of action, the prolonged use of CS is generally associated with a range of undesirable side-effects. In this study, we compared the activity of pimecrolimus, a novel immunomodulatory drug for the treatment of inflammatory skin disorders, and the CS dexamethasone (Dex) and beta-methasone-valerate (beta-MSV) in different in vitro assays addressing the cytokine-induced differentiation and maturation of monocyte-derived dendritic cells (M-DC), the susceptibility of M-DC to drug-induced apoptosis and the potency of differentiated M-DC to induce primary T cell activation. In contrast to pimecrolimus, Dex and beta-MSV strongly induced apoptosis of M-DC precursors if added at the start of the DC differentiation culture. Flow cytometric analysis of surviving cells on day 6 of culture showed that the expression of several DC-specific antigens such as CD1a, CD40 and CD80 was inhibited by 50% to 80% at concentrations between 1 nm and 10 nm of either Dex or beta-MSV. Furthermore, the presence of CS during the final maturation of M-DC inhibited the synthesis of IL-12p70, the expression of critical DC costimulatory molecules, such as CD83 and CD86 and impaired their ability to activate primary CD4+ T cell proliferation. In contrast, pimecrolimus did not inhibit the LPS-induced secretion of IL-12, surface expression of costimulatory molecules or the maturation of M-DC into potent stimulators of T cells. Taken together, these data indicate that pimecrolimus does not interfere with the differentiation and viability of dendritic cells and their precursors or with the function of mature M-DC to prime naive T lymphocytes, and thus may have a lower potential than CS to interfere with DC-mediated immunosurveillance.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12930360&dopt=Abstract pimecrolimus Elidel