The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981)
is a potent inhibitor of mediator release from human dermal mast cells and
peripheral blood basophils.
Zuberbier T, Chong SU, Grunow K, Guhl S, Welker P, Grassberger M, Henz BM.
Department of Dermatology and Allergy, Charite, Humboldt University Berlin,
BACKGROUND: The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) has
recently been developed as a novel and cell-selective inhibitor of inflammatory
cytokine secretion; it has fewer adverse effects than currently available drugs.
OBJECTIVE: In this study, we investigated the capacity of pimecrolimus to
directly inhibit in vitro mediator release from human skin mast cells and
basophils. METHODS: Purified cutaneous mast cells or basophil-containing
peripheral blood leukocytes were obtained from healthy human donors and
preincubated with pimecrolimus (0.1 nmol/L to 1 micromol/L) in the absence or
presence of its specific antagonist (rapamycin), cyclosporin A (100 nmol/L to 1
micromol/L), or dexamethasone (1 micromol/L) and then stimulated with anti-IgE
or with calcium ionophore A23187 plus phorbol myristate acetate. Cell
supernatants were kept for analysis of histamine, tryptase, LTC4, and TNF-alpha.
RESULTS: Pimecrolimus caused a strong and dose-dependent inhibition of anti-IgE--induced
release of histamine from mast cells and basophils (maximally 73% and 82%,
respectively, at 500 nmol/L pimecrolimus) and of mast cell tryptase (maximally
75%) and a less pronounced inhibition of LTC4 (maximally 32%) and of calcium
ionophore plus phorbol myristate acetate--induced mast cell TNF-alpha release
(90% maximum at 100 nmol/L pimecrolimus). In contrast, inhibition achieved
during mast cell histamine release was maximally 60% with cyclosporin A and only
28% with dexamethasone. CONCLUSION: These data demonstrate a marked inhibitory
capacity of pimecrolimus on mediator release from human mast cells and basophils
with a potency exceeding that of cyclosporin A and dexamethasone. Pimecrolimus
might thus be expected to be effective in the treatment of mast cell-- and