title: The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) is a potent inhibitor of mediator release from human dermal mast cells and peripheral blood basophils.
abstract: 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.
  
  
  CONCLUSIONS
  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 basophil-dependent diseases.
authors.affiliation: Department of Dermatology and Allergy, Charité, Humboldt University Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Zuberbier
authors.forename: S U
authors.initials: SU
authors.lastname: Chong
authors.forename: K
authors.initials: K
authors.lastname: Grunow
authors.forename: S
authors.initials: S
authors.lastname: Guhl
authors.forename: P
authors.initials: P
authors.lastname: Welker
authors.forename: M
authors.initials: M
authors.lastname: Grassberger
authors.forename: B M
authors.initials: BM
authors.lastname: Henz
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001491:Basophils / Q000187:drug effects*; D000001:Calcimycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy; D007073:Immunoglobulin E / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008407:Mast Cells / Q000187:drug effects*; D012867:Skin / Q000166:cytology / Q000187:drug effects*; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators; D007073:Immunoglobulin E; D000001:Calcimycin; C117268:pimecrolimus; D013755:Tetradecanoylphorbol Acetate; D016559:Tacrolimus