title: Preliminary in vivo pharmacokinetic and pharmacodynamic evaluation of a novel calcineurin-independent inhibitor of NFAT.
abstract: A-285222 (A-285) is a bis-trifluoromethyl-pyrazole (BTP), a novel class of immunosuppressive agents that inhibit NFAT activity in vitro in human and non-human primate cells through a calcineurin-independent mechanism. In this preliminary study, we treated cynomolgus monkeys with different doses of A-285 for several days. Blood was collected from all animals at different times during the study. From these samples, plasma concentrations of A-285 were measured by liquid chromatography/mass spectrometry (LC/MS), and intracellular T-cell production of the cytokines IL-2, IFN-gamma, and TNF-alpha was quantified by flow cytometry using a mitogen-stimulated whole blood assay. Marked inhibition of cytokine production occurred after administration of the first dose of A-285, and this effect was comparable to that of cyclosporine. While neurological toxic side effects were seen when the plasma concentration of A-285 exceeded 4 microg/ml, at lower plasma levels the drug was well tolerated over 2 weeks and its pharmacodynamic effects were sustained throughout this time.
authors.affiliation: Department of Cardiothoracic Surgery, Transplantation Immunology Laboratory, Stanford, California, USA.
authors.forename: Tudor
authors.initials: T
authors.lastname: Bîrsan
authors.forename: Camille
authors.initials: C
authors.lastname: Dambrin
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jacobsen
authors.forename: Stevan W
authors.initials: SW
authors.lastname: Djuric
authors.forename: Karl W
authors.initials: KW
authors.lastname: Mollison
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.forename: George W
authors.initials: GW
authors.lastname: Carter
authors.forename: Randall E
authors.initials: RE
authors.lastname: Morris
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019703:Calcineurin / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D008252:Macaca fascicularis; D008297:Male; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014157:Transcription Factors; D014297:Trimethylsilyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: C494244:A 285222; D016207:Cytokines; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011720:Pyrazoles; D014157:Transcription Factors; D014297:Trimethylsilyl Compounds; D019703:Calcineurin