title: Effects of a cytokine inhibitor, JTE-607, on the response to endotoxin in healthy human volunteers.
abstract: It is generally regarded that the excessive production of cytokines plays an important role in the pathology of autoimmune diseases and septic shock. We have investigated the ability of JTE-607, a novel inhibitor of cytokine production, to modulate the inflammatory response to endotoxin in healthy human volunteers. Three cohorts of healthy male volunteers were recruited for a randomized, placebo-controlled, double-blind study. Within each cohort, 6 subjects received a single 8-hour intravenous infusion of JTE-607 (either 0.03, 0.1 or 0.3 mg/kg/h) and 3 subjects received a placebo infusion. Two hours after the start of the JTE-607 infusion, all subjects received a 30 unit/kg bolus infusion of endotoxin. JTE-607 administration resulted in the decrease in endotoxin-induced IL-10 production with mean % difference from placebo of -79.5% (P=0.040) and -86.2% (P=0.026) at 0.1 and 0.3 mg/kg/h dose, respectively. The production of endotoxin-mediated interleukin (IL)-1 receptor antagonist was significantly inhibited at 0.3 mg/kg/h dose with mean % difference from placebo of -60% (P=0.0037). Endotoxin-induced C-reactive protein decreased with the increasing dose of JTE-607 with mean % difference from placebo of -32.1% (P=0.322), -82.9% (P=0.0001) and -90.3% (P<0.0001) at 0.03, 0.1 and 0.3 mg/kg/h dose, respectively. In conclusion, this study describes a cytokine modulator JTE-607, which inhibits production of IL-10, IL-1ra and C-reactive protein in a human model of endotoxemia.
authors.affiliation: Quintiles Drug Research Unit, London, SE1 1YR, UK.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Borozdenkova
authors.forename: Timothy G K
authors.initials: TG
authors.lastname: Mant
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Allen
authors.forename: Kewei
authors.initials: K
authors.lastname: Pu
authors.forename: Shoji
authors.initials: S
authors.lastname: Hoshino
authors.forename: Stipo
authors.initials: S
authors.lastname: Jurcevic
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis / Q000037:antagonists & inhibitors; D015331:Cohort Studies; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D019446:Endotoxemia / Q000276:immunology / Q000517:prevention & control; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007262:Infusions, Intravenous; D053590:Interleukin 1 Receptor Antagonist Protein / Q000037:antagonists & inhibitors / Q000097:blood; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010649:Phenylalanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines; C508609:IL10 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; C468268:JTE 607; D008070:Lipopolysaccharides; D010879:Piperazines; D016753:Interleukin-10; D010649:Phenylalanine; D002097:C-Reactive Protein