• Svetlana Borozdenkova, Timothy G K Mant, Elizabeth Allen, Kewei Pu, Shoji Hoshino, and Stipo Jurcevic.
• Quintiles Drug Research Unit, London, SE1 1YR, UK.
• Int. Immunopharmacol. 2011 Nov 1; 11 (11): 1837-43.

AbstractIt 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.Copyright © 2011 Elsevier B.V. All rights reserved.

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