Effect of FR167653, a cytokine suppressive agent, on endotoxin-induced disseminated intravascular coagulation.
FR167653 (1-[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8-(4-pyridyl)pyrazolo[5-1-c] [1,2,4]triazin-2-yl]-2-phenylethanedione sulfate monohydrate) is a low molecular weight inflammatory cytokine inhibitor that inhibits the production of interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor-alpha (TNF-alpha) in human monocytes stimulated with lipopolysaccharide, and in human lymphocytes stimulated with phytohemagglutinin-M. FR167653 inhibited these cytokines in a dose-dependent manner (IC50 values were 0.84, 0.088, 1.1 microM and 0.072, respectively). However, FR167653 did not inhibit even at 10 microM interleukin-6 production by human monocytes, and the production of interleukin-2 and interferon-gamma by human lymphocytes. We evaluated the effect of FR167653 on lipopolysaccharide-induced disseminated intravascular coagulation in rats. FR167653 (0.032-0.32 mg/kg/h for 4 h, intravenous infusion) markedly improved thrombocytopenia and plasma coagulation parameters in a dose-dependent manner, but not leukopenia in this mode. Plasma interleukin-1 and TNF-alpha levels were elevated by lipopolysaccharide administration and the treatment with FR167653 (0.31 mg/kg/h for 4 h) inhibited the increased plasma interleukin-1 (100.0%) and plasma TNF-alpha (89.2%) levels. These results suggest that interleukin-1 and TNF-alpha may play a pivotal role in the pathogenesis of DIC. FR167653 can act as a protective drug in lipopolysaccharide-induced DIC, and this protection is due to an inhibition of increased plasma interleukin-1 and TNF-alpha.
Yamamoto
N
N
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
Sakai
F
F
Yamazaki
H
H
Nakahara
K
K
Okuhara
M
M
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors; D004211:Disseminated Intravascular Coagulation / Q000517:prevention & control*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000097:blood; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism
D016207:Cytokines; C104334:FR 167653; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha