FR167653, a dual inhibitor of interleukin-1 and tumor necrosis factor-alpha, ameliorates endotoxin-induced shock.
Increased production of interleukin-1 and tumor necrosis factor-alpha (TNF-alpha) have been implicated in the pathophysiology of a variety of diseases including circulatory shock. The present study evaluated the efficacy of FR167653 (1-[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8-pyridylpyrazolo[5,1-c] [1,2,4]triazin-2-yl]-2-phenylethanedione sulfate monohydrate), a dual inhibitor of interleukin-1 and TNF-alpha production, to protect rabbits from the shock and lethality induced by lipopolysaccharide. In this sepsis model, FR167653 at a dose of 0.32 mg/kg per h ameliorated the 7-day mortality from 93% in the placebo group to 47% in the FR167653-treated group and, at doses of 0.10-0.32 mg/kg per h, attenuated the hypotensive response to lipopolysaccharide challenge and returned mean arterial blood pressure to almost normal levels. The increases in plasma interleukin-1 and TNF-alpha levels evoked by lipopolysaccharide administration were also inhibited by treatment with FR167653, which was efficacious at doses of 0.1-0.32 mg/kg per h. In addition, FR167653 treatment attenuated the increases in plasma creatinine concentrations consistent with renal damage in a dose-dependent manner. These findings suggested that FR 167653 has a beneficial potential as a drug for septic shock or multiple organ dysfunction syndrome.
Yamamoto
N
N
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
Sakai
F
F
Yamazaki
H
H
Sato
N
N
Nakahara
K
K
Okuhara
M
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D003404:Creatinine / Q000097:blood; D005260:Female; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000097:blood*; D008070:Lipopolysaccharides; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D012772:Shock, Septic / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
C104334:FR 167653; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D003404:Creatinine