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FR167653, a dual inhibitor of interleukin-1 and tumor necrosis factor-alpha, ameliorates endotoxin-induced shock.

Abstract
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.
AuthorsN Yamamoto, F Sakai, H Yamazaki, N Sato, K Nakahara, M Okuhara
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 327 Issue 2-3 Pg. 169-74 (May 30 1997) ISSN: 0014-2999 [Print] Netherlands
PMID9200556 (Publication Type: Journal Article)
Chemical References
  • FR 167653
  • Interleukin-1
  • Lipopolysaccharides
  • Pyrazoles
  • Pyridines
  • Tumor Necrosis Factor-alpha
  • Creatinine
Topics
  • Animals
  • Blood Pressure (drug effects)
  • Creatinine (blood)
  • Female
  • Interleukin-1 (antagonists & inhibitors, blood)
  • Lipopolysaccharides
  • Pyrazoles (pharmacology)
  • Pyridines (pharmacology)
  • Rabbits
  • Shock, Septic (blood, chemically induced, drug therapy)
  • Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)

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