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-l 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 FR167653 has a beneficial potential as a drug for septic shock or multiple organ dysfunction syndrome.