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.