Acute, subchronic, and chronic toxicity studies were conducted with isomazole, a new (investigational) inotropic agent with significant vasodilator properties. When given acutely to either young adult rats or mice, the oral median lethal dose was approximately 135 or 525 mg/kg, respectively. Clinical signs of toxicity were leg weakness, hypoactivity, tremors, clonic convulsions, and ataxia. Fischer 344 rats (15/sex/group) were fed diets containing isomazole in concentrations of 0, 0.03, 0.1, or 0.3% for 3 months with no resulting mortality or clinical signs of toxicity. The average daily intake of the compound was approximately 0, 20, 65, or 198 mg/kg in both sexes. Body weight gain, food consumption, and efficiency of food utilization were significantly reduced only in males in the 198 mg/kg dose group. There were no changes of toxicological significance in any of the hematology, clinical chemistry, or urine parameters. Isomazole produced significant increases in hepatic p-nitroanisole O-demethylase activity and relative liver weight primarily at the 65 and 198 mg/kg treatment levels. These effects were consistent with induction of the hepatic drug-metabolizing enzyme system. Histopathologic findings consisted of centrilobular fat deposition in the livers of 9 of 15 males in the 198 mg/kg dose group, and periarteritis in the adventitia of small and medium-sized arteries in the mesentery in 3 of 30 and 12 of 30 animals from the 65 and 198 mg/kg dose groups, respectively. The plasma levels of isomazole had a tendency to drop after 90 days compared to Day 2 in all dose groups and was more apparent in male rats. There was no accumulation of either isomazole or the two metabolites in the serum over the 3-month period. The average daily intake of isomazole was 0, 12, 30, or 76 mg/kg/day in the 6-month rat study(l0 animals/sex/group) and 0, 10, 26, or 68 mg/kg/day in the 1-year rat study (20 animals/sex/group). Qualitatively, no findings occurred in the 6-month and 1-year study which differed from those in the 3-month study.
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