Acute, subchronic, and chronic toxicity of the cardiotonic isomazole in rats.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Sandusky
G E
GE
Toxicology Division, Eli Lilly and Company, Greenfield, Indiana 46140.
Franklin
R B
RB
Means
J R
JR
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D004032:Diet; D005260:Female; D007093:Imidazoles / Q000493:pharmacokinetics / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009929:Organ Size / Q000187:drug effects; D010179:Pancreas / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D013997:Time Factors
D002316:Cardiotonic Agents; D007093:Imidazoles; C029758:sulmazole