Acute, subchronic, and chronic toxicity of the cardiotonic isomazole in rats

George Sandusky, Ronald B. Franklin, Jeffrey R. Means

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)409-417
Number of pages9
JournalToxicological Sciences
Volume13
Issue number3
DOIs
StatePublished - Oct 1989
Externally publishedYes

Fingerprint

sulmazole
Cardiotonic Agents
Toxicity
Rats
Animals
Liver
Food
Adventitia
Clinical Chemistry
Mesentery
Inbred F344 Rats
Tremor
Hematology
Ataxia
Nutrition
Metabolites
Vasodilator Agents
Toxicology
Weight Gain
Young Adult

ASJC Scopus subject areas

  • Molecular Biology
  • Embryology
  • Cell Biology
  • Genetics
  • Developmental Biology
  • Toxicology

Cite this

Acute, subchronic, and chronic toxicity of the cardiotonic isomazole in rats. / Sandusky, George; Franklin, Ronald B.; Means, Jeffrey R.

In: Toxicological Sciences, Vol. 13, No. 3, 10.1989, p. 409-417.

Research output: Contribution to journalArticle

Sandusky, George ; Franklin, Ronald B. ; Means, Jeffrey R. / Acute, subchronic, and chronic toxicity of the cardiotonic isomazole in rats. In: Toxicological Sciences. 1989 ; Vol. 13, No. 3. pp. 409-417.
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