Preclinical toxicology studies with nizatidine, a new H2-receptor antagonist: acute, subchronic, and chronic toxicity evaluations
| Autor: | John P. Mcgrath, John L. Emmerson, Gary L. Higdon, Karen S. Probst, Lawrence F. Fisher, E. R. Adams |
|---|---|
| Rok vydání: | 1989 |
| Předmět: |
Male
medicine.medical_specialty Antiulcer drug Genitalia Male Toxicology Route of administration Mice Dogs Species Specificity Weight loss Internal medicine medicine Animals Chronic toxicity Nizatidine Mice Inbred ICR business.industry Stomach Organ Size Macaca mulatta Acute toxicity Rats Inbred F344 Rats Thiazoles Endocrinology Histamine H2 Antagonists Liver Toxicity Androgens Female medicine.symptom business Weight gain medicine.drug |
| Zdroj: | Fundamental and applied toxicology : official journal of the Society of Toxicology. 13(4) |
| ISSN: | 0272-0590 |
| Popis: | Nizatidine (NIZ), a new antiulcer drug, was evaluated for toxicity in acute, subchronic, and chronic tests. Acute toxicity studies were conducted in rats, mice, dogs, and monkeys. Median lethal doses (MLD) in rodents were greater than 1600, 230, and 1000 mg/kg by oral (po), iv, and sc administration, respectively. No deaths occurred in dogs given single doses of 800 mg/kg (po), 75 mg/kg (iv), or 225 mg/kg (im) or in monkeys given 1200 mg/kg (po) or 200 mg/kg (iv). Rats survived up to 1.0% dietary NIZ (daily intake ranging from 24 to 800 mg/kg/day) for 1 year. Slight decreases in body weight gain and increases in liver and kidney weights occurred. Slight decreases in erythrocytic parameters at 3 months were not present at 6 or 12 months. Mice survived up to 1.5% dietary NIZ for 3 months and effects were limited to slight decreases in body weight gain and increases in relative liver weight. Dogs survived oral doses up to 800 mg/kg/day for 3 months but had numerous clinical signs of toxicity and body weight loss. All dogs given oral NIZ doses up to 400 mg/kg/day survived except for one high-dose dog that was killed in a moribund condition following convulsions in the 41st week of treatment. Effects in dogs included miosis, body weight loss, increased thrombocyte counts, and decreased hepatic microsomal enzyme activity and P450 content. The increase in thrombocyte counts was unaccompanied by changes in thrombocyte function and did not reoccur in a subsequent study. A decrease in plasma testosterone in two of three surviving male dogs given 400 mg/kg/day for 1 year was unaccompanied by effects on the size or morphology of testes or prostate. Peak plasma levels of NIZ in all species tested were in excess of human plasma levels after therapeutic doses. In conclusion, there was no evidence of significant toxicity in organs or tissues including those sites (gastric mucosa, male sex organs, and liver) that have been affected by some agents of this therapeutic class. |
| Databáze: | OpenAIRE |
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