Preclinical toxicology of pirmenol hydrochloride.
Pirmenol hydrochloride, a novel pyridinemethanol derivative, is a long-acting class Ia antiarrhythmic agent. Preclinical toxicology data were obtained in rat, mouse, dog and rabbit. In acute toxicity studies by oral and intravenous routes, no pathologic changes were observed in surviving mice, rats and dogs. In repeated dose toxicity studies, no drug-related pathologic changes were evident; dryness of the oral mucosa in dogs and body weight gain reductions in rodents were the only significant clinical signs. In a chronic (52 week) toxicity study in rats, pirmenol given in the diet was tolerated clinically at doses up to 100 mg/kg/day. No drug-related aberrations in clinical laboratory parameters or ophthalmic or pathologic findings were evident. In a similar study in beagle dogs, pirmenol was tolerated clinically at a dosage up to 30 mg/kg/day. No significant changes in biochemical, hematologic, urinary or bone marrow determinations were found in either species. In reproductive toxicology studies in rats, pirmenol had no significant effect on litter size or embryonic viability. In rabbits pirmenol had no effect on average litter size, embryonic viability or fetal wastage. Given to male rats, pirmenol had no overt effects on fertility. Pirmenol failed to elicit deoxyribonucleic acid damage or induce cytogenetic alterations. Pirmenol appears to be without significant limiting toxicologic properties.
D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D004285:Dogs; D005260:Female; D005333:Fetus / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012098:Reproduction / Q000187:drug effects; D013045:Species Specificity; D014987:Xerostomia / Q000139:chemically induced
D000889:Anti-Arrhythmia Agents; D010880:Piperidines; C024318:pirmenol