Preclinical toxicology of pirmenol hydrochloride.
Pirmenol hydrochloride (CI-845), a new orally effective antiarrhythmic agent, has undergone a comprehensive preclinical safety evaluation program. Repeated dose studies to evaluate chronic toxicity in rodents revealed few drug-related findings. A dose-related body weight gain suppression occurred in mice receiving up to 160 mg/kg for thirteen weeks. Rats also exhibited decreased body weight in a fifty-two-week study. Depressed fasting glucose levels were seen in rats at 50 mg/kg after thirteen weeks, but this effect was less prominent following fifty-two weeks of dosing. No other drug-related signs of toxicity were seen in rodents. Four-week repeated-dose intravenous studies in rats were uneventful. Occasional emesis and salivation, together with dryness of the oral mucosa, occurred in dogs given 10 mg/kg intravenously for four weeks. Drug-related increased heart rates, increased QRS duration, and reduced ST interval were seen thirty minutes postdose in dogs receiving 5 mg/kg or more intravenously. When dogs received pirmenol orally for fifty-two weeks, electrocardiographic and heart rate changes were variable and less pronounced than seen in the intravenous study. Clinical signs consisted of exaggerated pharmacologic responses similar to those found after intravenous dosing. Reproduction studies in rats and rabbits showed that pirmenol is not teratogenic. Reduced food intake and a 50% decrease in body weight gain were seen in rats at the top dose level of 150 mg/kg. Significantly reduced mean fetal weight and increased postimplantation loss indicated that 150 mg/kg was embryotoxic to rats. A top dose of 50 mg/kg in rabbits did not produce any signs of maternal or fetotoxicity, aside from a moderate suppression of maternal weight gain.(ABSTRACT TRUNCATED AT 250 WORDS)
Martin
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Department of Pathology and Experimental Toxicology, Warner-Lambert/Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan.
de la Iglesia
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D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects; D007275:Injections, Intravenous; D051379:Mice; D010880:Piperidines / Q000008:administration & dosage / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D012098:Reproduction / Q000187:drug effects; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D010880:Piperidines; C024318:pirmenol