Pirmenol hydrochloride (CI-845): antiarrhythmic profile in coronary artery ligated conscious dogs.
The antiarrhythmic profile of CI-845 (pirmenol hydrochloride) was assessed in conscious, coronary artery ligated dogs. In single-dose studies in these arrhythmic dogs, CI-845 administered by the intravenous, intranuscular, and oral routes was highly effective in restoring normal sinus rhythm. A 2.5 mg/kg dose was effective against the arrhythmias occurring on the second day after ligation, while 5 mg/kg was effective against the higher-rate arhythmias of the first day after ligation. The reference agents ajmaline, aprindine, disopyramide, lidocaine, mexiletine, procainamide, and quinidine were also tested, and in this model, CI-845 had greater efficacy, a longer duration of activity, and/or a wider safety margin. In slow rate intravenous infusion studies, 1-2 mg/kg/hr of CI-845 maintained near total arrhythmia conversion in first-day postligation dogs. Rapid rate intravenous infusion studies (10 mg/kg/hr) demonstrated a good correlation between the CI-845 dose, plasma level, and arrhythmia conversion, as well as a wide margin of safety. Mean conversions to 80% normal rhythm were achieved at 2.5 mg/kg, with associated plasma levels of 0.8 +/- 0.1 micron/ml, while first sings or gross toxicity occurred at 21.7 +/- 2.4 mg/kg at plasma levels of 6.2 +/- 0.4 micron/ml. There were minimal effects on cardiac conduction and blood pressure even at large doses. In drug interaction studies, CI-845 was safe and effective in combination with disopyramide, lidocaine, procainamide, propranolol, and quinidine. The results clearly show CI-845 to be an orally effective, long-acting antiarrhythmic agent with a favorable margin of safety in the coronary artery ligated dog model.
D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents; D003331:Coronary Vessels / Q000502:physiology*; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D007263:Infusions, Parenteral; D007273:Injections, Intramuscular; D008026:Ligation; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D010880:Piperidines; C024318:pirmenol