Abstract
The 2,6-dimethylanilide of quinuclidine-3-carboxylic acid hydrochloride (EO-122), a new structural analog of lidocaine, has been shown to possess po tent antiarrhythmic activity in experimentally induced arrhythmias in animals. Restoration of normal sinus rhythm and suppression of ouabain-induced ar rhythmia in cats and dogs, and of coronary occlusion-induced arrhythmia in dogs, followed a single IV injection of 1-3 mg/kg, with an onset of 2 minutes and a duration of 20-240 minutes. Occlusion-induced arrhythmia was likewise suppressed after an oral dose of 10-20 mg/kg, with an onset of 11-65 minutes and a duration of 25-120 minutes. Under similar conditions, lidocaine was ei ther totally ineffective or of ultra-short duration.
The bioavailability of EO-122 by the oral route exceeded 80% of the oral dose. Therapeutic blood concentrations were in the range 0.5-7 μg/ml. At about 5μg/ml there was a slight depression of cardiac function in the anesthe tized cat, but not in the conscious dog. In cats, complete A-V block occurred at concentrations of 60-70 μg/ml. The IV LDso in mice was 22 mg/kg, and in rabbits 8.5 mg/kg. No overt signs of neurotoxicity could be observed at any dose of EO-122. The pharmacokinetic profile of the drug fits a two-com partment open model, with t½ ≃ 150 min and Vd (ss) ≃ 1.5 1/kg.
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