A preclinical study of EO-122, a new lidocaine-like antiarrhythmic drug.

Abstract

The 2,6-dimethylanilide of quinuclidine-3-carboxylic acid hydrochloride (EO-122), a new structural analog of lidocaine, has been shown to possess potent antiarrhythmic activity in experimentally induced arrhythmias in animals. Restoration of normal sinus rhythm and suppression of ouabain-induced arrhythmia 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 either totally ineffective or of ultra-short duration. The bioavailability of EO0122 by the oral route exceeded 80% of the oral dose. Therapeutic blood concentrations were in the range 0.5--7 microgram/ml. At about 5 microgram/ml there was a slight depression of cardiac function in the anesthetized cat, but not in the conscious dog. In cats, complete A-V block occurred at concentrations of 60--70 microgram/ml. The IV LD50 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-compartment open model, with t1/2 congruent to 150 min and Vd (SS) congruent to 1.5 l/kg.