The Antiarrhythmic Activity of Meobentine Sulfate in Man

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Abstract
Meobentine (sulfate) has antifibrillatory and antiarrhythmic activity in canine models. The antiarrhythmic, pharmacokinetic and adrenergic neuronal blocking effects of meobentine were assessed in 15 patients with chronic, high-frequency ventricular ectopic depolarizations (VED). Eleven of the 15 patients had recurrent nonsustained ventricular tachycardia. The patients were given a series of gradually increasing single doses of meobentine; 6 received oral meobentine and 9 had infusions. The antiarrhythmic efficacy of meobentine was assessed by a comparison of arrhythmia frequency during placebo given on days just prior to meobentine. Oral therapy with meobentine at dosages above 20 mg/kg caused diarrhea, and well-tolerated dosages achieved peak concentrations of 0.69 .mu.g/ml (range 0.5-1.0 .mu.g/ml). Antiarrhythmic activity was seen in only one patient with oral meobentine. I.v. infusions (6.75-34.2 mg/kg) achieved concentrations ranging from 1.3-9.8 .mu.g/ml. There was a linear relationship between pseudo-steady-state plasma concentrations and dosage, r = 0.82, P < 0.01. Antiarrhythmic activity was seen in 4 of 9 patients who received i.v. meobentine over a range of concentrations from 2.5-4.5 .mu.g/ml. Four patients developed evidence of adrenergic neuronal blockage (loss of the venous reflex response); two at dosages of 16.2 mg/kg, one at 24.3 mg/kg and one at 34.2 mg/kg. In one individual (24.3 mg/kg), the adrenergic neuronal blockade was associated with an acute episode of shortness of breath, orthopnea and cough. With i.v. meobentine, there was a linear relationship between dosage and AUC [area under the concentration-time curve], and the elimination half-life ranged from 11-27 h. Although meobentine has antiarrhythmic activity in man, treatment with large, single oral doses of meobentine was associated with diarrhea while large i.v. dosages were associated with adrenergic neuronal blockade and symptoms compatible with left ventricular dysfunction. The range between plasma concentrations associated with side effects and those required for suppression of chronic stable ventricular ectopic depolarizations appears to be narrow with meobentine.

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