Electrophysiologic effects of cibenzoline in humans related to dose and plasma concentration

Abstract

The electrophysiologic effects of a new antiarrhythmic agent, cibenzoline, were investigated in 25 patients with an average age of 62 years. The compound was administered intravenously, as a bolus given over 2 minutes, then as a slow infusion over 40 minutes. Each subject was randomly allocated to receive one of the following four doses: 1.55 mg/kg (six patients), 1.8 mg/kg (six patients), 2.2 mg/kg (six patients), or 2.6 mg/kg (seven patients). Plasma cibenzoline concentrations at these doses were 378 ± 80, 525 ± 194, 618 ± 72, and 731 ± 196 ng/ml, respectively. Administration of 1.55 mg/kg cibenzoline significantly shortened the sinus cycle (60 msec on average; p < 0.025) and increased intraatrial (+8 msec; p < 0.05) and His-Purkinje conduction times (HV interval +13 msec; p < 0.001). At 1.80 mg/kg, prolongation occurred in the HV interval (+9 msec; p < 0.02), the duration of the QRS complex (+20 msec; p > 0.05), and the QT interval (+18 msec; p < 0.025). At the higher doses these changes became more marked (maximum increase: HV = +16 msec, p < 0.001; QRS + 25 msec; p < 0.001; QT + 26 msec, p < 0.05), and additional effects on atrioventricular nodal conduction time (AH interval + 17 msec; p < 0.05) and atrial (+20 msec; p < 0.05) and ventricular (+10 msec; p > 0.05) effective refractory periods were observed. Prolongation of the QRS duration was the effect that correlated best with plasma cibenzoline levels ( r = 0.47; p < 0.05). These results allow an understanding of the antiarrhythmic activity of cibenzoline in humans.