Electrophysiologic effects and arrhythmogenic potential of diphemanil methylsulfate on rabbit purkinje fibers. Correlations with clinical observations of QT prolongation in pediatrics

Serious undesirable cardiac side effects have been reported with treatment with diphemanil methylsulfate (Prantal) in premature babies or neonates. To understand the origin of this problem, the authors undertook an electrophysiological study of the effects of this product in vitro on rabbit Purkinje fibres. In three separate series (N = 5 to N = 8), the effects of increasing concentrations (0.1 microM-30 microM) of diphemanil methylsulfate, different frequencies of stimulation (0.2 Hz, 1 Hz, 2 Hz) and duration of exposition (60 min followed by 120 min washout) were observed on the properties of the action potential. The results show a clearcut antiarrhythmic Class III type action characterised by a concentration-dependent prolongation of the action potential duration with an inverse frequency dependency without significant changes of the other parameters. During stimulation at 0.2 Hz, early post-depolarizations and induced activity were observed in 3/8 of the fibres exposed to 10 microM and 8/8 fibres exposed to 30 microM. The effect did not attain a steady state after 60 min of exposition. It was not reversed by 120 min of washout of the preparation. These results were compatible with the reported cardiac arrhythmic effects of prolongation of the QT interval and torsades de pointe.