Electrophysiological effects and arrhythmogenic potential of diphemanil methylsulfate on Purkinje fibres of the rabbit. Correlations with clinical observations of QT prolongation in paediatrics

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 electrophy siological 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 concentr ations (0.1 mu M-30 mu M) of diphemanil methylsulfate, different frequencie s of stimulation (0.2 Hz, 1 Hz, 2 Hz) and duration of exposition (60 min fo llowed by 120 min washout) were observed on the properties of the action po tential. The results show a clearcut antiarrhythmic Class III type action c haracterised by a concentration-dependant prolongation of the action potent ial duration with an inverse frequency dependency without significant chang es of the other parameters. During stimulation at 0.2 Hz, early postdepolar isations and induced activity were observed in 3/8 of the fibres exposed to 10 mu M and 8/8 fibres exposed to 30 mu M. The effect did not attain a ste ady state after 60 min of exposition. It was not reversed by 120 min of was hout of the preparation. These results were compatible with the reported cardiac arrhythmic effects of prolongation of the QT interval and torsades de pointe.