PMID: 9437877Jul 1, 1997Paper

Pre-clinical and clinical electrophysiological studies for the prediction of iatrogenic proarrhythmic effect (torsade de pointes)

Thérapie
P JaillonR Dahan

Abstract

The risk of drug-induced torsade de pointes, a potentially lethal ventricular arrhythmia, raises the problem of the early detection of the effects of any new chemical entity (NCE) on ventricular repolarization since prolongation of myocardial repolarization is a major trigger among others (hypokalaemia, bradycardia, congenital abnormalities in cellular ionic channels) for this arrhythmia. During pre-clinical studies, the effects of a range of concentrations (10(-9) M to 10(-4) M) of NCE on the duration of the action potential of Purkinje and left ventricular myocardial cells (guinea-pig and rabbit) have to be measured. If these effects are present, the duration of QT interval on ECG recorded in animal studies (dogs) has to be carefully measured and correlated with plasma concentrations of NCE and/or its metabolite(s). During clinical trials, additional studies have to be performed in order to document QT interval-plasma concentration relationships and the influence of heart rate on QT interval duration. Ambulatory ECG recordings will attest to the safety of the NCE and precautions for use of the drug will be established according to our knowledge of predisposing factors for a proarrhythmic effect. Should there be a notification...Continue Reading

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