Drug‐induced torsades de pointes and implications for drug development

RR Fenichel, M Malik, C Antzelevitch… - Journal of …, 2004 - Wiley Online Library
RR Fenichel, M Malik, C Antzelevitch, M Sanguinetti, DM Roden, SG Priori, JN Ruskin…
Journal of cardiovascular electrophysiology, 2004Wiley Online Library
Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an
adverse effect of pharmacotherapy. Recently developed understanding of the underlying
electrophysiology allows better estimation of the drug‐induced risks and explains the
failures of older approaches through the surface ECG. This article expresses a consensus
reached by an independent academic task force on the physiologic understanding of drug‐
induced repolarization changes, their preclinical and clinical evaluation, and the risk‐to …
Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently developed understanding of the underlying electrophysiology allows better estimation of the drug‐induced risks and explains the failures of older approaches through the surface ECG. This article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug‐induced repolarization changes, their preclinical and clinical evaluation, and the risk‐to‐benefit interpretation of drug‐induced torsades de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsades within drug development programs. Individual sections of the text discuss the techniques and limitations of methods directed at drug‐related ion channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and interpretation of human ECGs obtained in clinical studies. The final section of the text discusses drug‐induced torsades within the larger evaluation of drug‐related risks and benefits. (J Cardiovasc Electrophysiol, Vol. 15, pp. 475‐495, April 2004)
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