Drug-induced torsades de pointes and implications for drug development.

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

Inactivation of muscle chloride channel by transposon insertion in myotonic mice

Steinmeyer K, Klocke R, Ortland C, et al. Inactivation of muscle chloride channel by transposon insertion in myotonic mice. NATURE. 1991;354(6351):304-308.MYOTONIA (stiffness and impaired relaxation of skeletal muscle) is a symptom of several diseases caused by repetitive firing of action potentials in muscle membranes 1. Purely myotonic human diseases are dominant myotonia congenita (Thomsen) and recessive generalized myotonia (Becker), whereas myotonic dystrophy is a systemic disease. Muscle hyperexcitability was attributed to defects in sodium channels 2,3 and/or to a decrease in chloride conductance (in Becker's myotonia 4 and in genetic animal models 5-10). Experimental blockage of Cl- conductance (normally 70-85% of resting conductance in muscle") in fact elicits myotonia 1,9. ADR (ref. 12) mice are a realistic animal model 5-7,12-18 for recessive autosomal myotonia. In addition to Cl- conductance 5, many other parameters 6,12,16 are changed in muscles of homozygous animals. We have now cloned the major mammalian skeletal muscle chloride channel (ClC-1) 19. Here we report that in ADR mice a transposon of the ETn family 20-23 has inserted into the corresponding gene, destroying its coding potential for several membrane-spanning domains. Together with the lack of recombination between the Clc-1 gene and the adr locus, this strongly suggests a lack of functional chloride channels as the primary cause of mouse myotonia