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Clin Pharmacol Ther. 2014 Nov;96(5):549-58. doi: 10.1038/clpt.2014.155. Epub 2014 Jul 23.

Differentiating drug-induced multichannel block on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and verapamil.

Author information

1
1] Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA [2] Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
2
1] Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA [2] BSICoS Group, Aragón Institute of Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Aragon, Spain.
3
Spaulding Clinical Research, West Bend, Wisconsin, USA.
4
Frontage Laboratories, Exton, Pennsylvania, USA.
5
Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
6
Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.
7
Division of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.

Abstract

Block of the hERG potassium channel and prolongation of the QT interval are predictors of drug-induced torsade de pointes. However, drugs that block the hERG potassium channel may also block other channels that mitigate torsade risk. We hypothesized that the electrocardiogram can differentiate the effects of multichannel drug block by separate analysis of early repolarization (global J-Tpeak) and late repolarization (global Tpeak-Tend). In this prospective randomized controlled clinical trial, 22 subjects received a pure hERG potassium channel blocker (dofetilide) and three drugs that block hERG and either calcium or late sodium currents (quinidine, ranolazine, and verapamil). The results show that hERG potassium channel block equally prolongs early and late repolarization, whereas additional inward current block (calcium or late sodium) preferentially shortens early repolarization. Characterization of multichannel drug effects on human cardiac repolarization is possible and may improve the utility of the electrocardiogram in the assessment of drug-related cardiac electrophysiology.

PMID:
25054430
DOI:
10.1038/clpt.2014.155
[Indexed for MEDLINE]

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