title: Differentiating drug-induced multichannel block on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and verapamil.
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.
authors: 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.
authors: L
authors: L
authors: Johannesen
authors: 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.
authors: J
authors: J
authors: Vicente
authors: Spaulding Clinical Research, West Bend, Wisconsin, USA.
authors: J W
authors: JW
authors: Mason
authors: Spaulding Clinical Research, West Bend, Wisconsin, USA.
authors: C
authors: C
authors: Sanabria
authors: Spaulding Clinical Research, West Bend, Wisconsin, USA.
authors: K
authors: K
authors: Waite-Labott
authors: Frontage Laboratories, Exton, Pennsylvania, USA.
authors: M
authors: M
authors: Hong
authors: Frontage Laboratories, Exton, Pennsylvania, USA.
authors: P
authors: P
authors: Guo
authors: Frontage Laboratories, Exton, Pennsylvania, USA.
authors: J
authors: J
authors: Lin
authors: 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.
authors: J S
authors: JS
authors: Sørensen
authors: Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors: L
authors: L
authors: Galeotti
authors: 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.
authors: J
authors: J
authors: Florian
authors: 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.
authors: M
authors: M
authors: Ugander
authors: 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.
authors: N
authors: N
authors: Stockbridge
authors: 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.
authors: D G
authors: DG
authors: Strauss
mesh_terms: D000083:Acetanilides / Q000009:adverse effects* / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000187:drug effects*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D010627:Phenethylamines / Q000009:adverse effects* / Q000493:pharmacokinetics; D010879:Piperazines / Q000009:adverse effects* / Q000493:pharmacokinetics; D026902:Potassium Channel Blockers / Q000009:adverse effects*; D011446:Prospective Studies; D011802:Quinidine / Q000009:adverse effects* / Q000493:pharmacokinetics; D000069458:Ranolazine; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013449:Sulfonamides / Q000009:adverse effects* / Q000493:pharmacokinetics; D014700:Verapamil / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D000083:Acetanilides; D002121:Calcium Channel Blockers; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010627:Phenethylamines; D010879:Piperazines; D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers; D013449:Sulfonamides; D000069458:Ranolazine; D014700:Verapamil; D011802:Quinidine; C063533:dofetilide