Late Sodium Current Block for Drug-Induced Long QT Syndrome: Results From a Prospective Clinical Trial

Feb 01, 2016 • By L Johannesen, J Vicente, JW Mason, C Erato, C Sanabria, K Waite-Labott, M Hong, J Lin, P Guo, A Mutlib, J Wang, WJ Crumb, K Blinova, D Chan, J Stohlman, J Florian, M Ugander, N Stockbridge, and DG Strauss

Abstract Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the…

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Comprehensive T wave Morphology Assessment in a Randomized Clinical Study of Dofetilide, Quinidine, Ranolazine, and Verapamil

Mar 06, 2015 • By Jose Vicente, MSc; Lars Johannesen, MSc; Jay W. Mason, MD; William J. Crumb, PhD; Esther Pueyo, PhD; Norman Stockbridge, MD, PhD; David G. Strauss, MD, PhD

Background-—Congenital long QT syndrome type 2 (abnormal hERG potassium channel) patients can develop flat, asymmetric, and notched T waves. Similar observations have been made with a limited number of hERG-blocking drugs. However, it is not known how additional calcium or late sodium block, that c…

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A New Perspective in the Field of Cardiac Safety Testing through the Comprehensive In Vitro Proarrhythmia Assay Paradigm

Apr 01, 2015 • By Bernard Fermini, Jules C. Hancox, Najah Abi-Gerges, Matthew Bridgland-Taylor, Khuram W. Chaudhary, Thomas Colatsky, Krystle Correll, William Crumb, Bruce Damiano, Gul Erdemli, Gary Gintant, John Imredy, John Koerner, James Kramer, Paul Levesque, Zhihua Li, Anders Lindqvist, Carlos A. Obejero-Paz, David Rampe, Kohei Sawada, David G. Strauss, and Jamie I. Vandenberg

Abstract For the past decade, cardiac safety screening to evaluate the propensity of drugs to produce QT interval prolongation and Torsades de Pointes (TdP) arrhythmia has been conducted according to ICH S7B and ICH E14 guidelines. Central to the existing approach are hERG channel assays and in…

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A Novel, Potent, and Selective Inhibitor of Cardiac Late Sodium Current Suppresses Experimental Arrhythmias

Sep 19, 2012 • By Luiz Belardinelli, Gongxin Liu, Cathy Smith-Maxwell, Wei-Qun Wang, Nesrine El-Bizri, Ryoko Hirakawa, Serge Karpinski, Cindy Hong Li, Lufei Hu, Xiao-Jun Li, William Crumb, Lin Wu, Dmitry Koltun, Jeff Zablocki, Lina Yao, Arvinder K. Dhalla, Sridharan Rajamani, John C. Shryock

Abstract Inhibition of cardiac late sodium current (late INa) is a strategy to suppress arrhythmias and sodium-dependent calcium overload associated with myocardial ischemia and heart failure. Current inhibitors of late INa are unselective and can be proarrhythmic. This study introduces GS967…

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In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials

Feb 26, 2012 • By Franco Borsini, William Crumb, Silvia Pace, David Ubben, Barb Wible, Gan-Xin Yan, and Christian Funck-Brentanof

The in vitro cardiac properties of dihydroartemisinin (DHA) plus piperaquine phosphate (PQP) were compared with those of other antimalarial compounds. Results with antimalarial drugs, chosen on the basis of their free therapeutic maximum concentration in plasma (Cmax), were expressed as the fold of…

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