%P 573-603
%R MTMT:1474991 10.2165/11535230-000000000-00000
%O Department of Medicine and Research Center, Montreal Heart Institute, University of Montreal, Montreal, QC, Canada            
            Department of Pharmacology, McGill University, Montreal, QC, Canada            
            Montreal Heart Institute Research Center, 5000 BĂŠlanger Street E., Montreal, QC H1T 1C8, Canada            
            Cited By :54            
            Export Date: 5 November 2021            
            CODEN: DRUGA            
            Correspondence Address: Nattel, S.; Montreal Heart Institute Research Center, 5000 BĂŠlanger Street E., Montreal, QC H1T 1C8, Canada; email: stanley.nattel@icm-mhi.org            
            Chemicals/CAS: amiodarone, 1951-25-3, 19774-82-4, 62067-87-2; cisapride, 81098-60-4; encainide, 66778-36-7; flecainide, 54143-55-4; halothane, 151-67-7, 66524-48-9; isoflurane, 26675-46-7; ketoconazole, 65277-42-1; lemakalim, 94535-50-9; lidocaine, 137-58-6, 24847-67-4, 56934-02-2, 73-78-9; methoxamine, 390-28-3, 61-16-5; mexiletine, 31828-71-4, 5370-01-4; moracizine, 29560-58-5, 31883-05-3; nicorandil, 65141-46-0; nisoldipine, 63675-72-9; pentobarbital, 57-33-0, 76-74-4; propafenone, 34183-22-7, 54063-53-5; quinidine, 56-54-2; ranolazine, 95635-55-5; rufinamide, 106308-44-5; terfenadine, 50679-08-8; verapamil, 152-11-4, 52-53-9; Biological Markers            
            Funding details: 07-CVD-03            
            Funding details: American-Scandinavian Foundation, ASF            
            Funding details: Canadian Institutes of Health Research, CIHR, MOP 68929            
            Funding details: Heart and Stroke Foundation of Canada, HSF            
            Funding text 1: The authors thank France Theriault for secretarial support, the Canadian Institutes for Health Research (MOP 68929) and the European-North American Atrial Fibrillation Research Alliance (ENAFRA) network award from Fonda-tion Leducq (07-CVD-03) for funding, and the Heart and Stroke Foundation of Canada for fellowship support to ASF. The authors have no conflicts of interest that are directly relevant to the content of this review.
%N 5
%T Minimizing repolarization-related proarrhythmic risk in drug development and clinical practice
%A  Farkas Attila
%A  Nattel Stanley
%L publicatio22866
%X Proarrhythmia, the development of new or worse arrhythmias in response to drug therapy, is a major limitation to the development and use of new drugs. There are different types of drug-induced proarrhythmia, including long-QT syndrome (LQTS), short-QT syndrome and proarrhythmia related to Na+-channel blockade/conduction impairment. By far the most important form of proarrhythmia at present is drug-induced LQTS and its associated characteristic tachyarrhythmia, torsades de pointes (TdP). TdP arises when cellular action potentials (APs) are excessively prolonged, leading to arrhythmogenic afterdepolarizations, especially early afterdepolarizations (EADs), which trigger complex re-entry in a substrate involving increased transmural dispersion of repolarization. In vitro screening, increasingly involving high-throughput assays, is used to assess potential candidate molecules and eliminate potentially problematic structures at an early stage of development. The most commonly used screening assays assess drug block of the K+ current carried by human ether-a-go-go (hERG) subunits, corresponding to the rapid delayed-rectifier K+ channel, the overwhelmingly most common target of TdP-inducing drugs. In addition, the effects of drugs on AP duration or the in vivo equivalent, QT interval, are often assessed in animal models. Methods available for repolarization-related proarrhythmic risk assessment include in vitro (Langendorff-perfused rabbit or guinea pig hearts) and in vivo models (such as alpha-adrenoceptor-stimulated rabbits, rabbits with reduced repolarization reserve due to block of slow delayed-rectifier current, animals with chronic atrioventricular block or animals with cardiac remodelling caused by congestive heart failure). In silico modelling may be helpful for molecular design of non-hERG blocking candidates and for optimization of compound selection (at the molecular and pharmacological profile levels). Finally, clinical evaluation of effects on electrocardiographic intervals (particularly QT) and cardiac rhythm are often needed, both prior to drug approval and after successful introduction on the market (postmarketing surveillance). The successful avoidance of proarrhythmic complications is a shared responsibility of the innovative pharmaceutical industry, regulatory authorities, partners in the clinical drug development phase and practicing physicians. This paper reviews the principal forms of proarrhythmia and the methods that can be used to minimize the risk of proarrhythmia in drug development and clinical practice, with particular emphasis on the most common and problematic form, acquired LQTS.
%V 70
%D 2010
%J DRUGS
%I szte