ArticleBritish journal of pharmacology2010
Predicting drug-induced slowing of conduction and pro-arrhythmia: identifying the 'bad' sodium current blockers.
Article in British journal of pharmacology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 68 citations in OpenAlex.
- Role of mixed ion channel effects in the cardiovascular safety assessment of the novel anti-MRSA fluoroquinolone JNJ-Q2.British journal of pharmacology · 2012Trial
- An overview of drug-induced sodium channel blockade and changes in cardiac conduction: Implications for drug safety.Clinical and translational science · 2024Review
- The Potential Mechanisms behind Loperamide-Induced Cardiac Arrhythmias Associated with Human Abuse and Extreme Overdose.Biomolecules · 2023Article
- Identifying Acute Cardiac Hazard in Early Drug Discovery Using a Calcium Transient High-Throughput Assay in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.Frontiers in physiology · 2022Article
- Rate-dependent effects of lidocaine on cardiac dynamics: Development and analysis of a low-dimensional drug-channel interaction model.PLoS computational biology · 2021Article
- A Computational Pipeline to Predict Cardiotoxicity: From the Atom to the Rhythm.Circulation research · 2020Article
- Assessing Drug-Induced Long QT and Proarrhythmic Risk Using Human Stem-Cell-Derived Cardiomyocytes in a Ca2+ Imaging Assay: Evaluation of 28 CiPA Compounds at Three Test Sites.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- Interventricular Differences in Action Potential Duration Restitution Contribute to Dissimilar Ventricular Rhythms inFrontiers in cardiovascular medicine · 2019Article
- Pharmacological Profile of the Sodium Current in Human Stem Cell-Derived Cardiomyocytes Compares to Heterologous Nav1.5+β1 Model.Frontiers in pharmacology · 2019Article
- Development of a Human iPSC Cardiomyocyte-Based Scoring System for Cardiac Hazard Identification in Early Drug Safety De-risking.Stem cell reports · 2018Article
- Synergistic Effect of Dofetilide and Mexiletine on Prevention of Atrial Fibrillation.Journal of the American Heart Association · 2017Article
- The novel late NaBritish journal of pharmacology · 2016Article
- Evaluation of Index of Cardio-Electrophysiological Balance (iCEB) as a New Biomarker for the Identification of Patients at Increased Arrhythmic Risk.Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc · 2016Article
- Shensong Yangxin (SSYX) ameliorates disordered excitation transmission by suppressing cardiac collagen hyperplasia in rabbits with chronic myocardial infarction.Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban · 2016Article
- Article
- Rate-dependent activation failure in isolated cardiac cells and tissue due to Na+ channel block.American journal of physiology. Heart and circulatory physiology · 2015Article
- Engineered heart slices for electrophysiological and contractile studies.Biomaterials · 2015Article
- Pharmacology and Toxicology of Nav1.5-Class 1 anti-arrhythmic drugs.Cardiac electrophysiology clinics · 2014Article
- Investigation of connexin 43 uncoupling and prolongation of the cardiac QRS complex in preclinical and marketed drugs.British journal of pharmacology · 2014Article
- Ranolazine for congenital and acquired late INa-linked arrhythmias: in silico pharmacological screening.Circulation research · 2013Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeThe regulatory guidelines (ICHS7B) for the identification of only drug-induced long QT and pro-arrhythmias have certain limitations. EXPERIMENTAL APPROACH: Conduction time (CT) was measured in isolated Purkinje fibres, left ventricular perfused wedges and perfused hearts from rabbits, and sodium current was measured in Chinese hamster ovary cells, transfected with Na(v)1.5 channels. KEY
resultsA total of 355 compounds were screened for their effects on CT: 32% of these compounds slowed conduction, 65% had no effect and 3% accelerated conduction. Lidocaine and flecainide, which slow conduction, were tested in more detail as reference compounds. In isolated Purkinje fibres, flecainide largely slowed conduction and markedly increased triangulation, while lidocaine slightly slowed conduction and did not produce significant triangulation. Also in isolated left ventricular wedge preparations, flecainide largely slowed conduction in a rate-dependent manner, and elicited ventricular tachycardia (VT). Lidocaine slightly slowed conduction, reduced Tp-Te and did not induce VT. Similarly in isolated hearts, flecainide markedly slowed conduction, increased Tp-Te and elicited VT or ventricular fibrillation (VF). The slowing of conduction and induction of VT/VF with flecainide was much more evident in a condition of ischaemia/reperfusion. Lidocaine abolished ischaemia/reperfusion-induced VT/VF. Flecainide blocked sodium current (I(Na)) preferentially in the activated state (i.e. open channel) with slow binding and dissociation rates in a use-dependent manner, and lidocaine weakly blocked I(Na). CONCLUSION AND IMPLICATIONS: Slowing conduction by blocking I(Na) could be potentially pro-arrhythmic. It is possible to differentiate between compounds with 'good' (lidocaine-like) and 'bad' (flecainide-like) I(Na) blocking activities in these models.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.