ArticleBritish journal of pharmacology2012
Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes.
Article in British journal of pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 69 citations in OpenAlex.
- Arrhythmia risk predictions from molecular simulations of cardiac ion channel-drug interactions.Biophysical journal · 2026Article
- The Methanesulfonamide Group: Bright and Dark Sides of hERG Potassium Channel Inhibition.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Prediction of TdP Arrhythmia Risk Through Molecular Simulations of Conformation-specific Drug Interactions with the hERG KbioRxiv : the preprint server for biology · 2025Article
- Arrhythmia Inducibility in the CAVB Dog Model, A Critical Analysis on Underlying Factors.Cardiovascular toxicology · 2025Article
- Evaluating the predictive accuracy of ion-channel models using data from multiple experimental designs.Philosophical transactions. Series A, Mathematical, physical, and engineering sciences · 2025Article
- The canine chronic atrioventricular block model in cardiovascular preclinical drug research.British journal of pharmacology · 2022Review
- hERG-deficient human embryonic stem cell-derived cardiomyocytes for modelling QT prolongation.Stem cell research & therapy · 2021Article
- Human perinatal stem cell derived extracellular matrix enables rapid maturation of hiPSC-CM structural and functional phenotypes.Scientific reports · 2020Article
- Repolarization instability and arrhythmia by IKr block in single human-induced pluripotent stem cell-derived cardiomyocytes and 2D monolayers.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2020Article
- A Computational Pipeline to Predict Cardiotoxicity: From the Atom to the Rhythm.Circulation research · 2020Article
- Dominant rule of community effect in synchronized beating behavior of cardiomyocyte networks.Biophysical reviews · 2020Review
- Contribution of potassium channels to action potential repolarization of human embryonic stem cell-derived cardiomyocytes.British journal of pharmacology · 2019Article
- Stem cell models as anThe Biochemical journal · 2019Review
- Facilitation ofThe Journal of general physiology · 2019Article
- On-chip spatiotemporal electrophysiological analysis of human stem cell derived cardiomyocytes enables quantitative assessment of proarrhythmia in drug development.Scientific reports · 2018Article
- Selective late sodium current inhibitor GS-458967 suppresses Torsades de Pointes by mostly affecting perpetuation but not initiation of the arrhythmia.British journal of pharmacology · 2018Article
- Development of In Vitro Drug-Induced Cardiotoxicity Assay by Using Three-Dimensional Cardiac Tissues Derived from Human Induced Pluripotent Stem Cells.Tissue engineering. Part C, Methods · 2018Article
- Class III antiarrhythmic drugs amiodarone and dronedarone impair KJournal of cellular and molecular medicine · 2017Article
- The inward rectifier current inhibitor PA-6 terminates atrial fibrillation and does not cause ventricular arrhythmias in goat and dog models.British journal of pharmacology · 2017Article
- Short-term Variability of Repolarization Is Superior to Other Repolarization Parameters in the Evaluation of Diverse Antiarrhythmic Interventions in the Chronic Atrioventricular Block Dog.Journal of cardiovascular pharmacology · 2017Review
Corrections and comments
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Authors and funding
15 authors at 2 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeDrug development requires the testing of new chemical entities for adverse effects. For cardiac safety screening, improved assays are urgently needed. Isolated adult cardiomyocytes (CM) and human embryonic stem cell-derived cardiomyocytes (hESC-CM) could be used to identify pro-arrhythmic compounds. In the present study, five assays were employed to investigate their sensitivity and specificity for evaluating the pro-arrhythmic properties of I(Kr) blockers, using moxifloxacin (safe compound) and dofetilide or E-4031 (unsafe compounds). EXPERIMENTAL APPROACH: Assays included the anaesthetized remodelled chronic complete AV block (CAVB) dog, the anaesthetized methoxamine-sensitized unremodelled rabbit, multi-cellular hESC-CM clusters, isolated CM obtained from CAVB dogs and isolated CM obtained from the normal rabbit. Arrhythmic outcome was defined as Torsade de Pointes (TdP) in the animal models and early afterdepolarizations (EADs) in the cell models. KEY
resultsAt clinically relevant concentrations (5-12 µM), moxifloxacin was free of pro-arrhythmic properties in all assays with the exception of the isolated CM, in which 10 µM induced EADs in 35% of the CAVB CM and in 23% of the rabbit CM. At supra-therapeutic concentrations (≥100 µM), moxifloxacin was pro-arrhythmic in the isolated rabbit CM (33%), in the hESC-CM clusters (18%), and in the methoxamine rabbit (17%). Dofetilide and E-4031 induced EADs or TdP in all assays (50-83%), and the induction correlated with a significant increase in beat-to-beat variability of repolarization. CONCLUSION AND IMPLICATIONS: Isolated cardiomyocytes lack specificity to discriminate between TdP liability of the I(Kr) blocking drugs moxifloxacin and dofetilide or E4031.
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