ArticleBritish journal of pharmacology2006
A rabbit Langendorff heart proarrhythmia model: predictive value for clinical identification of Torsades de Pointes.
Article in British journal of pharmacology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- Cardiovascular Diseases in the Digital Health Era: A Translational Approach from the Lab to the Clinic.Biotech (Basel (Switzerland)) · 2022Review
- Classifying Drugs by their Arrhythmogenic Risk Using Machine Learning.Biophysical journal · 2020Article
- General Principles for the Validation of Proarrhythmia Risk Prediction Models: An Extension of the CiPA In Silico Strategy.Clinical pharmacology and therapeutics · 2020Article
- Drug-induced shortening of the electromechanical window is an effective biomarker for in silico prediction of clinical risk of arrhythmias.British journal of pharmacology · 2019Article
- BlindedFrontiers in pharmacology · 2019Article
- Arrhythmic hazard map for a 3D whole-ventricle model under multiple ion channel block.British journal of pharmacology · 2018Article
- Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator.Toxicology research · 2017Article
- HumanFrontiers in physiology · 2017Article
- Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae.Frontiers in physiology · 2017Article
- Evolution of strategies to improve preclinical cardiac safety testing.Nature reviews. Drug discovery · 2016Review
- Induced pluripotent stem cells: at the heart of cardiovascular precision medicine.Nature reviews. Cardiology · 2016Review
- A phenotypic in vitro model for the main determinants of human whole heart function.Biomaterials · 2015Article
- Screening system for drug-induced arrhythmogenic risk combining a patch clamp and heart simulator.Science advances · 2015Article
- Oxytocin does not directly alter cardiac repolarization in rabbit or human cardiac myocytes.Pharmacology research & perspectives · 2015Article
- Absence of QTc Prolongation with Domperidone: A Randomized, Double-Blind, Placebo- and Positive-Controlled Thorough QT/QTc Study in Healthy Volunteers.Clinical pharmacology in drug development · 2015Article
- On-chip in vitro cell-network pre-clinical cardiac toxicity using spatiotemporal human cardiomyocyte measurement on a chip.Scientific reports · 2014Article
- Article
- Sensitivity of rabbit ventricular action potential and Ca²⁺ dynamics to small variations in membrane currents and ion diffusion coefficients.BioMed research international · 2013Article
- Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes.British journal of pharmacology · 2012Article
- Effect of cleistanthin A and B on adrenergic and cholinergic receptors.Pharmacognosy magazine · 2011Article
Corrections and comments
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeThe rabbit isolated Langendorff heart model (SCREENIT) was used to investigate the proarrhythmic potential of a range of marketed drugs or drugs intended for market. These data were used to validate the SCREENIT model against clinical outcomes. EXPERIMENTAL APPROACH: Fifty-five drugs, 3 replicates and 2 controls were tested in a blinded manner. Proarrhythmia variables included a 10% change in MAPD(60), triangulation, instability and reverse frequency-dependence of the MAP. Early after-depolarisations, ventricular tachycardia, TdP and ventricular fibrillation were noted. Data are reported at nominal concentrations relative to EFTPC(max). Proarrhythmic scores were assigned to each drug and each drug category. KEY
resultsCategory 1 and 2 drugs have the highest number of proarrhythmia variables and overt proarrhythmia while Category 5 drugs have the lowest, at every margin. At 30-fold the EFTPC(max), the mean proarrhythmic scores are: Category 1, 101+/-24; Category 2, 101+/-14; Category 3, 72+/-20; Category 4, 59+/-16 and Category 5, 22+/-9 points. Only drugs in Category 5 have mean proarrhythmic scores, below 30-fold, that remain within the Safety Zone. CONCLUSIONS AND IMPLICATIONS: A 30-fold margin between effects and EFTPC(max) is sufficiently stringent to provide confidence to proceed with a new chemical entity, without incurring the risk of eliminating potentially beneficial drugs. The model is particularly useful where compounds have small margins between the hERG IC(50) and predicted EFTPC(max). These data suggest this is a robust and reliable assay that can add value to an integrated QT/TdP risk assessment.
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