ArticleBritish journal of pharmacology2008
Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines.
Article in British journal of pharmacology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 130 citations in OpenAlex.
- NS1643 enhances the activity of T1019PfsX38 and Q1070X hERG channels associated with long QT syndrome type 2.Pflugers Archiv : European journal of physiology · 2026Article
- A PAS-targeting hERG1 activator reduces arrhythmic events in Jervell and Lange-Nielsen syndrome patient-derived hiPSC-CMs.JCI insight · 2025Article
- Pharmacological activation of the hERG KJournal of arrhythmia · 2022Review
- The Challenges of Predicting Drug-Induced QTc Prolongation in Humans.Toxicological sciences : an official journal of the Society of Toxicology · 2022Review
- Deriving waveform parameters from calcium transients in human iPSC-derived cardiomyocytes to predict cardiac activity with machine learning.Stem cell reports · 2022Article
- Perspectives of future lung toxicology studies using human pluripotent stem cells.Archives of toxicology · 2022Review
- 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
- Zebrafish, an In Vivo Platform to Screen Drugs and Proteins for Biomedical Use.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Cardiac hERG KHandbook of experimental pharmacology · 2021Article
- Drug Screening with Genetically Encoded Fluorescent Sensors: Today and Tomorrow.International journal of molecular sciences · 2020Review
- Myocardial slices come to age: an intermediate complexity in vitro cardiac model for translational research.Cardiovascular research · 2020Review
- Human Induced Pluripotent Stem Cells Derived from a Cardiac Somatic Source: Insights for an In-Vitro Cardiomyocyte Platform.International journal of molecular sciences · 2020Review
- Utility of Zebrafish Models of Acquired and Inherited Long QT Syndrome.Frontiers in physiology · 2020Review
- Investigating the utility of adult zebrafish ex vivo whole hearts to pharmacologically screen hERG channel activator compounds.American journal of physiology. Regulatory, integrative and comparative physiology · 2019Article
- 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
- Stem cell models as anThe Biochemical journal · 2019Review
- Electrophysiological and Pharmacological Characterization of Human Inwardly Rectifying KAssay and drug development technologies · 2019Article
- Development of a Human iPSC Cardiomyocyte-Based Scoring System for Cardiac Hazard Identification in Early Drug Safety De-risking.Stem cell reports · 2018Article
- Reflective lens-free imaging on high-density silicon microelectrode arrays for monitoring and evaluation ofBiomedical optics express · 2018Article
- Cardiac Arrhythmias and Antiarrhythmic Drugs: An Autophagic Perspective.Frontiers in physiology · 2018Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeThe regulatory guidelines (ICHS7B) recommending inhibition of the delayed rectifier K(+) current (I(Kr)), carried by human ether-a-go-go-related gene (hERG) channels in cardiac cells (the hERG test), as a 'first line' test for identifying compounds inducing QT prolongation, have limitations, some of which are outlined here. EXPERIMENTAL APPROACH: hERG current was measured in HEK293 cells, stably transfected with hERG channels; action potential duration (APD) and arrhythmogenic effects were measured in isolated Purkinje fibres and perfused hearts from rabbits. KEY
results576 compounds were screened in the hERG test: 58% were identified as hERG inhibitors, 39% had no effect and 3% were classified as stimulators. Of the hERG inhibitors, 92 were tested in the APD assay: 55.4% of these prolonged APD, 28.3% had no effect and 16.3% shortened APD. Of the 70 compounds without effect on hERG channels, 54.3% did not affect APD, 25.7% prolonged, while 20% significantly shortened APD. Dofetilide (hERG inhibitor; IC(50), 29 nM) prolonged QT and elicited early after-depolarizations and/or torsade de pointes (TdP) in isolated hearts. Mallotoxin and NS1643 (hERG current stimulators at 3 microM), levcromakalim and nicorandil (no effect on hERG current), all significantly shortened APD and QT, and elicited ventricular fibrillation (VF) in isolated hearts. CONCLUSION AND IMPLICATIONS: The hERG assay alone did not adequately identify drugs inducing QT prolongation. It is also important to detect drug-induced QT shortening, as this effect is associated with a potential risk for ventricular tachycardia and VF, the latter being invariably fatal, whereas TdP has an approximately 15-25% incidence of death.
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