Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines
| Autor: | H R, Lu, E, Vlaminckx, A N, Hermans, J, Rohrbacher, K, Van Ammel, R, Towart, M, Pugsley, D J, Gallacher |
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| Rok vydání: | 2008 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Drug-Related Side Effects and Adverse Reactions K+ channel Action Potentials Guidelines as Topic QT prolongation Models Biological Cell Line Purkinje Fibers action potential duration Torsades de Pointes human ether-a-go-go-related gene short QT Animals Humans hERG cardiovascular diseases ventricular fibrillation Research Papers Cardiovascular and Pulmonary Pharmacology Ether-A-Go-Go Potassium Channels Long QT Syndrome cardiovascular system Tachycardia Ventricular Female Rabbits VF |
| Zdroj: | British Journal of Pharmacology |
| ISSN: | 0007-1188 |
| Popis: | Background and purpose: The regulatory guidelines (ICHS7B) recommending inhibition of the delayed rectifier K+ current (IKr), 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 results: 576 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; IC50, 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 μM), 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 ∼15–25% incidence of death. |
| Databáze: | OpenAIRE |
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