Cargando…

Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines

BACKGROUND AND PURPOSE: The 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 prolongati...

Descripción completa

Detalles Bibliográficos
Autores principales: Lu, H R, Vlaminckx, E, Hermans, A N, Rohrbacher, J, Van Ammel, K, Towart, R, Pugsley, M, Gallacher, D J
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440085/
https://www.ncbi.nlm.nih.gov/pubmed/18493243
http://dx.doi.org/10.1038/bjp.2008.191
_version_ 1782156530664079360
author Lu, H R
Vlaminckx, E
Hermans, A N
Rohrbacher, J
Van Ammel, K
Towart, R
Pugsley, M
Gallacher, D J
author_facet Lu, H R
Vlaminckx, E
Hermans, A N
Rohrbacher, J
Van Ammel, K
Towart, R
Pugsley, M
Gallacher, D J
author_sort Lu, H R
collection PubMed
description BACKGROUND AND PURPOSE: The 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 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; 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 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.
format Text
id pubmed-2440085
institution National Center for Biotechnology Information
language English
publishDate 2008
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-24400852008-06-27 Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines Lu, H R Vlaminckx, E Hermans, A N Rohrbacher, J Van Ammel, K Towart, R Pugsley, M Gallacher, D J Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: The 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 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; 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 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. Nature Publishing Group 2008-05-19 2008-08 /pmc/articles/PMC2440085/ /pubmed/18493243 http://dx.doi.org/10.1038/bjp.2008.191 Text en Copyright 2008, Nature Publishing Group http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/.
spellingShingle Research Papers
Lu, H R
Vlaminckx, E
Hermans, A N
Rohrbacher, J
Van Ammel, K
Towart, R
Pugsley, M
Gallacher, D J
Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines
title Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines
title_full Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines
title_fullStr Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines
title_full_unstemmed Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines
title_short Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines
title_sort predicting drug-induced changes in qt interval and arrhythmias: qt-shortening drugs point to gaps in the ichs7b guidelines
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440085/
https://www.ncbi.nlm.nih.gov/pubmed/18493243
http://dx.doi.org/10.1038/bjp.2008.191
work_keys_str_mv AT luhr predictingdruginducedchangesinqtintervalandarrhythmiasqtshorteningdrugspointtogapsintheichs7bguidelines
AT vlaminckxe predictingdruginducedchangesinqtintervalandarrhythmiasqtshorteningdrugspointtogapsintheichs7bguidelines
AT hermansan predictingdruginducedchangesinqtintervalandarrhythmiasqtshorteningdrugspointtogapsintheichs7bguidelines
AT rohrbacherj predictingdruginducedchangesinqtintervalandarrhythmiasqtshorteningdrugspointtogapsintheichs7bguidelines
AT vanammelk predictingdruginducedchangesinqtintervalandarrhythmiasqtshorteningdrugspointtogapsintheichs7bguidelines
AT towartr predictingdruginducedchangesinqtintervalandarrhythmiasqtshorteningdrugspointtogapsintheichs7bguidelines
AT pugsleym predictingdruginducedchangesinqtintervalandarrhythmiasqtshorteningdrugspointtogapsintheichs7bguidelines
AT gallacherdj predictingdruginducedchangesinqtintervalandarrhythmiasqtshorteningdrugspointtogapsintheichs7bguidelines