Acquired QT interval prolongation and HERG: implications for drug discovery and development |
| |
Authors: | Finlayson Keith Witchel Harry J McCulloch James Sharkey John |
| |
Institution: | aFujisawa Institute of Neuroscience in Edinburgh, University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, UK bCardiovascular Research Laboratories, Department of Physiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK |
| |
Abstract: | Putative interactions between the Human Ether-a-go-go Related Gene (HERG), QT interval prolongation and Torsades de Pointes (TdP) are now integral components of any discussion on drug safety. HERG encodes for the inwardly rectifying potassium channel (IKr), which is essential to the maintenance of normal cardiac function. HERG channel mutations are responsible for one form of familial long QT syndrome, a potentially deadly inherited cardiac disorder associated with TdP. Moreover, drug-induced (acquired) QT interval prolongation has been associated with an increase in the incidence of sudden unexplained deaths, with HERG inhibition implicated as the underlying cause. Subsequently, a number of non-cardiovascular drugs which induce QT interval prolongation and/or TdP have been withdrawn. However, a definitive link between HERG, QT interval prolongation and arrhythmogenesis has not been established. Nevertheless, this area is subject to ever increasing regulatory scrutiny. Here we review the relationship between HERG, long QT syndrome and TdP, together with a summary of the associated regulatory issues, and developments in pre-clinical screening. |
| |
Keywords: | Long QT syndrome Iatrogenic disease HERG protein Torsades de Pointes Drug discovery High-throughput screening |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|