Millipore Technical Publications |
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Beyond hERG: The Role of Ion Channel Profiling in Cardiac Safety Assessment | ||
| Lit No: | TB1787EN00 | |
| Year: | 2008 | |
| Safety assessment has long been a critical step during drug development. Yet, cardiac safety issues have received heightened emphasis recently due to a growing awareness that non cardiovascular drugs can carry a potential risk of rare but life threatening arrhythmias. This has resulted in relabeling or withdrawal of major drugs, such as terfenadine, astemizole, grepafloxin and cisapride. The risk arises from the discovery that drugs spanning a range of therapeutic indications, molecular targets and structural classes can induce a particular form of ventricular tachyarrhythmia known as torsades de pointes (TdP). This is characterized in the electrocardiogram (ECG) by a lengthened QT interval followed by a “twisting” of the waveform around the isoelectric line. Drug-induced TdP can revert spontaneously without serious symptoms, but it can also cause syncope or degenerate into ventricular fibrillation and cause sudden death. This phenomenon had previously been recognized in a very rare inherited condition, known as long QT Syndrome (LQTS), which is caused by mutations in any of a number of different genes that predominantly encode ion channels. At a cellular level, the prolonged QT interval results from lengthening of the action potential in ventricular myocytes, which at a molecular level (as indicated by LQT mutations), can be caused by functional modulation of a number of the ion channels that mediate this. To date, the vast majority of clinical cases of drug induced (or acquired) LQTS have been found to be due to blockade of the hERG channel (human ether-a-go-go related gene). This underlies the rapid delayed rectifier potassium current (IKr) that has a major role in terminating the plateau phase of the action potential. Although the events leading to TdP and sudden death have been established, the mechanistic links between these processes are not well understood. As more and more examples of drug-induced TdP are uncovered, it is apparent that the correlations of hERG blockade with QT prolongation and TdP are imperfect, and other risk factors are important. Thus, the development and interpretation of definitive assays for predicting pro-arrhythmic risk remain problematic. Click the pdf for the entire document. |
