File(s) not publicly available
Drug-induced hERG Block and Long QT Syndrome
Drug-induced long QT syndrome is a cardiac safety issue that all drugs seeking approval must currently address, in part via in vitro electrophysiological testing of the drug's effects on the function of the human Ether-a-go-go Related Gene (hERG) potassium channel. This regulatory strategy has also been scientifically successful, in that these in vitro assays are cheaper and faster than are many other surrogates for arrhythmogenic risk, including QT prolongation in humans and action potential prolongation in cardiomyocytes. In some ways hERG assays are also more sensitive to the underlying repolarization anomalies that lead to the risk of the Torsades de pointes arrhythmia. In addition, the higher throughput of hERG assays combined with advances in our understanding of the molecular structures underlying this pathophysiology have led to new approaches in the medicinal chemistry of "designing out" hERG liability from lead compounds. While generally effectual, hERG screening produces some false positives: drugs with an apparent liability that are known not to be clinically arrhythmogenic. New technologies continue to be developed to improve hERG screening, while further insights into the molecular pharmacology of hERG and cardiac repolarization are providing avenues to mitigate and make sense of the lack of torsadogenic specificity in extant hERG assays.
History
Publication status
- Published
Journal
Cardiovascular TherapeuticsISSN
1755-5914Publisher
Blackwell PublishingExternal DOI
Issue
4Volume
29Page range
251-259Department affiliated with
- Clinical and Experimental Medicine Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2011-08-23Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC