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QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development.
Med Res Rev. 2005 Mar; 25(2):133-66.MR

Abstract

Prolongation of the QT interval of the electrocardiogram is a typical effect of Class III antiarrhythmic drugs, achieved through blockade of potassium channels. In the past decade, evidence has accrued that several classes of drugs used for non-cardiovascular indications may prolong the QT interval with the same mechanism (namely, human ether-a-go-go-related gene (hERG) K(+) channel blockade). The great interest in QT prolongation is because of several reasons. First, drug-induced QT prolongation increases the likelihood of a polymorphous ventricular arrhythmia (namely, torsades de pointes, TdP), which may cause syncope and degenerate into ventricular fibrillation and sudden death. Second, the fact that several classes of drugs, such as antihistamines, fluoroquinolones, macrolides, and neuroleptics may cause the long QT syndrome (LQTS) raises the question whether this is a class effect (e.g., shared by all agents of a given pharmacological class) or a specific effect of single agents within a class. There is now consensus that, in most cases, only a few agents within a therapeutic class share the ability to significantly affect hERG K(+) channels. These compounds should be identified as early as possible during drug development. Third, QT prolongation and interaction with hERG K(+) channels have become surrogate markers of cardiotoxicity and have received increasing regulatory attention. This review briefly outlines the mechanisms leading to QT prolongation and the different strategies that can be followed to predict this unwanted effect. In particular, it will focus on the approaches recently proposed for the in silico screening of new compounds.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, Via Belmeloro 6, University of Bologna, I-40126 Bologna, Italy. maurizio.recanatini@unibo.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

15389727

Citation

Recanatini, Maurizio, et al. "QT Prolongation Through hERG K(+) Channel Blockade: Current Knowledge and Strategies for the Early Prediction During Drug Development." Medicinal Research Reviews, vol. 25, no. 2, 2005, pp. 133-66.
Recanatini M, Poluzzi E, Masetti M, et al. QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development. Med Res Rev. 2005;25(2):133-66.
Recanatini, M., Poluzzi, E., Masetti, M., Cavalli, A., & De Ponti, F. (2005). QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development. Medicinal Research Reviews, 25(2), 133-66.
Recanatini M, et al. QT Prolongation Through hERG K(+) Channel Blockade: Current Knowledge and Strategies for the Early Prediction During Drug Development. Med Res Rev. 2005;25(2):133-66. PubMed PMID: 15389727.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development. AU - Recanatini,Maurizio, AU - Poluzzi,Elisabetta, AU - Masetti,Matteo, AU - Cavalli,Andrea, AU - De Ponti,Fabrizio, PY - 2004/9/25/pubmed PY - 2005/6/4/medline PY - 2004/9/25/entrez SP - 133 EP - 66 JF - Medicinal research reviews JO - Med Res Rev VL - 25 IS - 2 N2 - Prolongation of the QT interval of the electrocardiogram is a typical effect of Class III antiarrhythmic drugs, achieved through blockade of potassium channels. In the past decade, evidence has accrued that several classes of drugs used for non-cardiovascular indications may prolong the QT interval with the same mechanism (namely, human ether-a-go-go-related gene (hERG) K(+) channel blockade). The great interest in QT prolongation is because of several reasons. First, drug-induced QT prolongation increases the likelihood of a polymorphous ventricular arrhythmia (namely, torsades de pointes, TdP), which may cause syncope and degenerate into ventricular fibrillation and sudden death. Second, the fact that several classes of drugs, such as antihistamines, fluoroquinolones, macrolides, and neuroleptics may cause the long QT syndrome (LQTS) raises the question whether this is a class effect (e.g., shared by all agents of a given pharmacological class) or a specific effect of single agents within a class. There is now consensus that, in most cases, only a few agents within a therapeutic class share the ability to significantly affect hERG K(+) channels. These compounds should be identified as early as possible during drug development. Third, QT prolongation and interaction with hERG K(+) channels have become surrogate markers of cardiotoxicity and have received increasing regulatory attention. This review briefly outlines the mechanisms leading to QT prolongation and the different strategies that can be followed to predict this unwanted effect. In particular, it will focus on the approaches recently proposed for the in silico screening of new compounds. SN - 0198-6325 UR - https://www.unboundmedicine.com/medline/citation/15389727/QT_prolongation_through_hERG_K_+__channel_blockade:_current_knowledge_and_strategies_for_the_early_prediction_during_drug_development_ L2 - https://doi.org/10.1002/med.20019 DB - PRIME DP - Unbound Medicine ER -