Domperidone: limited benefits with significant risk for sudden cardiac deathLuc M Hondeghem
Department of Pharmacology, Catholic University of Leuven, Leuven, Belgium
J Cardiovasc Pharmacol 61:218-25. 2013
..Domperidone (antinausea/vomiting agent) was recently shown by several groups to increase sudden cardiac death (SCD). Drug-induced disturbances of cardiac repolarization may be a major mechanism...
- Preclinical cardiovascular safety evaluations of biologics: optimizing the approach and follow-up
Luc Hondeghem
Department of Pharmacology, Catholic University Leuven, Belgium
BioDrugs 26:275-82. 2012
..However, because of the potential variability in composition of biologics between production batches and sources, evaluations of such products needs to be performed more frequently than for uniformly produced STA...
Low safety index of domperidone: mechanism for increased odds ratio for sudden cardiac deathLuc M Hondeghem
Dept of Pharmacology, K U Leuven, Leuven, Belgium
Acta Cardiol 66:421-5. 2011
..I therefore tested domperidone for liability of cardiac repolarization disturbances (triangulation, reverse use dependence, instability and dispersion or TRIaD) and induction of arrhythmias...
- Drug-induced QTC prolongation dangerously underestimates proarrhythmic potential: lessons from terfenadine
Luc M Hondeghem
Department of Pharmacology, KU Leuven, Leuven, Belgium
J Cardiovasc Pharmacol 57:589-97. 2011
..Terfenadine's proarrhythmia prompted market withdrawal; therapeutic antihistaminic concentration is less than 1 nM, whereas IC50 of IKr and INa exceed 200 nM...
- Oscillations of cardiac wave length and proarrhythmia
L M Hondeghem
Department of Pharmacology, Catholic University, Leuven, Belgium
Naunyn Schmiedebergs Arch Pharmacol 382:367-76. 2010
..Torsade de pointes can result not only from disturbances of repolarization but also from disturbances of conduction...
- QT prolongation is an unreliable predictor of ventricular arrhythmia
Luc M Hondeghem
Department of Pharmacology, Katholieke Universiteit Leuven, Leuven, Belgium
Heart Rhythm 5:1210-2. 2008
..Cardiac safety is better evaluated in terms of lambda, TRIaD (Triangulation, Reverse use dependence, Instability, and Dispersion), and disturbances of automaticity...
- QT and TdP. QT: an unreliable predictor of proarrhythmia
Luc M Hondeghem
Dept of Pharmacology, KU Leuven, Leuven, Belgium
Acta Cardiol 63:1-7. 2008
..In patients,TRIaD equivalents in the ECG may likewise be more important than QT interval...
- Use and abuse of QT and TRIaD in cardiac safety research: importance of study design and conduct
Luc M Hondeghem
Catholic University Leuven, Westlaan 85, B 8400 Oostende, Belgium
Eur J Pharmacol 584:1-9. 2008
....
- Short patent lives jeopardize drug and patient safety
Luc M Hondeghem
Department of Pharmacology, Catholic University of Leuven, Belgium
J Cardiovasc Pharmacol 50:353-7. 2007
..Therefore, we suggest that the potential benefits of patent life prolongation should be considered, under certain conditions for the sake of patient safety...
- Thorough QT/QTc not so thorough: removes torsadogenic predictors from the T-wave, incriminates safe drugs, and misses profibrillatory drugs
Luc M Hondeghem
Catholic University, Leuven, Belgium
J Cardiovasc Electrophysiol 17:337-40. 2006
..Worse, available evidence suggests that there is more death from drug-induced fibrillation than TdP. Thus, QT prolongation alone is not very useful. Instead, the T-wave should be used in alternate ways: extraction of TRIaD...
- Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic
L M Hondeghem
Department of Pharmacology, Leuven, Belgium
Circulation 103:2004-13. 2001
..Prolongation of action potential duration (APD) is considered a major antiarrhythmic mechanism (class 2I), but paradoxically, it frequently is also proarrhythmic (torsade de pointes)...
- Phase 2 prolongation, in the absence of instability and triangulation, antagonizes class III proarrhythmia
L M Hondeghem
Department of Pharmacology, K U L, Leuven B 3000, Belgium
Cardiovasc Res 50:345-53. 2001
..To evaluate whether prolongation of the plateau of the action potential duration, in the absence of instability and triangulation, can reverse the proarrhythmia elicited by a class III antiarrhythmic agent...
- Detection of proarrhythmia in the female rabbit heart: blinded validation
Luc M Hondeghem
Department of Pharmacology, K U Leuven, Leuven, Belgium
J Cardiovasc Electrophysiol 14:287-94. 2003
..Reliable detection of drug-induced proarrhythmia, especially the potential for polymorphic ventricular tachycardia, is of great importance in the development of new compounds that are safe for the heart and was evaluated in a blinded study...
- Blinded test in isolated female rabbit heart reliably identifies action potential duration prolongation and proarrhythmic drugs: importance of triangulation, reverse use dependence, and instability
Luc M Hondeghem
Department of Pharmacology, Catholic University of Leuven, Leuven, Belgium
J Cardiovasc Pharmacol 41:14-24. 2003
..Thus, the isolated perfused rabbit heart can be a valuable tool in a preclinical proarrhythmia test battery in drug development...
- Relative contributions of TRIaD and QT to proarrhythmia
Luc M Hondeghem
J Cardiovasc Electrophysiol 18:655-7. 2007
- TRIad: foundation for proarrhythmia (triangulation, reverse use dependence and instability)
Luc M Hondeghem
Novartis Found Symp 266:235-44; discussion 244-50. 2005
..It is concluded that proarrhythmic characteristics of drugs can readily be recognized and that hope exists for an effective and safe class III antiarrhythmic agent after all...
- Refining detection of drug-induced proarrhythmia: QT interval and TRIaD
Rashmi R Shah
Medicines and Healthcare products Regulatory Agency, London, UK
Heart Rhythm 2:758-72. 2005
..Detecting drug-induced augmentation of TRIaD may offer an additional, more sensitive, and accurate indicator of the broader proarrhythmic potential of a drug than may QT interval prolongation alone...
