Document Detail


Does terfenadine-induced ventricular tachycardia/fibrillation directly relate to its QT prolongation and Torsades de Pointes?
MedLine Citation:
PMID:  22300168     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Terfenadine has been reported to cause cardiac death. Hence, we investigated its pro-arrhythmic potential in various in vitro models.
EXPERIMENTAL APPROACH: Pro-arrhythmic effects of terfenadine were investigated in rabbit isolated hearts and left ventricular wedge preparations. Also, using whole-cell patch-clamp recording, we examined its effect on the human ether-à-go-go-related gene (hERG) current in HEK293 cells transfected with hERG and on the I(Na) current in rabbit ventricular cells and human atrial myocytes.
KEY RESULTS: Terfenadine concentration- and use-dependently inhibited I(Na) in rabbit myocytes and in human atrial myocytes and also inhibited the hERG. In both the rabbit left ventricular wedge and heart preparations, terfenadine at 1 µM only slightly prolonged the QT- and JT-intervals but at 10 µM, it caused a marked widening of the QRS complex, cardiac wavelength shortening, incidences of in-excitability and non-TdP-like ventricular tachycardia/fibrillation (VT/VF) without prolongation of the QT/JT-interval. At 10 µM terfenadine elicited a lower incidence of early afterdepolarizations versus non- Torsades de Pointes (TdP)-like VT/VF (100% incidence), and did not induce TdPs. Although the concentration of terfenadine in the tissue-bath was low, it accumulated within the heart tissue.
CONCLUSION AND IMPLICATIONS: Our data suggest that: (i) the induction of non-TdP-like VT/VF, which is caused by slowing of conduction via blockade of I(Na) (like Class Ic flecainide), may constitute a more important risk for terfenadine-induced cardiac death; (ii) although terfenadine is a potent hERG blocker, the risk for non-TdP-like VT/VF exceeds the risk for TdPs; and (iii) cardiac wavelength (λ) could serve as a biomarker to predict terfenadine-induced VT/VF.
Authors:
Hua Rong Lu; An N Hermans; David J Gallacher
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  British journal of pharmacology     Volume:  166     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-18     Completed Date:  2012-10-09     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1490-502     Citation Subset:  IM    
Copyright Information:
© 2012 Janssen Pharmaceutica NV. British Journal of Pharmacology © 2012 The British Pharmacological Society.
Affiliation:
Center of Excellence for Cardiovascular Safety Research and Mechanistic Pharmacology, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium. hlu@its.jnj.com
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MeSH Terms
Descriptor/Qualifier:
Action Potentials / drug effects
Animals
Anti-Arrhythmia Agents / adverse effects,  metabolism,  pharmacology
Atrial Appendage / cytology,  drug effects,  metabolism
Biological Transport
Cells, Cultured
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors,  genetics,  metabolism
Female
HEK293 Cells
Heart Ventricles / cytology,  drug effects,  metabolism
Histamine H1 Antagonists, Non-Sedating / adverse effects,  metabolism,  pharmacology*
Humans
Long QT Syndrome / chemically induced*,  metabolism,  physiopathology
Myocytes, Cardiac / cytology,  drug effects*,  metabolism
Osmolar Concentration
Rabbits
Recombinant Proteins / antagonists & inhibitors,  metabolism
Sodium Channel Blockers / adverse effects,  metabolism,  pharmacology
Tachycardia, Ventricular / etiology*
Terfenadine / adverse effects,  metabolism,  pharmacology*
Torsades de Pointes / chemically induced*,  metabolism,  physiopathology
Ventricular Fibrillation / etiology*
Chemical
Reg. No./Substance:
0/Anti-Arrhythmia Agents; 0/Ether-A-Go-Go Potassium Channels; 0/Histamine H1 Antagonists, Non-Sedating; 0/Recombinant Proteins; 0/Sodium Channel Blockers; 50679-08-8/Terfenadine
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