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DISTURBANCES OF λ-TRIAD ARE MORE PREDICTIVE FOR PROARRHTHMIA THAN QT PROLONGATION: A CASE STUDY OF TERFENADINE

Hondeghem, Luc and Dujardin, Karl and Hoffmann, Peter and Dumotier, Berengere and Stockbridge, N and De Clerck, Frederic (2011) DISTURBANCES OF λ-TRIAD ARE MORE PREDICTIVE FOR PROARRHTHMIA THAN QT PROLONGATION: A CASE STUDY OF TERFENADINE. Journal of Cardiovascular Pharmacology 2011, 57 (5). pp. 589-597. ISSN 0160-2446

Abstract

BACKGROUND – Terfenadine was withdrawn because of proarrhythmia. Its therapeutic anti-histamine concentration is normally below 1 nM, while IKr and INa block have IC50 > 200 nM. Thus, IKr block singly is an unlikely proarrhythmic cause.
METHODS AND RESULTS – Rabbit hearts were perfused with 1-10,000 nM terfenadine for 10-450 min. Terfenadine (1 nM, 450 min) insignificantly shortened APD60; at 10 nM APD60 prolonged 46±11 ms (P < 0.05; n = 6), but 1 hour washout further prolonged APD60. Above 30 nM, APD60 shortening was followed by prolongation (23±7 ms; 300 nM;10 min; P < 0.05; n = 23). In the µM range, APD60 declined and conduction slowed (14±2%; 3 µM; 10 min; P < 0.05; n = 24). Terfenadine disturbed repolarization (TRIaD: triangulation, reverse use depen-dence, instability and dispersion) from 1 to 1000 nM, increasing with concentration (450 min: 1 nM yields 50%, 10 nM 100%) and exposure time (100 nM: 10 min yields 16%, 30 min yields 33%, 90 min 83%). TRIaD with APD prolongation yielded 2 TdP; TRIaD with APD shortening yielded 7 VT and 5 VF.
CONCLUSIONS –In the low nM and µM range TRIaD is accompanied by little change or shortening of APD; in the mid nM range APD shortening is followed by prolongation. TRIaD with APD prolongation preferentially induces TdP, but VT/VF in its absence. In patients ter-fenadine causes normally little QT prolongation and according to FDA records, VT/VF ap-pears indeed the primary tachycardia. Thus, TRIaD predicts proarrhythmia, while QT diffe-rentiates between VT/VF or TdP.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: terfenadine, torsade de pointes (TdP), ventricular tachycardia (VT), ventricular fibrillation (VF)
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2758

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