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Proarrhythmic potential of halofantrine, terfenadine and clofilium in an in vivo model of torsade de pointes

Batey, Andrew.J. and Coker, Susan J. (2002) Proarrhythmic potential of halofantrine, terfenadine and clofilium in an in vivo model of torsade de pointes. British Journal of Pharmacology, 135 (4). pp. 1003-1012. ISSN 0007-1188

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Abstract

This study was designed to compare the proarrhythmic activity of the antimalarial drug, halofantrine and the antihistamine, terfenadine, with that of clofilium a K+ channel blocking drug that can induce torsade de pointes. Experiments were performed in pentobarbitone-anaesthetized, open-chest rabbits. Each rabbit received intermittent, rising dose i.v. infusions of the α-adrenoceptor agonist phenylephrine. During these infusions rabbits also received increasing i.v. doses of clofilium (20, 60 and 200nmolkg−1 min−1), terfenadine (75, 250 and 750nmolkg−1min−1), halofantrine (6, 20 and 60μmolkg−1) or vehicle. Clofilium and halofantrine caused dose-dependent increases in the rate-corrected QT interval (QTc), whereas terfenadine prolonged PR and QRS intervals rather than prolonging cardiac repolarization. Progressive bradycardia occurred in all groups. After administration of the highest dose of each drug halofantrine caused a modest decrease in blood pressure, but terfenadine had profound hypotensive effects resulting in death of most rabbits. The total number of ventricular premature beats was highest in the clofilium group. Torsade de pointes occurred in 6 out of 8 clofilium-treated rabbits and 4 out of 6 of those which received halofantrine, but was not seen in any of the seven terfenadine-treated rabbits. These results show that, like clofilium, halofantrine can cause torsade de pointes in a modified anaesthetized rabbit model whereas the primary adverse effect of terfenadine was cardiac contractile failure. Keywords: Torsade de pointes, QT prolongation, halofantrine,

Item type: Article
ID code: 10482
Keywords: torsade de pointes, ECG intervals, α-agonist, , clofilium, terfenadine, halofantrine, , QT prolongation, Pharmacy and materia medica, Pharmacology
Subjects: Medicine > Pharmacy and materia medica
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
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    Depositing user: Strathprints Administrator
    Date Deposited: 03 Oct 2011 11:03
    Last modified: 04 Sep 2014 19:57
    URI: http://strathprints.strath.ac.uk/id/eprint/10482

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