Proarrhythmic potential of halofantrine, terfenadine and clofilium in a modified in vivo model of torsade de pointes.
1. 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. 2. Experiments were performed in pentobarbitone-anaesthetized, open-chest rabbits. Each rabbit received intermittent, rising dose i.v. infusions of the alpha-adrenoceptor agonist phenylephrine. During these infusions rabbits also received increasing i.v. doses of clofilium (20, 60 and 200 nmol kg(-1) min(-1)), terfenadine (75, 250 and 750 nmol kg(-1) min(-1)), halofantrine (6, 20 and 60 micromol kg(-1)) or vehicle. 3. 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. 4. 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. 5. 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.
Batey
Andrew J
AJ
Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street Medical School, Liverpool L69 3GE.
Coker
Susan J
SJ
D000818:Animals; D000962:Antimalarials / Q000009:adverse effects*; D004195:Disease Models, Animal; D004562:Electrocardiography; D006633:Histamine Antagonists / Q000009:adverse effects*; D008297:Male; D010616:Phenanthrenes / Q000009:adverse effects*; D026902:Potassium Channel Blockers / Q000009:adverse effects*; D000644:Quaternary Ammonium Compounds / Q000009:adverse effects*; D011817:Rabbits; D016593:Terfenadine / Q000009:adverse effects*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
D000962:Antimalarials; D006633:Histamine Antagonists; D010616:Phenanthrenes; D026902:Potassium Channel Blockers; D000644:Quaternary Ammonium Compounds; D016593:Terfenadine; C022799:clofilium; C023768:halofantrine