Comparison of the acute cardiotoxicity of the antimalarial drug halofantrine in vitro and in vivo in anaesthetized guinea‐pigs

Abstract

1 Several unrelated drugs have pro-arrhythmic activity associated with an ability to prolong the QT interval of the ECG. The aim of this work was to examine the eects of the antimalarial drug halofantrine in vivo and in vitro. 2 In anaesthetized guinea-pigs consecutive bolus doses of halofantrine (0.3, 1, 3, 10 and 30 mg kg 71 , i.v.) at 25 min intervals caused dose-dependent prolongation of the rate corrected QTc interval and bradycardia. The change in heart rate became signi®cant after administration of 10 mg kg 71 halofantrine (723+9 beats min 71 ) whereas the increase in QTc was signi®cant with only 1 mg kg 71 halofantrine (22+10 ms). It was only with the highest dose of halofantrine that the PR interval was increased (from 52+3 to 67+4 ms) and second degree atrioventricular (AV) block (type 1 Mobitz) occurred in all animals. No changes were observed in any parameters in a separate group of guinea-pigs which received vehicle (dimethylacetamide 60% propylene glycol 40%) at equivalent time points.3 The blood concentrations of halofantrine ranged from 0.26+0.17 mM after administration of 0.3 mg kg 71 to 2.79+0.87 mM after 30 mg kg 71, i.v. There was a signi®cant correlation between the blood concentrations of halofantrine and the changes in QTc interval. 4 In guinea-pig left papillary muscles the eective refractory period was increased signi®cantly 60 min after addition of halofantrine; from 161+4 to 173+6 ms with 10 mM, 156+8 to 174+6 ms with 30 mM and 165+6 to 179+5 ms with 100 mM halofantrine. However, the vehicle (0.1% Tween 80 in DMSO; ®nal concentration of vehicle in Krebs, 1%) also increased the eective refractory period from 164+5 to 173+6 ms. Similar results were obtained in right ventricular strips but left atrial eective refractory periods were not altered by either the vehicle or halofantrine. 5 The results of these experiments suggest that any direct eects that halofantrine may have had on the eective refractory period of cardiac muscle cannot be separated from those of the vehicle. The prolongation of QTc and consistent observation of AV block with halofantrine in anaesthetized guineapigs suggest that in vivo models may be more useful for further studies investigating the mechanisms underlying the cardiotoxicity of halofantrine.

Cardiotoxicity reduction induced by halofantrine entrapped in nanocapsule devices

“…Its ability to induce a QT interval prolongation has already been reported in anaesthetized guinea-pigs and rabbits (Batey et al, 1997;Lightbown et al, 2001). The mechanism of cardiotoxicity of the Hf is particularly based on the potassium channel inhibition (Wesche et al, 2000), responsible for potential action repolarization onset which determines the QT interval (Crumb and Cavero, 1999).…”

“…It is extremely lipophilic and, although it can be dissolved in the solvent system used to prepare the parenteral formulation (Krishna et al, 1993), it will not remain in solution upon dilution with physiological salt solutions (Batey et al, 1997). Krishna used dimethylacetamide-polyethyleneglycol (40:60 v/v) diluted in 5% w/v dextrose; however, local toxicity was a significant problem after IV infusion and this solution had to be prepared extemporaneously due the rapid precipitation of the drug.…”

“…In populations with multi-drug-resistance, an IV formulation of halofantrine would be a useful alternative to treat severe Life Sciences 80 (2007) 1327 -1334 www.elsevier.com/locate/lifescie malaria because it acts rapidly against blood erythrocytic stages of Plasmodium (Bryson and Goa, 1992). However, halofantrine exhibits low bioavailability by the oral route and has a potential arrhythmogenic effect, leading to a prolongation of the QT interval in the electrocardiogram (ECG), as demonstrated in humans (Krishna et al, 1993;Matson et al, 1996;Olivier et al, 1999;Abernethy et al, 2001) and other mammals (Batey et al, 1997;Lightbown et al, 2001). The QT interval prolongation is associated with episodes of torsade de pointes (Crumb and Cavero, 1999), severe ventricular arrhythmia, and sudden death in patients treated with Hf .…”

Piperaquine Population Pharmacokinetics and Cardiac Safety in Cambodia

“…A number of antimalarials have known QT interval-prolonging effects as well as present a clinical risk for polymorphic ventricular tachycardia, known as torsades de pointes (TdP). Drugs in the amino alcohol class generally have the highest risk, with quinidine (QND), quinine (QN), and, particularly, halofantrine (HF) having significant dose-dependent cardiotoxicities (QND [tmt] QN Ϸ HF) in in vitro studies (18,19) and in vivo animal models (20). HF was also found to potentiate the QT interval prolongation induced by mefloquine, which is not known to be toxic on its own in an animal model (21).…”

Proarrhythmic Potential of Antimicrobial Agents

“…In anaesthetized guinea-pigs iv.-administered consecutive bolus doses of halofantrine caused dose-dependent prolongation of the QT c interval and bradycardia. The change in heart rate became significant after administration of 10 mg/kg halofantrine, whereas the increase in QT c was significant with only 1 mg/kg halofantrine [67]. In anaesthetized rabbits increasing iv doses of halofantrine caused dose-dependent prolongation of the QT c interval with progressive bradycardia.…”