COMPARISON OF THE ACUTE CARDIOTOXICITY OF THE ANTIMALARIAL DRUG HALOFANTRINE IN-VITRO AND IN-VIVO IN ANESTHETIZED GUINEA-PIGS

1 Several unrelated drugs have pro-arrhythmic activity associated with an ability to prolong the QT interval of the ECG. The aim of this wor k was to examine the effects of the antimalarial drug halofantrine in vivo and in vitro. 2 In anaesthetized guinea-pigs consecutive bolus do ses of halofantrine (0.3, 1, 3, 10 and 30 mg kg(-1), i.v.) at 25 min i ntervals caused dose-dependent prolongation of the rate corrected QTc interval and bradycardia. The change in heart rate became significant after administration of 10 mg kg(-1) halofantrine (-23+/-9 beats min(- 1)) whereas the increase in QTc was significant with only 1 mg kg(-1) halofantrine (22+/-10 ms). It was only with the highest dose of halofa ntrine that the PR interval was increased (from 52+/-3 to 67+/-4 ms) a nd second degree atrioventricular (AV) block (type 1 Mobitz) occurred in all animals. No changes were observed in any parameters in a separa te group of guinea-pigs which received vehicle (dimethylacetamide 60% propylene glycol 40%) at equivalent time points. 3 The blood concentra tions of halofantrine ranged from 0.26+/-0.17 mu M after administratio n of 0.3 mg kg(-1) to 2.79+/-0.87 mu M after 30 mg kg(-1), i.v. There was a significant correlation between the blood concentrations of halo fantrine and the changes in QTc interval. 4 In guinea-pig left papilla ry muscles the effective refractory period was increased significantly 60 min after addition of halofantrine; from 161+/-4 to 173+/-6 ms wit h 10 mu M, 156+/-8 to 174+/-6 ms with 30 mu M and 165+/-6 to 179+/-5 m s with 100 mu M halofantrine. However, the vehicle (0.1% Tween 80 in D MSO; final concentration of Vehicle in Krebs, 1%) also increased the e ffective refractory period from 164+/-5 to 173+/-6 ms. Similar results were obtained in right ventricular strips but left atrial effective r efractory periods were not altered by either the vehicle or halofantri ne. 5 The results of these experiments suggest that any direct effects that halofantrine may have had on the effective refractory period of cardiac muscle cannot be separated from those of the vehicle. The prol ongation of QTc and consistent observation of AV block with halofantri ne in anaesthetized guineapigs suggest that in vivo models may be more useful for further studies investigating the mechanisms underlying th e cardiotoxicity of halofantrine.