1 This study was designed to compare the proarrhythmic activity of the antimalarial drug, halofantrine and the antihistamine, terfenadine, with that of clo®lium a K + channel blocking drug that can induce torsade de pointes. 3 Clo®lium 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 eects resulting in death of most rabbits. 4 The total number of ventricular premature beats was highest in the clo®lium group. Torsade de pointes occurred in 6 out of 8 clo®lium-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 clo®lium, halofantrine can cause torsade de pointes in a modi®ed anaesthetized rabbit model whereas the primary adverse eect of terfenadine was cardiac contractile failure.

1 To examine the possible cardiotoxicity of the antimalarial drug me¯oquine, increasing doses (0.3 ± 30 mg kg 71 ) were given i.v. to anaesthetized guinea-pigs. Me¯oquine did not alter ECG intervals signi®cantly but gradually increased systolic blood pressure (at 3 mg kg 71 ) then had a depressor e ect (at 10 mg kg 71 ). Death due to profound hypotension, probably resulting from cardiac contractile failure or AV block, occurred after either 10 mg kg 71 (2/6) or 30 mg kg 71 (4/6) me¯oquine. 2 In isolated cardiac preparations me¯oquine (3 ± 100 mM) did not alter the e ective refractory period but at the higher concentrations resting tension increased. Developed tension was reduced by 100 mM me¯oquine in left atria (from 5.8+1.7 to 2.2+0.4 mN) whereas in papillary muscles although 30 mM me¯oquine reduced developed tension (from 2.6+0.5 to 1.1+0.1 mN) subsequent addition of 100 mM caused a marked, but not sustained, positive inotropic e ect (from 1.2+0.1 to 3.8+0.8 mN). 3 In single ventricular myocytes, me¯oquine (10 mM) shortened action potential duration (e.g. APD 90 from 285+29 to 141+12 ms) and reduced the amplitude of the systolic Ca 2+ transient. These e ects were accompanied by a decrease in the L-type Ca 2+ current. 4 These results indicate that the main adverse e ect of me¯oquine on the heart is a negative inotropic action. This action can be explained by blockade of L-type Ca 2+ channels.

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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.