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Comparison of the acute cardiotoxicity of the antimalarial drug halofantrine in vitro and in vivo in anaesthetized guinea‐pigs
Author(s) -
Batey Andrew J.,
Lightbown Ian D.,
Lambert James P.,
Edwards Geoffrey,
Coker Susan J.
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701402
Subject(s) - halofantrine , qt interval , bolus (digestion) , medicine , bradycardia , pharmacology , effective refractory period , cardiotoxicity , anesthesia , in vivo , heart rate , toxicity , refractory period , blood pressure , biology , chloroquine , mefloquine , microbiology and biotechnology , malaria , immunology
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 effects 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 −1 , i.v.) at 25 min intervals 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 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 μ M after administration of 0.3 mg kg −1 to 2.79±0.87 μ M after 30 mg kg −1 , i.v. There was a significant correlation between the blood concentrations of halofantrine and the changes in QTc interval. 4 In guinea‐pig left papillary muscles the effective refractory period was increased significantly 60 min after addition of halofantrine; from 161±4 to 173±6 ms with 10 μ M , 156±8 to 174±6 ms with 30 μ M and 165±6 to 179±5 ms with 100 μ M halofantrine. However, the vehicle (0.1% Tween 80 in DMSO; final concentration of vehicle in Krebs, 1%) also increased the effective refractory period from 164±5 to 173±6 ms. Similar results were obtained in right ventricular strips but left atrial effective refractory periods were not altered by either the vehicle or halofantrine. 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 prolongation of QTc and consistent observation of AV block with halofantrine in anaesthetized guinea‐pigs suggest that in vivo models may be more useful for further studies investigating the mechanisms underlying the cardiotoxicity of halofantrine.British Journal of Pharmacology (1997) 122 , 563–569; doi: 10.1038/sj.bjp.0701402