title: Mechanism of cardiotoxicity of halofantrine.
abstract: OBJECTIVE
  To further evaluate the scope and mechanism of potential cardiotoxicity associated with the antimalarial drug halofantrine, case reports submitted to the US Food and Drug Administration Spontaneous Reporting System were examined. Because halofantrine was associated with electrocardiographic prolongation of the QT interval and ventricular arrhythmias, in vitro cardiac electrophysiologic studies (isolated perfused cardiac model and isolated ventricular myocytes) were conducted to test the hypothesis that halofantrine or its metabolite is responsible for cardiotoxicity.
  
  
  RESULTS
  Although it is difficult to ascertain causality and to estimate overall incidence, a significant number of adverse events related to the cardiovascular system were reported, including QT interval prolongation, life-threatening arrhythmias, and sudden death. The effect of halofantrine and its active metabolite (N-desbutylhalofantrine) on repolarization were examined in an isolated perfused heart model. Results indicate that halofantrine was able to prolong the QT interval, whereas N-desbutylhalofantrine had minimal effect on the QT interval relative to baseline. In an attempt to further elucidate the mechanism of QT interval prolongation, the effects of racemic halofantrine, its stereoisomers, and N-desbutylhalofantrine on repolarizing currents in isolated ventricular myocytes were studied with use of patch-clamp techniques. Halofantrine produced a stereoselective block of the delayed rectifier potassium channel in isolated feline myocytes.
  
  
  CONCLUSIONS
  These results indicate that halofantrine is similar to quinidine and class III antiarrhythmics in its ability to prolong repolarization. We conclude that high plasma concentrations of halofantrine should be avoided, especially in women, and that N-desbutylhalofantrine may have potential as a safer antimalarial drug.
authors.affiliation: Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20007-2195, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Wesche
authors.forename: B G
authors.initials: BG
authors.lastname: Schuster
authors.forename: W X
authors.initials: WX
authors.lastname: Wang
authors.forename: R L
authors.initials: RL
authors.lastname: Woosley
mesh_terms: D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000818:Animals; D000962:Antimalarials / Q000009:adverse effects*; D002318:Cardiovascular Diseases / Q000139:chemically induced; D002415:Cats; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000166:cytology*; D010616:Phenanthrenes / Q000009:adverse effects*
chemical_list: D000962:Antimalarials; D010616:Phenanthrenes; C044961:1,3-dichloro-6-trifluoromethyl-9-phenanthryl-3-(n-butyl)aminopropanol; C023768:halofantrine