Mechanism of cardiotoxicity of halofantrine

被引:60
作者
Wesche, DL
Schuster, BG
Wang, WX
Woosley, RL
机构
[1] Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA
[2] Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Div Expt Therapeut, Washington, DC 20307 USA
关键词
D O I
10.1067/mcp.2000.106127
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Objectives and Methods: 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.
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页码:521 / 529
页数:9
相关论文
共 27 条
[1]  
Akhtar Tasleem, 1994, JPMA (Journal of the Pakistan Medical Association), V44, P120
[2]   ACTIVITY INVITRO OF THE ENANTIOMERS OF HALOFANTRINE [J].
BASCO, LK ;
GILLOTIN, C ;
GIMENEZ, F ;
FARINOTTI, R ;
LEBRAS, J .
TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, 1993, 87 (01) :78-79
[3]   ANTIMALARIAL ACTIVITY INVITRO OF THE N-DESBUTYL DERIVATIVE OF HALOFANTRINE [J].
BASCO, LK ;
GILLOTIN, C ;
GIMENEZ, F ;
FARINOTTI, R ;
LEBRAS, J .
TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, 1992, 86 (01) :12-13
[4]  
CASTOT A, 1993, LANCET, V341, P1541, DOI 10.1016/0140-6736(93)90685-A
[5]   Sex hormones prolong the QT interval and downregulate potassium channel expression in the rabbit heart [J].
Drici, MD ;
Burklow, TR ;
Haridasse, V ;
Glazer, RI ;
Woosley, RL .
CIRCULATION, 1996, 94 (06) :1471-1474
[6]  
Fourcade L, 1995, Med Trop (Mars), V55, P182
[7]   THE DETERMINATION OF THE ENANTIOMERS OF HALOFANTRINE AND MONODESBUTYLHALOFANTRINE IN PLASMA AND WHOLE-BLOOD USING SEQUENTIAL ACHIRAL CHIRAL HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY [J].
GIMENEZ, F ;
AUBRY, AF ;
FARINOTTI, R ;
KIRKLAND, K ;
WAINER, IW .
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, 1992, 10 (2-3) :245-250
[8]   IMPROVED PATCH-CLAMP TECHNIQUES FOR HIGH-RESOLUTION CURRENT RECORDING FROM CELLS AND CELL-FREE MEMBRANE PATCHES [J].
HAMILL, OP ;
MARTY, A ;
NEHER, E ;
SAKMANN, B ;
SIGWORTH, FJ .
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 1981, 391 (02) :85-100
[9]   CARDIAC EFFECT OF HALOFANTRINE [J].
KARBWANG, J ;
BANGCHANG, KN ;
BUNNAG, D ;
HARINASUTA, T ;
LAOTHAVORN, P .
LANCET, 1993, 342 (8869) :501-501
[10]   INTRODUCING MEDWATCH - A NEW APPROACH TO REPORTING MEDICATION AND DEVICE ADVERSE-EFFECTS AND PRODUCT PROBLEMS [J].
KESSLER, DA .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 1993, 269 (21) :2765-2768