Abstract
BackgroundSeveral anti-malarial drugs are associated with adverse cardiovascular effects. These effects may be exacerbated when different anti-malarials are used in combination. There has been no report yet on the potential cardiac effects of the combination artesunate-amodiaquine.MethodsElectrocardiographic (ECG) intervals in Ghanaian children with uncomplicated malaria treated with artesunate-amodiaquine (n=47), were compared with that of children treated with artemether-lumefantrine (n=30). The ECG measurements were repeated one, two, three, seven and 28 days after treatment. The ECG intervals of artesunate-amodiaquine treated subjects were correlated with plasma concentrations of desethylamodiaquine (DEAQ), the main metabolite of amodiaquine.ResultsThe mean ECG intervals were similar in both groups before treatment. After treatment (day 3), ECG intervals changed significantly from baseline in all subjects, but there were no differences between the two treatment groups. A significantly higher proportion of children treated with artesunate-amodiaquine developed sinus bradycardia compared with artemether-lumefantrine treated subjects (7/47 vs 0/30; χ2 p=0.03). Subjects who developed bradycardia were significantly older, and had higher DEAQ concentrations than those who did not develop bradycardia. The proportion of subjects with QTc interval prolongations did not differ significantly between the groups, and no relationship between prolonged QTc intervals and DEAQ levels were observed. No clinically significant rhythm disturbances were observed in any of the subjects.ConclusionArtesunate-amodiaquine treatment resulted in a higher incidence of sinus bradycardia than artemether-lumefantrine treatment in children with uncomplicated malaria, but no clinically significant rhythm disturbances were induced by combining artesunate with amodiaquine. These findings, although reassuring, may imply that non-amodiaquine based artemisinin combination therapy may be preferable for malaria treatment in patients who are otherwise at risk of cardiac effects.
Highlights
Several anti-malarial drugs are associated with adverse cardiovascular effects
Artesunate-amodiaquine combination is an efficacious artemisinin combination therapy (ACT) regimen that has been widely adopted for first-line treatment of uncomplicated malaria in many endemic countries [1,2,3]
The artemisinin derivatives on the other hand, are among the safest anti-malarials known; earlier studies in animals, especially of the oil-soluble derivatives have linked these anti-malarials with cardiac effects, including abnormalities in depolarization [7], or suppression of cardiac conduction [8]. These reported cardiovascular effects of amodiaquine or artemisinin or its derivatives are considered clinically insignificant, but there is the possibility that these effects could be potentiated when these anti-malarials are used in combination: e g, overlapping therapy of mefloquine and halofantrine has been shown to result in a QT interval prolongation greater than that of either drug alone [9,10], and the QT interval prolongation of quinine is enhanced by prior administration of artemetherlumefantrine [11]
Summary
Several anti-malarial drugs are associated with adverse cardiovascular effects. These effects may be exacerbated when different anti-malarials are used in combination. The artemisinin derivatives on the other hand, are among the safest anti-malarials known; earlier studies in animals, especially of the oil-soluble derivatives have linked these anti-malarials with cardiac effects, including abnormalities in depolarization [7], or suppression of cardiac conduction [8] These reported cardiovascular effects of amodiaquine or artemisinin or its derivatives are considered clinically insignificant, but there is the possibility that these effects could be potentiated when these anti-malarials are used in combination: e g, overlapping therapy of mefloquine and halofantrine has been shown to result in a QT interval prolongation greater than that of either drug alone [9,10], and the QT interval prolongation of quinine is enhanced by prior administration of artemetherlumefantrine [11]
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