Key result
Quinidine, quinine, and halofantrine dose-dependently prolong QaTc intervals, whereas mefloquine shows no effect.
Why the study?
Concern over cardiotoxicity of anti-malarial drugs causing QT interval prolongation led to withdrawal of halofantrine and motivated evaluation of other drugs' effects on QT interval.
Effect estimate: EC50: quinidine 0.49 μM, quinine 1.68 μM, halofantrine 1.59 μM
In an isolated perfused guinea pig heart model, quinidine, quinine, and halofantrine demonstrated dose-dependent QT prolongation, whereas mefloquine did not.
BACKGROUND: Concern over the potential cardiotoxicity of anti-malarial drugs inducing a prolonged electrocardiographic QT interval has resulted in the almost complete withdrawal from the market of one anti-malarial drug - halofantrine. The effects on the QT interval of four anti-malarial drugs were examined, using the guinea pig heart. METHODS: The guinea pig heart was isolated, mounted on a Langendorff apparatus, and was then perfused with pyruvate-added Klebs-Henseleit solutions containing graded concentrations of the four agents such as quinidine (0.15 - 1.2 μM), quinine (0.3 - 2.4 μM), halofantrine (0.1 - 2.0 μM) and mefloquine (0.1 - 2.0 μM). The heart rate-corrected QaTc intervals were measured to evaluate drug-induced QT prolongation effects. RESULTS: Quinidine, quinine, and halofantrine prolonged the QaTc interval in a dose-dependent manner, whereas no such effect was found with mefloquine. The EC50 values for the QaTc prolongation effects, the concentration that gives a half-maximum effect, were quinidine < quinine ≈ halofantrine. CONCLUSIONS: In this study, an isolated, perfused guinea pig heart system was constructed to assess the cardiotoxic potential of anti-malarial drugs. This isolated perfused guinea pig heart system could be used to test newly developed anti-malarial drugs for their inherent QT lengthening potential. More information is required on the potential variation in unbound drug concentrations in humans, and their role in cardiotoxicity.
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Kinoshita et al. (2010) studied Cardiotoxicity (QT prolongation). Anti-malarial drugs (quinidine, quinine, halofantrine, mefloquine) vs. Drug-free control solution was evaluated on QaTc interval prolongation (EC50) (EC50: quinidine 0.49 μM, quinine 1.68 μM, halofantrine 1.59 μM). Quinidine, quinine, and halofantrine prolonged the QaTc interval in a dose-dependent manner with EC50 values of 0.49 μM, 1.68 μM, and 1.59 μM respectively, whereas mefloquine had no such effect.
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