Effects of anti-malarial drugs on the electrocardiographic QT interval modelled in the isolated perfused guinea pig heart system

Malaria Journal

Research

Atsushi Kinoshita¹  Harumi Yamada²  Hajime Kotaki²  Mikio Kimura³ 

[1] Division of Drug Informatics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 7-2-1 Kamiono, 670-8524, Himeji, Hyogo, Japan;School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, 324-8501, Ootawara, Tochigi, Japan;Shin-Yamanote Hospital, Japan Anti-Tuberculosis Association, 3-6-1 Suwa-cho, 189-0021, Higashi-Murayama, Tokyo, Japan;

关键词: Malaria;    Quinidine;    Quinine;    Mefloquine;    Cerebral Malaria;   

DOI  :  10.1186/1475-2875-9-318

 received in 2010-05-19, accepted in 2010-11-10,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundConcern 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.MethodsThe 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.ResultsQuinidine, 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.ConclusionsIn 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.

【 授权许可】

CC BY   
© Kinoshita et al; licensee BioMed Central Ltd. 2010