Effects of anti-malarial drugs on the electrocardiographic QT interval modelled in the isolated perfused guinea pig heart system.
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.
Division of Drug Informatics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 7-2-1 Kamiono, Himeji, Hyogo, 670-8524 Japan. atsushi@himeji-du.ac.jp
Atsushi
A
Kinoshita
Harumi
H
Yamada
Hajime
H
Kotaki
Mikio
M
Kimura
D000818:Animals; D000962:Antimalarials / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D006329:Heart Conduction System / Q000187:drug effects* / Q000502:physiology*; D015767:Mefloquine / Q000009:adverse effects; D010616:Phenanthrenes / Q000009:adverse effects; D011802:Quinidine / Q000009:adverse effects; D011803:Quinine / Q000009:adverse effects; D013997:Time Factors
D000962:Antimalarials; D010616:Phenanthrenes; D011803:Quinine; D011802:Quinidine; C023768:halofantrine; D015767:Mefloquine