Malaria remains one of the most important and widespread diseases in the world. Chloroquine is the drug of choice for treatment of malaria. Increased resistance of P. falciparum to chloroquine has made the discovery of alternative therapies a high priority. These efforts have resulted in the development of halofantrine as an antimalarial drug. However, chloroquine and halofantrine slow ventricular conduction velocity and prolong the QTc interval. The mechanisms of these adverse effects are unknown, but our preliminary data suggest that impaired conduction results from block of Na+ current, whereas the prolonged QTc interval is caused by block of specific K+ currents that mediate ventricular repolarization. Mefloquine is another new antimalarial drug that has not been extensively studied, but may also have similar unwanted side effects. We propose to define the cellular mechanisms responsible for the cardiac effects of these antimalarial drugs.
The specific aims are to: 1) characterize the effects of antimalarial drugs on action potentials in feline ventricular myocytes; 2) characterize the effects of antimalarial drugs on inward sodium current and outward K+ currents in feline ventricular myocytes; and 3) determine the mechanism of block by antimalarial drugs of cloned human K+ channels (HERG, KvLQT1/minK, HIRK1) expressed in Xenopus oocytes. These studies will define the cellular and molecular mechanisms of slowed conduction and prolonged QTc interval by these widely used drugs, and provide baseline data to evaluate the potential adverse cardiac effects of new antimalarial drugs.
| Sanchez-Chapula, Jose A; Navarro-Polanco, Ricardo A; Culberson, Chris et al. (2002) Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block. J Biol Chem 277:23587-95 |
| Sanchez-Chapula, J A; Salinas-Stefanon, E; Torres-Jacome, J et al. (2001) Blockade of currents by the antimalarial drug chloroquine in feline ventricular myocytes. J Pharmacol Exp Ther 297:437-45 |
