SYNERGISM OF CIMETIDINE WITH ANTIMALARIAL AGENTS

The histamine type-2 receptor antagonist and cytochrome P450 inhibitor cimetidine was examined for its antimalarial properties in the presen ce or absence of chloroquine or pyrimethamine. When used alone, cimeti dine displayed little activity against a number of Plasmodium falcipar um clones in vitro, with an IC50 of 300-700 mu M. The compound was fou nd to be highly synergistic in combination with chloroquine and also d isplayed a degree of synergism when used in combination with pyrimetha mine. These synergistic effects were independent of the chloroquine- o r pyrimethamine-resistance status of the clones. The cytochrome P450 i nhibitor proadifen displayed weak synergism or antagonism with chloroq uine, depending on the clone tested, and clear antagonism with pyrimet hamine. The results with proadifen indicate that cimetidine was exerti ng its synergistic activity via a mechanism distinct from inhibition o f cyrochrome P450. Additional experiments have demonstrated that cimet idine interferes with neither plasmodial sterol metabolism nor heme po lymerization.