title: Synergism of cimetidine with anti-malarial agents.
abstract: The histamine type-2 receptor antagonist and cytochrome P450 inhibitor cimetidine was examined for its antimalarial properties in the presence or absence of chloroquine or pyrimethamine. When used alone, cimetidine displayed little activity against a number of Plasmodium falciparum clones in vitro, with an IC50 of 300-700 microM. The compound was found to be highly synergistic in combination with chloroquine and also displayed a degree of synergism when used in combination with pyrimethamine. These synergistic effects were independent of the chloroquine- or pyrimethamine-resistance status of the clones. The cytochrome P450 inhibitor proadifen displayed weak synergism or antagonism with chloroquine, depending on the clone tested, and clear antagonism with pyrimethamine. The results with proadifen indicate that cimetidine was exerting its synergistic activity via a mechanism distinct from inhibition of cytochrome P450. Additional experiments have demonstrated that cimetidine interferes with neither plasmodial sterol metabolism nor heme polymerization.
authors.affiliation: Picower Institute for Medical Research, Manhasset, New York 11030, USA.
authors.forename: A
authors.initials: A
authors.lastname: Paciorkowski
authors.forename: W W
authors.initials: WW
authors.lastname: Dai
authors.forename: A
authors.initials: A
authors.lastname: Cerami
authors.forename: B J
authors.initials: BJ
authors.lastname: Berger
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D002927:Cimetidine / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004351:Drug Resistance; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006418:Heme / Q000037:antagonists & inhibitors / Q000737:chemistry; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011108:Polymers; D011335:Proadifen / Q000494:pharmacology; D011739:Pyrimethamine / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006635:Histamine H2 Antagonists; D011108:Polymers; D006418:Heme; D002927:Cimetidine; D002738:Chloroquine; D011335:Proadifen; D011739:Pyrimethamine