The chemotherapy of rodent malaria. LIX. Drug combinations to impede the selection of drug resistance, Part 3: Observations on cyproheptadine, an antihistaminic agent, with chloroquine.
Several compounds in current clinical use as antihistaminic agents, among them cyproheptadine (CYP), have been shown, in experimental models, to reverse resistance of the asexual, intra-erythrocytic stages of rodent or human malarial parasites to chloroquine (CQ). Although preliminary clinical trials with CYP failed to confirm such activity in subjects with naturally acquired infection with Plasmodium falciparum, Nigerian investigators have reported that another antihistaminic, chlorpheniramine, significantly restores the blood schizontocidal action of CQ in semi-immune patients with CQ-resistant P. falciparum, when the two compounds are administered together. The rates at which resistance to CYP can be produced, in mice infected either with CQ-resistant P. yoelii ssp. NS or CQ-resistant P. yoelii nigeriensis, when drug-selection pressure is exerted with this compound alone have now been compared with the rate and extent to which resistance develops in infected animals that are treated with various combinations of CYP and CQ. The data indicate that, in both parasites, stable resistance develops slowly to CYP alone and that exposure to a combination of CYP plus CQ significantly impedes the selection of resistance to CYP. Although the antimalarial action of CYP is reported to extend to the pre-erythrocytic hepatic stages, there was no evidence of gametocytocidal activity in the present study. The future implications of these observations are discussed in relation to the clinical potential of CYP + CQ and similar combinations and possible future research.
Peters
W
W
Tropical Parasitic Diseases Unit, Northwick Park Institute for Medical Research, Harrow HA1 3UJ, U.K. w.peters@ic.ac.uk
Robinson
B L
BL
Stewart
L B
LB
Butcher
G A
GA
D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D002738:Chloroquine / Q000627:therapeutic use*; D003533:Cyproheptadine / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004351:Drug Resistance; D006634:Histamine H1 Antagonists / Q000627:therapeutic use*; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D051379:Mice; D018512:Parasitemia / Q000188:drug therapy; D010967:Plasmodium yoelii; D012377:Rodentia; D013997:Time Factors
D000962:Antimalarials; D004338:Drug Combinations; D006634:Histamine H1 Antagonists; D003533:Cyproheptadine; D002738:Chloroquine