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 t hem cyproheptadine (CYP), have been shown, in experimental models, to rever se resistance of the asexual, intra-erythrocytic stages of rodent or human malarial parasites to chloroquine (CQ). Although preliminary clinical trial s with CYP failed to confirm such activity in subjects with naturally acqui red infection with Plasmodium falciparum, Nigerian investigators have repor ted that another antihistaminic, chlorpheniramine, significantly restores t he blood schizontocidal action of CQ in semi-immune patients with CQ-resist ant P. falciparum, when the two compounds are administered together. The ra tes at which resistance to CYP can be produced, in mice infected either wit h CQ-resistant P. yoelii ssp. NS or CQ-resistant P. yoelii nigeriensis, whe n 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 impe des the selection of resistance to CYP. Although the antimalarial action of CYP is reported to extend to the pre-erythrocytic hepatic stages, there wa s no evidence of gametocytocidal activity in the present study. The future implications of these observations are discussed in relation to the clinica l potential of CYP + CQ and similar combinations and possible future resear ch.