EFFECTS OF FOLIC AND FOLINIC ACIDS ON THE ACTIVITIES OF CYCLOGUANIL AND WR99210 AGAINST PLASMODIUM-FALCIPARUM IN ERYTHROCYTIC CULTURE

The in-vitro effects of folinic acid on the antimalarial activities of the triazine antifolates, cycloguanil and WR99210, were compared with those of their parent biguanides, proguanil and PS-15, a dihydrofolat e-reductase inhibitor, pyrimethamine, and a pyrimidine antagonist, ato vaquone. It was found that the minimum inhibitory concentrations of cy cloguanil and WR99210 were not affected by physiological concentration s of folic or folinic acids in human serum. Experiments with Plasmodiu m falciparum growing in erythrocytic culture showed that the antimalar ial effect of cycloguanil is readily antagonised by folinic acid, wher eas WR99210 is much more refractory. Plasmodium falciparum exposed to cycloguanil (2.5 mu M, 6 h) and WR99210 (1 mu M, 6 h) showed depressed levels of thymidine 5'-triphosphate (dTTP) in the absence and presenc e of folinic acid (25 mu M and 10 mu M, respectively). The decrease in dTTP may be attributed to inhibition of dihydrofolate reductase. Howe ver, as the addition of folinic acid did not restore dTTP levels in th e parasites, the drugs may have an additional or different mechanism o f toxicity.