Effects of folic and folinic acids in 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 dihydrofolate-reductase inhibitor, pyrimethamine, and a pyrimidine antagonist, atovaquone. It was found that the minimum inhibitory concentrations of cycloguanil and WR99210 were not affected by physiological concentrations of folic or folinic acids in human serum. Experiments with Plasmodium falciparum growing in erythrocytic culture showed that the antimalarial effect of cycloguanil is readily antagonised by folinic acid, whereas WR99210 is much more refractory. Plasmodium falciparum exposed to cycloguanil (2.5 microM, 6 h) and WR99210 (1 microM, 6 h), showed depressed levels of thymidine 5'-triphosphate (dTTP) in the absence and presence of folinic acid (25 microM and 10 microM, respectively). The decrease in dTTP may be attributed to inhibition of dihydrofolate reductase. However, as the addition of folinic acid did not restore dTTP levels in the parasites, the drugs may have an additional or different mechanism of toxicity.