levoleucovorin and cycloguanil

The folate derivatives folic acid (FA) and folinic acid (FNA) decrease the in vivo and in vitro activities of antifolate drugs in Plasmodium falciparum. However, the effects of 5-methyl-tetrahydrofolate (5-Me-THF) and tetrahydrofolate (THF), the two dominant circulating folate forms in humans, have not been explored yet. We have investigated the effects of FA, FNA, 5-Me-THF, and THF on the in vitro activity of the antimalarial antifolates pyrimethamine and chlorcycloguanil and the anticancer antifolates methotrexate (MTX), aminopterin, and trimetrexate (TMX), against P. falciparum. The results indicate that these anticancers are potent against P. falciparum, with IC50 < 50 nM. 5-Me-THF does not significantly decrease the activity of all tested drugs, and none of the tested folate derivatives significantly decrease the activity of these anticancers. Thus, malaria folate metabolism has features different from those in human, and the exploitation of this difference could lead to the discovery of new drugs to treat malaria. For instance, the combination of 5-Me-THF with a low dose of TMX could be used to treat malaria. In addition, the safety of a low dose of MTX in the treatment of arthritis indicates that this drug could be used alone to treat malaria.

Topics: Aminopterin; Animals; Antimalarials; Antineoplastic Agents; Folic Acid; Folic Acid Antagonists; Inhibitory Concentration 50; Leucovorin; Methotrexate; Molecular Structure; Plasmodium falciparum; Proguanil; Pyrimethamine; Tetrahydrofolates; Triazines; Trimetrexate

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.

Topics: Animals; Antimalarials; Atovaquone; Drug Interactions; Folic Acid; Humans; Leucovorin; Naphthoquinones; Plasmodium falciparum; Proguanil; Purine Nucleotides; Pyrimethamine; Pyrimidine Nucleotides; Triazines

The in vitro effect of proguanil and its active metabolite cycloguanil on proliferating human blood mononuclear cells was studied. Proguanil had no effect on 14C-thymidine incorporation or on the number of cells. Cycloguanil, in concentrations corresponding to the plasma levels found in clinical practice, blocked the endogenous synthesis of thymidine and decreased the number of mitogen- and antigen-stimulated cells. The effect on phytohaemagglutinin-stimulated cells was transient. Higher concentrations of cycloguanil, corresponding to intralymphocytic levels in clinical practice, permanently suppressed the growth of lymphocytes. The effect of cycloguanil could be reversed by low doses of folinic acid and high doses of folic acid.

Topics: Humans; Leucovorin; Lymphocyte Activation; Proguanil; Thymidine; Triazines