Plasmodium berghei: efficacy of 5-fluoroorotate in combination with commonly used antimalarial drugs in a mouse model.
Resistance to antimalarial antifolates necessitates a search for new antimetabolites targeting other enzymes of the folate metabolic pathway. In this study, 5-fluoroorotate (FOA), reported to be an inhibitor of thymidylate synthase, was assayed against Plasmodium berghei NK 65 in mice, with(out) an oral uridine supplement. FOA (2.5 and 5.0 mg/kg bw.) was tested alone, or in a double and triple combination with a fixed oral dose of 1.25 and 2.5 mg/kg of pyrimethamine (PYR); 1.0 and 2.0 mg/kg of dapsone (DAP); 1.0 and 2.0 mg/kg of artesunate (ART). FOA achieved high suppression which ranged from 95.7% to aparasitaemic, activity that was dose-dependent. At the highest dosages used, FOA-PYR and FOA-DAP-ART combinations were synergistic with 100% cure rate, while FOA-PYR-ART was antagonistic. Drugs in a synergistic combination may exert less resistance selection pressure, thus FOA-PYR and FOA-DAP-ART warrant further evaluation with an ultimate object of possible clinical use against drug-resistant malaria.
Muregi
Francis W
FW
Department of Infectious Diseases, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan. fmuregi@hama-med.ac.jp
Kano
Shigeyuki
S
Kino
Hideto
H
Ishih
Akira
A
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use*; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use; D000077332:Artesunate; D003622:Dapsone / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009963:Orotic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018512:Parasitemia / Q000188:drug therapy; D010962:Plasmodium berghei / Q000187:drug effects*; D011739:Pyrimethamine / Q000494:pharmacology / Q000627:therapeutic use
D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; D009963:Orotic Acid; C001242:5-fluoroorotic acid; D003622:Dapsone; D011739:Pyrimethamine