| Title | Plasmodium berghei: Efficacy of 5-fluoroorotate in combination with commonly used antimalarial drugs in a mouse model. | | Author(s) | Muregi FW, Kano S, Kino H, Ishih A | | Institution | Department of Infectious Diseases, Hamamatsu University School of Medicine,1-20-1, Handayama, Higashi-ku, Hamamatsu 431-3192, Japan; Center for Biotechnology Research and Development, Kenya Medical Research Institute (KEMRI) 54840-00200, Nairobi, Kenya. | | Source | Exp Parasitol 2009 Jan 19. | | Abstract | 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 P. 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 pyrimethanine (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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19545531 |
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