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Methotrexate Therapy for Plasmodium vivax Malaria

Thomas W. Sheehy, MD; Hugh Dempsey, MD, FRCP(C)
JAMA. 1970;214(1):109-114. doi:10.1001/jama.1970.03180010051011.
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Among the more promising groups of drugs undergoing evaluation as antimalarial agents are the folic acid antagonists. These agents destroy plasmodia presumably by competitive inhibition of dihydrofolate reductase, the enzyme that catalyzes the conversion of dihydrofolic acid to metabolically active tetrahydrofolic acid. This reaction is necessary for nucleic acid synthesis and cell mitosis.1-3 Pyrimethamine (2, 4-diamino-5-[p - chlorophenyl]- 6 - ethylprimi dine) and chloroguanide (N1- [pchlorophenyl]- N5 - isopropyldiguanide) have been used extensively for malarial chemoprophylaxis and treatment during the past 20 years; only recently they have been recognized as folic acid antagonists. Unfortunately, these agents are too slow acting to be used for treatment of established infections with Plasmodium falciparum. Their use in such cases may lead to a fatal outcome for the patient or to the development of resistant strains.4

In addition to these observations, the appearance of chloroquine-resistant falciparum malaria in many


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