The anti-malarial activity of the anti-cancer drug methotrexate against chloroquine-sensitive T9-96 and the multidrug-resistant K1 strains of Plasmodium  falciparum was assessed in vitro. Mean IC(50) values of 0.32 + 0.05 nM and 48.02 + 4.40 nM were obtained for T9-96 and K1, respectively, indicating methotrexate's high potency against both sensitive and resistant P. falciparum strains in vitro. Our results suggest that methotrexate is potentially effective  against falciparum malaria in short-term, low-dose regimens, minimizing the risk  of toxicity. This, along with the practical advantages of methotrexate, warrants  the clinical investigation of methotrexate in human cases of falciparum malaria.

Reduced microcirculatory flow is a fundamental feature in the pathophysiology of  severe Plasmodium falciparum malaria and sequestration of red blood cells containing mature parasites is considered a central cause of this. Direct microscopic observation of the microcirculation in the living patient with severe malaria has enabled us to quantify this phenomenon and link it to severity of disease, supporting the findings of pathology studies. Moreover, the sequestered  parasite biomass, calculated from parasite derived plasma PfHRP2 concentrations,  strongly correlates with disease severity. Artesunate prevents sequestration by killing ring form parasites, aborting their maturation, which can explain the mortality benefit of this drug compared to quinine in the treatment of adult severe malaria. Levamisole is currently tried as adjunctive treatment in severe malaria targeting sequestration.