Mefloquine and halofantrine are quinoline and phenanthrene methanols respectively, developed in response to the global unrelenting problem of chloroquine resistant Plasmodium falciparum. However, resistance of the parasite to these second generation agents is rapidly emerging. Drug combination is one strategy that can be used to combat this major public health concern.

Probenecid is an organic anion inhibitor that is often used in combination with antibiotics. Probenecid has recently been shown to enhance in vitro anti-malarial properties of chloroquine and antimalarial antifolates. The mechanism by which this is achieved is unknown at present but is likely to involve blockade of drug efflux or nutrient uptake in the parasite. Probenecid is inexpensive and well tolerated and is therefore an ideal agent for combination therapy. Therefore, we evaluated the effects of this inexpensive agent in combination with the second generation antimalarials mefloquine and halofantrine on resistant strains of Plasmodium falciparum.Under normal dosage regimens a peak plasma concentration of 500-700µM probenecid is achieved. Our results indicate significant chemosensitization by probenecid of parasites to mefloquine at 50µM (P<0.06) and in halofantrine at 100µM (P<0.03). These concentrations are well below the peak plasma concentrations, raising the realistic prospect of using probenecid clinically in this context. The interaction of probenecid with putative parasite drug transporter molecules is currently being investigated.

Values are in nM, Mean ± SD, n=4, *P<0.06, **p<0.03. Mann Whitney tests were used to assess statistical significance

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