ONE of the most challenging features of malarial parasite Plasmodium falciparum is its ability to evolve and render anti-malarial drugs ineffective. The emergence of multidrug resistant strains of the parasite in South-East Asia and other tropical countries in recent years is undermining international efforts to eradicate malaria. So much so that in April the WHO announced investing $400 million to combat resistant strains of the debilitating disease.
A recent study by researchers from the Central Drug Research Institute of Council of Scientific and Industrial Research (CSIR-CDRI), in Lucknow, holds out fresh hope for conquering the disease. CSIR-CDRI scientists have found that an antifungal drug can kill multidrug-resistant malaria parasite in mice by enhancing the efficacy of widely used, artimisinin-based anti-malarial drugs artesunate, artemether and arteether. The study was published in the May issue of Acta Tropica.
The scientists had earlier demonstrated that the antifungal drug, ketoconazole, could reverse the resistance of P falciparum to anti-malarial drug mefloquine. Ketoconazole, works by inhibiting the activity of cytochrome P450 3A4 (CYP3A4), an enzyme found in liver. Inhibition of the activity of CYP3A4 slows down the metabolism of mefloquine and thus prolongs its plasma life or the time period for which the drug remains in blood, says one of the authors Renu Tripathi. A prolonged plasma life enhances the anti-malarial activity of mefloquine to the extent that it can act against the resistant P falciparum.
To find out the efficacy of ketoconazole on artimisinin-based anti-malarial drugs, the researchers tested it on mice infected with multi-drug resistant Plasmodium yoelli nigeriensis, which is known to cause malaria in rodents. When ketoconazole was used in combination with artimisinin-based drugs, it cured the infected mice. Analysis of their livers revealed that CYP3A4 enzyme was suppressed by 59 per cent in mice treated with both ketoconazole and artimisinin-based drugs, while the enzyme was not suppressed in mice treated with the drugs alone.
“Inhibition of CYP3A4 enzyme slowed down the conversion of artimisinin into its metabolite, dihydroartemisinin. This increases its anti-malarial activity,” says Tripathi. The therapeutic approach can lower the effective dose of artimisinin-based drugs, reducing the cost of malaria treatment, she adds.