Safer and more effective oral drugs are required to treat visceral leishmaniasis, a parasitic disease that kills 50-60,000 people each year. Here we report that fexinidazole, a drug currently in phase I clinical trials for treating African trypanosomiasis, shows promise for treating visceral leishmaniasis. This 2-substituted 5-nitroimidazole drug is rapidly oxidized in vivo in mice, dogs and humans to sulfoxide and sulfone metabolites. Both metabolites of fexinidazole were active against Leishmania donovani amastigotes grown in macrophages, whereas the parent compound was inactive. Pharmacokinetic studies with fexinidazole (200 mg kg−1) showed that fexinidazole sulfone achieves blood concentrations in mice above the EC99 value for at least 24h following a single oral dose. A once daily regimen for 5 days at this dose resulted in a 98.4% suppression of infection in a mouse model of visceral leishmaniasis, equivalent to that seen with the drugs miltefosine and Pentostam, which are currently used clinically to treat visceral leishmaniasis. In African trypanosomes, the mode of action of nitro-drugs involves reductive activation via an NADH-dependent bacterial-like nitroreductase. Overexpression of the leishmanial homologue of this nitroreductase in L. donovani increased sensitivity to fexinidazole by 19-fold indicating that a similar mechanism is involved in both parasites. These findings illustrate the potential of fexinidazole as an oral drug therapy for treating visceral leishmaniasis.
01 Feb 2012