Trypanosomiasis and leishmaniasis are two tropical diseases caused by protozoan parasites. Both diseases are difficult to treat due to the toxicity of currently available drugs, and efforts to eradicate the parasites by destroying the insect vectors have been unsuccessful.
Fexinidazole, a drug discovered in the 1980s but subsequently abandoned, has recently shown promise in phase I clinical trials against African trypanosomes. In the current study, investigators at the University of Dundee (United Kingdom) have examined the drug’s ability to kill the Leishmania parasite L. donovani.
They reported in the February 1, 2012, online edition of the journal Science Translational Medicine that the 2-substituted 5-nitroimidazole drug was rapidly oxidized in vivo in mice, dogs, and humans to sulfoxide and sulfone metabolites. Both metabolites of fexinidazole were active against L donovani amastigotes grown in macrophages, whereas the parent compound was inactive.
Pharmacokinetic studies with fexinidazole showed that fexinidazole sulfone achieved blood concentrations in mice above the EC99 (effective concentration inhibiting growth by 99%) value for at least 24 hours after a single oral dose. A once-daily regimen for five 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 this tropical disease.
“Visceral leishmaniasis is a neglected disease of poverty which causes huge problems across Africa, Asia, and Latin America, killing tens of thousands of people every year,” said senior author Dr. Alan Fairlamb, professor of biochemistry at the University of Dundee. “The current treatments are far from ideal and we need to find better, cheaper and more easily delivered drugs to tackle the disease. Our research suggests that fexinidazole has strong potential to do that.”
“Drugs for Neglected Diseases initiative have already established that fexinidazole is safe in early clinical trials for African sleeping sickness, so it is some way along the development path,” said Dr. Fairlamb. “This has been a great team effort, and I would like to acknowledge the dedication and enthusiasm of the biologists, chemists, and pharmacologists involved in this discovery. Our hope is that fexinidazole can follow them and provide relief from a disease that is a major blight across the world.”
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