S. Wyllie, Stephen Patterson, L. Stojanovski
Feb 1, 2012
Citations
3
Influential Citations
145
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Journal
Science Translational Medicine
Abstract
Fexinidazole, a drug in clinical testing for African sleeping sickness, shows potential as an oral treatment for another neglected tropical disease. A New Job for an Old Drug Fever, fatigue, weight loss, and swelling of the spleen and liver are all symptoms of visceral leishmaniasis—a tropical disease that is also known as kala-azar or black fever. Caused by the protozoan parasite Leishmania donovani, which is transmitted to people through the bite of a sand fly, the disease is almost always fatal if untreated. Although several drugs exist, they are costly and not always safe, effective, or easy to administer. To address the need for better drugs, Wyllie et al. investigated the possibility of using fexinidazole to treat visceral leishmaniasis. This antiparasitic compound, developed decades ago, is now undergoing early clinical trials as an oral therapy for African sleeping sickness, a disease that is caused by a related protozoan parasite called Trypanosoma brucei. Fexinidazole’s mode of action is thought to involve a trypanosome nitroreductase; the finding that a closely related enzyme is encoded by the leishmania genome inspired Wyllie et al. to pursue fexinidazole as a therapy for visceral leishmaniasis. They found that the compound and two of its metabolites (which rapidly form in vivo) showed activity against both developmental stages of L. donovani in vitro. The metabolites were cytotoxic, killing all the parasites within 30 hours. For unclear reasons, only the metabolites were active against L. donovani grown in macrophages (the cells in which the parasite reproduces during infection). In a mouse model of visceral leishmaniasis, a daily oral dose of fexinidazole for 5 days almost completely suppressed infection—an activity that is comparable to that of drugs currently in clinical use against this deadly tropical disease. Visceral leishmaniasis kills more people than any other parasitic disease except malaria. The clinical trials of fexinidazole for African sleeping sickness have already shown that the drug is extremely safe. The discovery that it may also be a viable oral treatment for visceral leishmaniasis bodes well for those afflicted with this disease. Safer and more effective oral drugs are required to treat visceral leishmaniasis, a parasitic disease that kills 50,000 to 60,000 people each year in parts of Asia, Africa, and Latin America. Here, we report that fexinidazole, a drug currently in phase 1 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) showed that fexinidazole sulfone achieves 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 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 this tropical disease. In African trypanosomes, the mode of action of nitro drugs involves reductive activation via a NADH (reduced form of nicotinamide adenine dinucleotide)–dependent bacterial-like nitroreductase. Overexpression of the leishmanial homolog 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.