Melarsoprol is a trivalent arsenical that has been available since 1949 and is first-line therapy for advanced central nervous system East African trypanosomiasis, and second-line therapy (after eflornithine) for advanced West African trypanosomiasis. After intravenous administration it is excreted rapidly, but clinically relevant concentrations accumulate in the central nervous system within 4 days. Melarsoprol is administered in propylene glycol by slow intravenous infusion at a dosage of 3.6 mg/kg/d for 3–4 days, with repeated courses at weekly intervals, if needed. A new regimen of 2.2 mg/kg daily for 10 days had efficacy and toxicity similar to what was observed with three courses over 26 days. Melarsoprol is extremely toxic. The use of such a toxic drug is justified only by the severity of advanced trypanosomiasis and the lack of available alternatives. Immediate adverse effects include fever, vomiting, abdominal pain, and arthralgias. The most important toxicity is a reactive encephalopathy that generally appears within the first week of therapy (in 5–10% of patients) and is probably due to disruption of trypanosomes in the central nervous system. Coadministration of corticosteroids may decrease the likelihood of encephalopathy. Common consequences of the encephalopathy include cerebral edema, seizures, coma, and death. Other serious toxicities include renal and cardiac disease and hypersensitivity reactions. Failure rates with melarsoprol appear to have increased recently in parts of Africa, suggesting drug resistance.
Eflornithine (difluoromethylornithine), an inhibitor of ornithine decarboxylase, is the only new drug registered to treat African trypanosomiasis in the last half-century. It is now the first-line drug for advanced West African trypanosomiasis, but is not effective for East African disease. Eflornithine is administered intravenously, and good central nervous system drug levels are achieved. The elimination half-life is about 3 hours. The usual regimen is 100 mg/kg intravenously every 6 hours for 7–14 days (14 days was superior for a newly diagnosed infection). Eflornithine appears to be as effective as melarsoprol against advanced T brucei gambiense infection, but its efficacy against T brucei rhodesiense is limited by drug resistance. Combining eflornithine with a 10-day course of nifurtimox afforded efficacy against West African trypanosomiasis similar to a 14-day regimen of eflornithine alone, with simpler and shorter treatment (injections every 12 hours for 7 days). Toxicity from eflornithine is significant, but considerably less than that from melarsoprol. Adverse effects include diarrhea, vomiting, anemia, thrombocytopenia, leukopenia, and seizures. These effects are generally reversible. Increased experience with eflornithine and increased availability of the compound in endemic areas may lead to its replacement of suramin, pentamidine, and melarsoprol in the treatment of T brucei gambiense infection.
Benznidazole is an orally administered nitroimidazole for the treatment of American trypanosomiasis (Chagas disease) that probably has improved efficacy and safety compared to nifurtimox. These drugs can eliminate parasites and prevent progression when used to treat acute infection, but activity against chronic Chagas disease is suboptimal. In a recent randomized trial, treatment of Chagas cardiomyopathy with benznidazole did not offer clinical benefit. Standard dosage is 5 mg/kg/d in two or three divided doses for 60 days, given with meals. Important toxicities, which are generally reversible, include rash (in 20–30% of those treated), peripheral neuropathy, gastrointestinal symptoms, and myelosuppression.