nifurtimox and Brain-Diseases

Treatment of second-stage sleeping sickness relies mainly on melarsoprol. Nifurtimox has been successfully used to cure melarsoprol-refractory sleeping sickness caused by Trypanosoma brucei gambiense infection.. An open, randomized trial was conducted to test for equivalence between the standard melarsoprol regimen and 3 other regimens, as follows: standard melarsoprol therapy (3 series of 3.6 mg/kg/day intravenously [iv] for 3 days, with 7-day breaks between the series); 10-day incremental-dose melarsoprol therapy (0.6 mg/kg iv on day 1, 1.2 mg/kg iv on day 2, and 1.8 mg/kg iv on days 3-10); nifurtimox monotherapy for 14 days (5 mg/kg orally 3 times per day); and consecutive 10-day melarsoprol-nifurtimox combination therapy (0.6 mg/kg iv melarsoprol on day 1, 1.2 mg/kg iv melarsoprol on day 2, and 1.2 mg/kg/day iv melarsoprol combined with oral 7.5 mg/kg nifurtimox twice a day on days 3-10). Primary outcomes were relapse, severe adverse events, and death attributed to treatment.. A total of 278 patients were randomized. The frequency of adverse events was similar between the standard melarsoprol regimen and the other regimens. Encephalopathic syndromes occurred in all groups and caused all deaths that were likely due to treatment. Relapses (n=48) were observed only with the 3 monotherapy regimens.. A consecutive 10-day low-dose melarsoprol-nifurtimox combination is more effective than the standard melarsoprol regimen.

Topics: Administration, Oral; Adult; Animals; Brain Diseases; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Injections, Intravenous; Male; Melarsoprol; Nifurtimox; Recurrence; Treatment Outcome; Trypanocidal Agents; Trypanosoma brucei gambiense; Trypanosomiasis, African

In trypanosomiasis chemotherapy the main mode of action of the nitro-compounds, including the 5-nitroimidazoles or nitrofurans (nifurtimox) is to increase the oxidative stress on the organism either directly by the production of peroxides or indirectly by "futile redox cycling". If this is the case, then these nitro-compounds and the arsenicals should act in combination on the trypanothione oxidation-reduction reaction of the trypanosome. In this paper this has been demonstrated to occur with all those nitro-compounds which have exhibited reasonable trypanocidal action in monotherapy or other combination chemotherapeutic regimens. A major advantage is the short treatment period of approximately 5 days. Pretreatment with a single dose of suramin increased the efficacy of the nitroimidazole-arsenical combination.

Topics: Animals; Antiprotozoal Agents; Arsenicals; Brain Diseases; Drug Synergism; Drug Therapy, Combination; Female; Ketoconazole; Metronidazole; Mice; Nifurtimox; Nitro Compounds; Nitroimidazoles; Oxidation-Reduction; Suramin; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African