New, combined, and reduced dosing treatment protocols cure Trypanosoma cruzi infection in mice.
The development of treatment protocols with reduced toxicity and equivalent or improved efficacy for Trypanosoma cruzi infection is a priority. We tested the effectiveness of benznidazole (BZ), nifurtimox (NFX), other prospective drugs in intermittent and combined treatment protocols to cure T. cruzi infection initiated with susceptible and drug-resistant parasite strains. A 40-day course of BZ, NFX, or the oxaborale AN4169 cured 100% of mice, whereas posaconazole (POS), and NTLA-1 (a nitro-triazole) cured approximately 90% and 20% of mice, respectively. Reducing the overall dosage of BZ or NFX by using an intermittent (once every 5 days) schedule or combining 5 daily doses of POS with 7 intermittent doses of BZ also provided approximately 100% cure. T. cruzi strains resistant to BZ were also found to be resistant to other drugs (POS), and extending the time of treatment or combining drugs did not increase cure rates with these isolates. Thus, dosing schedules for anti-T. cruzi compounds should be determined empirically, and compounds targeting different pathways may be combined to yield effective therapies with reduced toxicity. This work also suggests that standard treatment protocols using BZ and NFX may be significantly overdosing patients, perhaps contributing to the adverse events.
Center for Tropical and Emerging Global Diseases.
Juan M
JM
Bustamante
Julie M
JM
Craft
Byron D
BD
Crowe
Sarah A
SA
Ketchie
Rick L
RL
Tarleton
D000818:Animals; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D014355:Chagas Disease / Q000188:drug therapy* / Q000276:immunology; D004247:DNA / Q000032:analysis; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D016130:Immunophenotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D018512:Parasitemia / Q000188:drug therapy; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification
D015415:Biomarkers; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; D004247:DNA; C009999:benzonidazole
Chagas disease; Trypanosoma cruzi; benznidazole; drug discovery; intermittent treatment