The Anti-Trypanosoma cruzi activity of posaconazole in a murine model of acute Chagas' disease is less dependent on gamma interferon than that of benznidazole.
We have investigated the influences of gamma interferon (IFN-gamma) and interleukin-12 (IL-12) on the efficacy of posaconazole (POS) treatment of acute experimental infections with Trypanosoma cruzi; the standard drug, benznidazole (BZ), was used as a positive control. Wild-type (WT) mice infected with T. cruzi and treated with POS or BZ had no parasitemia, 100% survival, and cure rates of 86 to 89%. IFN-gamma-knockout (KO) mice infected with T. cruzi and treated with BZ controlled the infection during treatment but relapsed after the drug pressure ceased and had 0% survival, while those receiving POS better controlled the infection after the end of treatment and had 70% survival (P<0.0001 compared to the results for both untreated and BZ-treated animals). IL-12-KO mice infected and treated with POS or BZ had intermediate results, displaying enhanced parasitemia, decreased survival (77 to 83%), and reduced cure rates (35 to 39%) compared with those of the WT animals. Our results demonstrate that either IFN-gamma or IL-12 deficiency reduces the efficacy of POS or BZ in this experimental model but also indicate that the anti-T. cruzi activity of POS is much less dependent on the activity of IFN-gamma than that of BZ is.
Ferraz
Marcela L
ML
Laboratório de Parasitologia Celular e Molecular, Centro de Pesquisa René Rachou, FIOCRUZ, Av. Augusto de Lima, 1715, 30190-002 Belo Horizonte, MG, Brazil.
Gazzinelli
Ricardo T
RT
Alves
Rosana O
RO
Urbina
Julio A
JA
Romanha
Alvaro J
AJ
D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy*; D007371:Interferon-gamma / Q000494:pharmacology / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009593:Nitroimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014344:Trypanocidal Agents / Q000627:therapeutic use*; D014349:Trypanosoma cruzi / Q000187:drug effects*
D009593:Nitroimidazoles; D014230:Triazoles; D014344:Trypanocidal Agents; D018664:Interleukin-12; C101425:posaconazole; D007371:Interferon-gamma; C009999:benzonidazole