title: Benznidazole and posaconazole in experimental Chagas disease: positive interaction in concomitant and sequential treatments.
abstract: BACKGROUND
  Current chemotherapy for Chagas disease is unsatisfactory due to its limited efficacy, particularly in the chronic phase, with frequent side effects that can lead to treatment discontinuation. Combined therapy is envisioned as an ideal approach since it may improve treatment efficacy whilst decreasing toxicity and the likelihood of resistance development. We evaluated the efficacy of posaconazole in combination with benznidazole on Trypanosoma cruzi infection in vivo.
  
  
  RESULTS
  Benznidazole and posaconazole were administered individually or in combination in an experimental acute murine infection model. Using a rapid treatment protocol for 7 days, the combined treatments were more efficacious in reducing parasitemia levels than the drugs given alone, with the effects most evident in combinations of sub-optimal doses of the drugs. Subsequently, the curative action of these drug combinations was investigated, using the same infection model and 25, 50, 75 or 100 mg/kg/day (mpk) of benznidazole in combination with 5, 10 or 20 mpk of posaconazole, given alone or concomitantly for 20 days. The effects of the combination treatments on parasitological cures were higher than the sum of such effects when the drugs were administered separately at the same doses, indicating synergistic activity. Finally, sequential therapy experiments were carried out with benznidazole or posaconazole over a short interval (10 days), followed by the second drug administered for the same period of time. It was found that the sequence of benznidazole (100 mpk) followed by posaconazole (20 mpk) provided cure rates comparable to those obtained with the full (20 days) treatments with either drug alone, and no cure was observed for the short treatments with drugs given alone.
  
  
  CONCLUSIONS
  Our data demonstrate the importance of investigating the potential beneficial effects of combination treatments with marketed compounds, and showed that combinations of benznidazole with posaconazole have a positive interaction in murine models of Chagas disease.
authors: Laboratório de Doença de Chagas, Departamento de Ciências Biológicas & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil. liviadiniz@nupeb.ufop.br
authors: Lívia de Figueiredo
authors: Lde F
authors: Diniz
authors: Julio A
authors: JA
authors: Urbina
authors: Isabel Mayer
authors: IM
authors: de Andrade
authors: Ana Lia
authors: AL
authors: Mazzeti
authors: Tassiane Assíria F
authors: TA
authors: Martins
authors: Ivo Santana
authors: IS
authors: Caldas
authors: André
authors: A
authors: Talvani
authors: Isabela
authors: I
authors: Ribeiro
authors: Maria Terezinha
authors: MT
authors: Bahia
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage*; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D051379:Mice; D009593:Nitroimidazoles / Q000008:administration & dosage*; D018512:Parasitemia / Q000188:drug therapy; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000302:isolation & purification
chemical_list: D000981:Antiprotozoal Agents; D009593:Nitroimidazoles; D014230:Triazoles; C101425:posaconazole; C009999:benzonidazole
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