A comparative study of posaconazole and benznidazole in the prevention of heart damage and promotion of trypanocidal immune response in a murine model of Chagas disease

Abstract

A comparative study was performed between the trypanocidal efficacy of and associated immune response to benznidazole and posaconazole in a murine model of Chagas disease. Both drugs led to 100% survival, suppression of parasitaemia and reduction of specific anti-Trypanosoma cruzi antibodies following chronic infection. All posaconazole-treated animals had negative haemocultures at 54 days post infection, whilst 50% of those treated with benznidazole had positive results. Although both drugs were effective in reducing parasitism and inflammation in the heart, posaconazole-treated animals had plasma enzymatic levels of cardiac lesion that were indistinguishable from those of uninfected mice, whilst for benznidazole the enzyme levels were significantly higher than those of uninfected controls 31 days after the start of treatment. Posaconazole was more effective than benznidazole in controlling spleen enlargement and unspecific splenocyte proliferation in the early acute phase, but allowed higher levels of activation of CD4(+) and CD8(+) T-cells in the late acute phase when the adaptive immune response takes control of the infection. These results support the notion that posaconazole could be superior to benznidazole for the treatment of T. cruzi infection in humans.

Antitrypanosomal Treatment with Benznidazole Is Superior to Posaconazole Regimens in Mouse Models of Chagas Disease

“…In subsequent studies, a dose of 20 mg/kg q.d. was typically used to characterize the in vivo anti-T. cruzi activity of posaconazole (9,17). In our experiments, such a regimen translated into a maximum plasma concentration (C max, total ) of 5.9 M and an AUC 0 -24, total of 97 h · M at steady state.…”

A therapeutic nanoparticle vaccine againstTrypanosoma cruziin a BALB/c mouse model of Chagas disease

“…Ultimately, vaccine development is a stepwise process and using the acute model for screening vaccine candidates can be used as an effective in vivo model to determine whether a vaccine would stimulate a sufficient immune response to control parasitemia, and is frequently used in drug efficacy testing. [53][54][55] Additionally, while a concerted effort has been made to select mouse models that closely mimic human disease, the Tcell response is not directly translatable between the two species. While we predict that our findings of immunogenicity and Figure 6.…”

Evaluation of benznidazole treatment combined with nifurtimox, posaconazole or AmBisome® in mice infected with Trypanosoma cruzi strains

“…As ergosterol is the predominant sterol of the parasite membrane [11], several inhibitors of ergosterol synthesis, initially developed for the treatment of invasive fungal infections, have appeared as alternatives. One of these inhibitors, namely posaconazole (POS), a triazole derivative that potentially inhibits the course of T. cruzi infection in mice, is presently undergoing clinical trials [4,12]. Another compound, AmBisome ® (AMB) (a liposomal formulation of the macrolide polyene amphotericin B), displays a high affinity for ergosterol and is also a current and potent treatment of invasive fungal infections as well as visceral leishmaniasis.…”