CONICET | Buscador de Institutos y Recursos Humanos

Chagas disease is endemic in Latin America and a global burden due to migration. Benznidazole (BZ) and nifurtimox (NFX) are the only drugs available for treatment but are not exempt of severe adverse events. Thus, better drugs for Chagas disease are needed. Drug repositioning is a cost-effective strategy to identify active compounds that may move forward to clinical use. Taking advantage of phylogenetic similarities and common metabolic pathways between Toxoplasma gondii and Trypanosoma cruzi, drugs currently used for Toxoplasmosis were sequentially assessed for anti-T. cruzi activity in in vitro and in vivo models. Azithromycin, sulfadiazine, sulfamethoxazole, pyrimethamine (PYR), atovaquone (ATV) and paromomycin were initially evaluated in vitro by establishing the percentage of relative activity (%RA) compared to BZ and NFX on amastigote and trypomastigote stages at a fixed concentration (10 μM for each drug). PYR and ATV showed more than 98 %RA compared to NFX on amastigotes. Hence, these drugs were further evaluated to obtain the inhibitory concentration 50% (IC50) on amastigotes, and citotoxicity on Vero cells. IC50 values were 0.47 μM for PYR and 6.92 μM for ATV; citotoxicity was not significant. Due PYR well-known favorable human pharmacokinetics and safety properties, there was rationale enough to continue its evaluation in a murine model of acute infection. Female 5 week old BALB/c mice were infected and, at onset of patent parasitaemia, treated with PYR 50 mg/kg for 20 consecutive days. Non-treated (NT) and BZ- or NFX-treated groups (100 mg/kg/day) were included as controls. PYR did not show a significant effect on parasitaemia levels or mortality (100%) compared to NT group at the end of the study. In this screening model, PYR was the most potent drug in vitro but this could not be demonstrated in vivo.

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