The repositioned drugs disulfiram/diethyldithiocarbamate combined to benznidazole: Searching for Chagas disease selective therapy, preventing toxicity and drug resistance.

Chagas disease (CD) affects at least 6 million people in 21 South American countries besides several thousand in other nations all over the world. It is estimated that at least 14,000 people die every year of CD. Since vaccines are not available, chemotherapy remains of pivotal relevance. About 30% of the treated patients cannot complete the therapy because of severe adverse reactions. Thus, the search for novel drugs is required. Here we tested the benznidazole (BZ) combination with the repositioned drug disulfiram (DSF) and its derivative diethyldithiocarbamate (DETC) upon Trypanosoma cruzi in vitro and in vivo. DETC-BZ combination was synergistic diminishing epimastigote proliferation and enhancing selective indexes up to over 10-fold. DETC was effective upon amastigotes of the BZ- partially resistant Y and the BZ-resistant Colombiana strains. The combination reduced proliferation even using low concentrations (e.g., 2.5 µM). Scanning electron microscopy revealed membrane discontinuities and cell body volume reduction. Transmission electron microscopy revealed remarkable enlargement of endoplasmic reticulum cisternae besides, dilated mitochondria with decreased electron density and disorganized kinetoplast DNA. At advanced stages, the cytoplasm vacuolation apparently impaired compartmentation. The fluorescent probe H2-DCFDA indicates the increased production of reactive oxygen species associated with enhanced lipid peroxidation in parasites incubated with DETC. The biochemical measurement indicates the downmodulation of thiol expression. DETC inhibited superoxide dismutase activity on parasites was more pronounced than in infected mice. In order to approach the DETC effects on intracellular infection, peritoneal macrophages were infected with Colombiana trypomastigotes. DETC addition diminished parasite numbers and the DETC-BZ combination was effective, despite the low concentrations used. In the murine infection, the combination significantly enhanced animal survival, decreasing parasitemia over BZ. Histopathology revealed that low doses of BZ-treated animals presented myocardial amastigote, not observed in combination-treated animals. The picrosirius collagen staining showed reduced myocardial fibrosis. Aminotransferase de aspartate, Aminotransferase de alanine, Creatine kinase, and urea plasma levels demonstrated that the combination was non-toxic. As DSF and DETC can reduce the toxicity of other drugs and resistance phenotypes, such a combination may be safe and effective.

Plants and intestinal parasitosis: a review on ethnopharmacological use by the Kantaruré-Batida indigenous community of Brazil / Plantas y parasitosis intestinal: una revisión sobre el uso etnofarmacológico de la comunidad indígena Kantaruré-Batida de Brasil

Indigenous knowledge is one of the most notable traditional sources about plants used to treat diseases. Thus, the aim of this study was to describe the botanical features and to investigate the pharmacological properties of plants used by the Kantaruré-Batida community to treat intestinal parasitosis. Botanical characterization was performed based on integrative review andon access to 'Flora do Brasil' platform, whereas plants' pharmacological properties were investigated through systematic review. Among the 21 ethnospecies used, 48% were described as having activity against intestinal parasites. Although 52% had no such activity described, other properties can account for their use, that indicates that further studies are required. Therefore, this review reinforces the importance of valuing indigenous knowledge as tool to guide antiparasitic agent trials.

El conocimiento indígena es una de las fuentes tradicionales más notables sobre las plantas utilizadas para tratar enfermedades. Por lo tanto, el objetivo de este estudio fue describir las características botánicas e investigar las propiedades farmacológicas de las plantas utilizadas por la comunidad Kantaruré-Batida para tratar la parasitosis intestinal. La caracterización botánica se realizó con base en una revisión integradora y en el acceso a la plataforma "Flora do Brasil", mientras que las propiedades farmacológicas de las plantas se investigaron mediante una revisión sistemática. Entre las 21 etnoespecies utilizadas, se describió que el 48% tenía actividad contra los parásitos intestinales. Aunque el 52% no tenía tal actividad descrita, otras propiedades pueden explicar su uso, lo que indica que se requieren más estudios. Por lo tanto, esta revisión refuerza la importancia de valorar el conocimiento indígena como herramienta para guiar los ensayos de agentes antiparasitarios.