American trypanosomiasis, or Chagas' disease, is caused by Trypanosoma cruzi and affects around 15 million people throughout the American continent. The available treatment is based on two nitroheterocyclic drugs, nifurtimox and benznidazole, both only partially effective and toxic. In this context, new drugs must be found. In our previous work, the tetrahydro-␤-carboline compound N-butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro-␤-carboline-3-carboxamide, named C4, showed a potent in vitro trypanocidal effect. The goal of this study was to evaluate the in vitro and in vivo trypanocidal effects of the compound C4 associated with other drugs (benznidazole, ketoconazole, and amphotericin B). For this, we used the checkerboard technique to analyze the effect of combinations of C4 reference drugs. C4 was assayed in a murine model alone as well as in association with benznidazole. We also evaluated the parasitemia, mortality, weight, and presence of amastigote nests in cardiac tissue. A synergic effect of C4 plus benznidazole against epimastigote and trypomastigote forms was observed in vitro, and in the murine model, we observed a substantial reduction in parasitemia levels and lowered mortality rates. These findings encourage supplementary investigations of carboline compounds as potential new trypanocidal drugs. C hagas' disease is an illness that affects around 15 million people on the American continent, and in Brazil, there are an estimated 3 million people infected with Trypanosoma cruzi, the causative agent of this disease (31).The currently available treatment is by two nitroheterocyclic drugs, nifurtimox and benznidazole (BZ), but both are unsatisfactory. Moreover, in Brazil, only BZ is available (19). In this context, new drugs or new therapeutic approaches must be developed. We recently reported that the tetrahydro-␤-carboline compound N-butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro-␤-carboline-3-carboxamide, named C4 (see Fig. 3), showed a strong in vitro trypanocidal effect (29).For the treatment of many infectious diseases, therapeutic associations are adopted, with very successful results. Previous works have shown the importance of combination therapy against several microorganisms such as bacteria (17,22,25), fungi (7,13,14), and protozoa such as Plasmodium (9, 21, 30), Leishmania (6, 16), and T. cruzi (3,20). In one of the few previous studies that reported synergistic activities of drugs for T. cruzi treatment, good synergistic activity between parthenolide and BZ was demonstrated (20).Therefore, based on the successful results of known therapeutic associations, the goal of this study was to evaluate the in vitro and in vivo trypanocidal activities of C4 associated with different reference drugs (BZ, ketoconazole, and amphotericin B). (ii) Checkerboard assay of effect of C4 on epimastigote and trypomastigote forms of Trypanosoma cruzi. For the checkerboard assay, we evaluated the trypanocidal effect of the compound C4 associated with other drugs (BZ, ketoconazole, and amphotericin B) on ep...

We evaluated the toxicity of a semipurified extract (EPA fraction, containing caffeine and several flavan-3-ols and proanthocyanidins) of seeds of the native Amazon plant Paullinia cupana (guaraná) in rodents. Acute toxicity was tested in male Swiss mice, which received different doses orally (OR) and intraperitoneally (ip); control groups received water. These tests produced acute mortality, with LD(50) of 1.825 g/kg (OR) and 0.827 g/kg (ip), and a significant weight decrease in lungs of mice receiving a dose of 0.1g/kg. In the repeated-dose toxicity test, the EPA was administered OR daily to male and female Wistar rats at doses of 30, 150, and 300 mg/kg/day/90 days. Their behavior, mortality, weight changes, laboratory tests, and the weights and histopathology of organs were evaluated. No rats died during the tests. Males dosed at 150 or 300 mg/kg gained weight more slowly and lost kidney weight (absolute and relative weights, compared to the control group). Hematological and biochemical tests showed few changes, differing somewhat between males and females; the histopathological evaluation indicated no significant changes. These results indicate that the EPA fraction of guaraná caused no toxicity in rats at the smallest dose evaluated (30 mg/kg). No other species was evaluated.

Stryphnodendron adstringens has a high tannin content and is used as an antiseptic and antimicrobial and in the treatment of leucorrhea, gonorrhea, wound healing, and gastritis. The present study evaluated the toxic effects of the heptamer prodelphinidin (F2) from the stem bark of S. adstringens in rodents. In the acute toxicity test, the mice that received oral doses exhibited reversible effects, with an LD50 of 3.015 mg · kg−1. In the chronic toxicity test at 90 days, Wistar rats were treated with different doses of F2 (10, 100, and 200 mg · kg−1). In the biochemical, hematological, and histopathological examinations and open-field test, the different dose groups did not exhibit significant differences compared with controls. The present results indicate that F2 from the stem bark of S. adstringens caused no toxicity with acute and chronic oral treatment in rodents at the doses administered.

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The pathogenic potential of Blastocystis sp. in experimental models requires further investigation. In this work, the pathogenicity of this parasite in the gastrointestinal tract of male Swiss mice was evaluated according to the inoculum size and period of infection. Animals were infected intragastrically, with 100, 500, 1,000, 5,000 and 10,000 Blastocystis sp. vacuolar forms obtained from a mixture of eight human isolates cultured axenically in Jones' medium. After seven, 14, 21, 28 and 60 days of infection, the animals were sacrificed and fragments of the small intestine (duodenum), large intestine, and cecum were subjected to histopathological analysis. Blastocystis sp. triggered an inflammatory response in the different tissues analyzed, with a predominance of mononuclear cells. The parasite was found in the muscular layer of the cecum, showing its invasive character. Larger inocula triggered inflammatory processes earlier (seven days) than smaller ones (from 21 days). We conclude that, in the proposed model, the pathogenicity of Blastocystis sp. isolates that were studied is related to inoculum size and period of infection.