DEFAR - Departamento de Farmácia

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Data inicial: 1988Assunto: search.filters.subject.Trypanosoma cruzi

Resultados da Pesquisa

Agora exibindo 1 - 10 de 13
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    Structure-activity relationship study of antitrypanosomal analogues of gibbilimbol B using multivariate analysis and computation-aided drug design.
    (2023) Leão, Luiz Paulo Melchior de Oliveira; Vieira, Nátalie de Barros; Oliveira, Paula P. S.; Paula, Daniela Aparecida Chagas de; Soares, Marisi Gomes; Souza, Thiago Belarmino de; Zanin, João Luiz Baldim; Silva, Thais Alves da Costa; Cardoso, André Gustavo Tempone; Dias, Danielle Ferreira; Lago, João Henrique Ghilardi
    Gibbilimbol B and analogues were isolated from the Brazilian plant Piper malacophyllum and displayed activity against trypomastigote forms of Trypanosoma cruzi as well as reduced toxicity against NCTC cells. These results stimulated the preparation of a series of 24 chemically related analogues to study the potential of these com- pounds against T. cruzi trypomastigotes and explore structure–activity relationships. Initially, 12 compounds were planned, maintaining the same extension of the linear side chain of gibbilimbol B and unsaturation on the C-4 position but changing the functional groups – ester and amide – and variating the substituent at the p-po- sition in the aromatic ring. Other 12 compounds were prepared using a branched side chain containing an ethyl group at the C-2 position. Overall, these structurally-related analogues demonstrated promising activity against trypomastigote forms (EC50 < 20 μM) and no mammalian cytotoxicity to fibroblasts (CC50 > 200 μM). Using multivariate statistics and machine learning analysis, aspects associated with structure/activity were related to their three-dimensional structure and, mainly, to the substituents on the aromatic ring. Obtained results sug- gested that the presence of t-butyl or nitro groups at p-position with appropriate side chains causes an alteration in the electron topological state, Van der Waals volumes, surface areas, and polarizabilities of tested compounds which seem to be essential for biological activity against T. cruzi parasites.
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    From rational design to serendipity : discovery of novel thiosemicarbazones as potent trypanocidal compounds.
    (2022) Braga, Saulo Fehelberg Pinto; Santos, Viviane Corrêa; Vieira, Rafael Pinto; Silva, Elany Barbosa da; Monti, Ludovica; Krake, Susann Hannelore; Martinez, Pablo D. G.; Dias, Luiz Carlos; Caffrey, Conor R.; Siqueira Neto, Jair Lage de; Oliveira, Renata Barbosa de; Ferreira, Rafaela Salgado
    Chagas disease is a major public health problem caused by Trypanosoma cruzi, with an estimated 6–7 million people infected and 70 million at risk of infection. T. brucei gambiense and T. brucei rhodesiense are two subspecies of related parasites that cause human African trypanosomiasis, a neglected tropical disease with also millions of people at risk of infection. Pharmacotherapy for both diseases suffers from low efficacy, side effects, or drug resistance. Recently, we reported a noncovalent competitive inhibitor of cruzain (IC50 26 μM, Ki 3 μM) and TbrCatL (IC50 50 μM), two cysteine proteases considered promising drug targets for trypanosomiasis. Here, we describe the design and synthesis of derivatives of our lead compound. The new thiosemicarbazone derivatives showed potency in the nanomolar concentration range against the two enzymes, but they were later charac- terized as aggregators. Nevertheless, the thiosemicarbazone derivatives showed promising antiparasitic activities against T. b. brucei (EC50 13–49.7 μM) and T. cruzi (EC50 0.027–0.59 μM) under in vitro conditions. The most active thiosemicarbazone was 200-fold more potent than the current anti-chagasic drug, benznidazole, and showed a selectivity index of 370 versus myoblast cells. We have identified an excellent candidate for further optimization and in vivo studies.
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    Benznidazole self-emulsifying delivery system : a novel alternative dosage form for Chagas disease treatment.
    (2020) Mazzeti, Ana Lia; Oliveira, Liliam Teixeira; Gonçalves, Karolina Ribeiro; Schaun, Géssica C.; Mosqueira, Vanessa Carla Furtado; Bahia, Maria Terezinha
    Benznidazole (BZ) tablets are a unique form of treatment available for treating Chagas disease. Development of a liquid formulation containing BZ easy to administer orally for the treatment of paediatric patients, particularly for newborns is urgently required, with the same efficacy, safety and suitable biopharmaceutical properties as BZ tablets. Self-emulsifying drug delivery systems (SEDDS) may improve bioavailability of drugs such as BZ, which have poor water solubility and low permeability. In this context, the aim of this work was to develop a liquid BZ-SEDDS formulation as an alternative to tablets and to evaluate its cytotoxicity in different host cell lines and its efficacy in experimental Trypanosoma cruzi infection in mice. The optimized SEDDS formulation (25 mg/ml of BZ) induced no cytotoxicity in H9c2, HepG2 and Caco2 cells in vitro at 25 μM level. BZ-SEDDS and free-BZ showed similar in vitro trypanocidal activity in H9c2 cells infected by T. cruzi Y strain, with IC50 values of 2.10 ± 0.41 μM and 1.29 ± 0.01 μM for BZ and BZ-SEDDS, respectively. A follow up of efficacy in an acute model of infected mice resulted in the same percentage of cure (57%) for both free-BZ and BZ-SEDDS- groups according to established parameters. Furthermore, no additional in vivo toxicity was observed in animals treated with BZ-SEDDS. Taken together, in vitro and in vivo data of BZ-SEDDS showed that the incorporation of BZ into SEDDS does not alter its potency, efficacy and safety. Thus, BZ-SEDDS can be a more practical and personalized orally administered liquid dosage form compared to suspension of crushed BZ-tablets to treat newborn and young children by emulsifying SEDDS in different aqueous liquids with advantage of dosing flexibility.
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    Immunohistochemical studies in acute and chronic canine chagasic cardiomyopathy.
    (2002) Caliari, Marcelo Vidigal; Lana, Marta de; Cajá, Rosângela Aparecida França; Carneiro, Cláudia Martins; Bahia, Maria Terezinha; Santos, César Augusto Bueno dos; Magalhães, Gustavo Albergaria; Sampaio, Ivan Barbosa Machado; Tafuri, Washington Luiz
    A major characteristic of Chagas’ disease is a myocarditis constituted primarily of mononuclear cells, both during the acute and chronic phases of the disease. Using monoclonal antibodies and image analyses we have quantified canine CD8+ T cells (caCD8+ T cells), canine CD4+ T cells (caCD4+ T cells) and neutrophils in canine chagasic myocardiopathy induced by two strains isolated from the first human clinical case of Chagas’ disease. We also evaluated the influence of tissue parasitism in the genesis of chronic myocarditis through immunohistochemistry. As in human myocarditis, there was a predominance of T lymphocytes in the inflammatory infiltrate in all animals studied. In the dogs inoculated with strain Berenice 78 (Be78) and necropsied during the acute phase of infection, we found 58% caCD8+ and 42% caCD4+ T cells. In chronically infected animals, 53% of T cells were represented by caCD8+ and 47% were caCD4+ T cells. Since normal canine lymphoid organs are constituted by 70–80% caCD4+ T cells and 20–30% caCD8+ T cells our results indicate a higher proliferation of caCD8+ T cells in dogs inoculated with the Be78 strain. In chronic myocarditis induced by the Berenice 62 (Be62) strain, caCD8+ cells constituted 33% of the T cells and 67% were caCD4+ T cells, a proportion similar to that found in normal canine lymphoid organs. Since the Be78 strain induces greater loss of myocardiocytes than strain Be62, we believe that the caCD8+ T cells, among other factors, can be important in the genesis of these lesions. Amastigote nests and immunohistochemically labelled Trypanosoma cruzi antigen were not found in dogs necropsied during the chronic phase. The absence of the parasite in the myocardium suggests the involvement of other
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    Increase of reactive oxygen species by desferrioxamine during experimental Chagas' disease.
    (2010) Francisco, Amanda Fortes; Vieira, Paula Melo de Abreu; Arantes, Jerusa Marilda; Silva, Maísa; Pedrosa, Maria Lúcia; Santos, Silvana Maria Elói; Martins Filho, Olindo Assis; Carvalho, Andréa Teixeira de; Araújo, Márcio Sobreira Silva
    Oxidative stress is common in inflammatory processes associated with many diseases including Chagas’ disease. The aim of the present study was to evaluate, in a murine model, biomarkers of oxidative stress together with components of the antioxidant system in order to provide an overview of the mechanism of action of the iron chelator desferrioxamine (DFO). The study population comprised 48 male Swiss mice, half of which were treated daily by intraperitoneal injection of DFO over a 35-day period, while half were administered sterile water in a similar manner. On the 14th day of the experiment, 12 DFO-treated mice and an equal number of untreated mice were experimentally infected with Trypanosoma cruzi. Serum concentrations of nitric oxide and superoxide dismutase and hepatic levels of total glutathione, thiobarbituric acid reactive species and protein carbonyl, were determined on days 0, 7, 14 and 21 post-infection. The results obtained revealed that DFO enhances antioxidant activity in the host but also increases oxidative stress, indicating that the mode of action of the drug involves a positive contribution to the host together with an effect that is not beneficial to the parasite.
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    Trypanosoma cruzi Discret Typing Units (TcII and TcVI) in samples of patients from two municipalities of the Jequitinhonha Valley, MG, Brazil, using two molecular typing strategies.
    (2015) Oliveira, Maykon Tavares de; Assis, Girley Francisco Machado de; Silva, Jaquelline Carla Valamiel de Oliveira e; Machado, Evandro Marques de Menezes; Silva, Glenda Nicioli da; Veloso, Vanja Maria; Macedo, Andréa Mara; Martins, Helen Rodrigues; Lana, Marta de
    Background: Trypanosoma cruzi is classified into six discrete taxonomic units (DTUs). For this classification, different biological markers and classification criteria have been used. The objective was to identify the genetic profile of T. cruzi samples isolated from patients of two municipalities of Jequitinhonha Valley, MG, Brazil. Methods: Molecular characterization was performed using two different criteria for T. cruzi typing to characterize 63 T. cruzi samples isolated from chronic Chagas disease patients. The characterizations followed two distinct methodologies. Additionally, the RAPD technique was used to evaluate the existence of genetic intragroup variability. Results: The first methodology identified 89 % of the samples as TcII, but it was not possible to define the genetic identity of seven isolates. The results obtained with the second methodology corroborated the classification as TcII of the same samples and defined the classification of the other seven as TcVI. RAPD analysis showed lower intra-group variability in TcII. Conclusions: The results confirmed the preliminary data obtained in other municipalities of the Jequitinhonha Valley, showing a predominance of TcII, similar to that verified in northeast/south axis of Brazil and the first detection of TcVI in the study region. The second protocol was more simple and reliable to identify samples of hybrid character.
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    Hematological alterations during experimental canine infection by Trypanosoma cruzi.
    (2012) Guedes, Paulo Marcos da Matta; Veloso, Vanja Maria; Mineo, Tiago Wilson Patriarca; Silva, Juliana Santiago; Crepalde, Geovam Pereira; Caldas, Ivo Santana; Nascimento, Manuela Sales Lima; Lana, Marta de; Chiari, Egler; Galvão, Lúcia Maria da Cunha; Bahia, Maria Terezinha
    Para confirmar que cães Beagle são um bom modelo para doença de Chagas, foram avaliadas as alterações hematológicas durante as fases aguda e crônica em cães Beagle infectados com as cepas Y, Berenice-78 (Be-78) e ABC de Trypanosoma cruzi, correlacionando os sinais clínicos com a curva de parasitemia. Foi demonstrado que a fase aguda da infecção foi marcada por letargia e perda de apetite. Simultaneamente, observou-se anemia, leucocitose e linfocitose. Ainda, foram descritas alterações hematológicas e sinais clínicos positivamente correlacionados com a parasitemia durante a infecção experimental com as três cepas de T. cruzi estudadas, demonstrando que a infecção em cães Beagle constitui um modelo fidedigno para a doença de Chagas.
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    IgG isotype profile is correlated with cardiomegaly in Beagle dogs infected with distinct Trypanosoma cruzi strains.
    (2008) Guedes, Paulo Marcos da Matta; Veloso, Vanja Maria; Gollob, Kenneth John; Afonso, Luís Carlos Crocco; Caldas, Ivo Santana; Vianna, Priscila; Lana, Marta de; Chiari, Egler; Bahia, Maria Terezinha; Galvão, Lúcia Maria da Cunha
    A systematic study following infection by various strains of the protozoan parasite, Trypanosoma cruzi, and the simultaneous monitoring of the humoral immune response together with the elicited cellular response, could add greatly to our understanding of differences between strains of this important human pathogen. In that sense, acute and chronic infections with distinct T. cruzi strains (Y, Berenice-78 and ABC) in Beagle dogs were studied through a longitudinal evaluation of immunoglobulin G (IgG), IgG1 and IgG2 isotypes (by ELISA and flow cytometry (FC)), as well as measurements of peripheral blood mononuclear cell (PBMC) proliferation over a 100-week period, and their correlation with cardiomegaly. Our results show that infected animals presenting cardiomegaly showed lower or absent levels of IgG1 during the chronic phase of the infection, when compared to those that did not show an increase in heart weight. In that manner, our results suggest that IgG1 could be used as a marker for cardiac pathogenicity in Chagas disease.
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    Short-term therapy with simvastatin reduces inflammatory mediators and heart inflammation during the acute phase of experimental Chagas disease.
    (2012) Silva, Rafael Rodrigues; Bajracharya, Deena Shrestha; Leite, Camila Megale Almeida; Leite, Romulo; Bahia, Maria Terezinha; Silva, André Talvani Pedrosa da
    Trypanosoma cruzi infection induces progressive cardiac inflammation that leads to fibrosis and modifications in the heart architecture and functionality. Statins, such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, have been studied due to their pleiotropic roles in modulating the inflammatory response. Our goal was to evaluate the effects of simvastatin on the cardiac inflammatory process using a cardiotropic strain of T. cruzi in a murine model of Chagas cardiomyopathy. C57BL/6 mice were infected with 500 trypomastigotes of the Colombian strain of T. cruzi and treated with an oral dose of simvastatin (20 mg/Kg/day) for one month and inflam-matory and morphometric parameters were subsequently evaluated in the serum and in the heart, respectively. Simvastatin reduced the total cholesterol and inflammatory mediators (interferon-gamma, tumour necrosis factor-alpha, CCL2 and CCL5) in the serum and in the heart tissue at 30 days post-infection. Additionally, a proportional reduction in heart weight and inflammatory infiltration was observed. Simvastatin also reduced epimastigote pro¬liferation in a dose-dependent manner in vitro and was able to reduce blood trypomastigotes and heart amastigote nests during the acute phase of Chagas disease in vivo. Based on these data, we conclude that simvastatin exerts a modulatory effect on the inflammatory mediators that are elicited by the Colombian strain of T. cruzi and amelio¬rates the heart damage that is observed in a murine model of Chagas disease.
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    Trypanosoma cruzi : induction of benznidazole resistance in vivo and its modulation by in vitro culturing and mice infection.
    (2008) Santos, Fabiane Matos dos; Caldas, Sérgio; Cáu, Stêfany Bruno de Assis; Crepalde, Geovam Pereira; Lana, Marta de; Coelho, George Luiz Lins Machado; Veloso, Vanja Maria; Bahia, Maria Terezinha
    Through a continuous in vivo drug pressure protocol, using mice as experimental model, we induced benznidazole resistance in Trypanosoma cruzi stocks. Full resistance was obtained for four out of five T. cruzi stocks analyzed. However, the number of benznidazole doses (40–180), as well as the time (4–18 months) necessary to induce resistance varied among the different T. cruzi stocks. The resistance phenotype remained stable after T. cruzi stocks has been maintained by 12 passages in mice (six months) and in acellular culture for the same time. However, the maintenance of resistant parasite for 12 months in acellular culture induces a reduction in its level of benznidazole resistance, while no alteration was detected in parasite maintained for the same time in mice. The data showed the stability of the resistance acquired by drug pressure, but suggest the possibility of reversible changes in the resistance levels after maintenance for long time in acellular culture.