DEFAR - Departamento de Farmácia
URI permanente desta comunidadehttp://www.hml.repositorio.ufop.br/handle/123456789/530
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Resultados da Pesquisa
Item 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 TerezinhaBenznidazole (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.Item 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 LuizA 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 otherItem 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 TerezinhaPara 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.Item 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 CunhaA 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.Item 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 daTrypanosoma 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.Item 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 TerezinhaThrough 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.Item Trypanosoma cruzi : acute and long-term infection in the vertebrate host can modify the response to benznidazole.(2008) Caldas, Sérgio; Santos, Fabiane Matos dos; Lana, Marta de; Diniz, Lívia de Figueiredo; Coelho, George Luiz Lins Machado; Veloso, Vanja Maria; Bahia, Maria TerezinhaWe analyzed the influence of Trypanosoma cruzi maintenance in different hosts (dog and mouse) on its susceptibility to benznidazole treatment. Five T. cruzi stocks were isolated from dogs inoculated with Be-62 or Be-78 strain (both sensitive to benznidazole) 2–10 years ago, and the benznidazole sensitivity was then determined using the mouse as experimental model. The different T. cruzi stocks obtained from long-term infected dogs showed 50–90% drug resistance right after isolation. However, maintenance of these T. cruzi stocks in mice, by successive blood passages (2.5 years), led to either a decrease or stability of the drug resistance pattern and an increase in parasite virulence. We also demonstrated the effectiveness of the induction of parasitemia reactivation by cyclophosphamide immunosuppression in the evaluation of the response to the specific drug treatment.Item Myenteric plexus is differentially affected by infection with distinct Trypanosoma cruzi strains in Beagle dogs.(2014) Paiva, Nívia Carolina Nogueira de; Fonseca, Kátia da Silva; Vieira, Paula Melo de Abreu; Diniz, Lívia de Figueiredo; Caldas, Ivo Santana; Moura, Sandra Aparecida Lima de; Veloso, Vanja Maria; Guedes, Paulo Marcos da Matta; Tafuri, Washington Luiz; Bahia, Maria Terezinha; Carneiro, Cláudia MartinsChagasic megaoesophagus and megacolon are characterised by motor abnormalities related to enteric nervous system lesions and their development seems to be related to geographic distribution of distinct Trypanosoma cruzi subpopulations. Beagle dogs were infected with Y or Berenice-78 (Be-78) T. cruzi strains and necropsied during the acute or chronic phase of experimental disease for post mortem histopathological evaluation of the oesophagus and colon. Both strains infected the oesophagus and colon and caused an inflammatory response during the acute phase. In the chronic phase, inflammatory process was observed exclusively in the Be-78 infected animals, possibly due to a parasitism persistent only in this group. Myenteric denervation occurred during the acute phase of infection for both strains, but persisted chronically only in Be-78 infected animals. Glial cell involvement occurred earlier in animals infected with the Y strain, while animals infected with the Be-78 strain showed reduced glial fibrillary acidic protein immunoreactive area of enteric glial cells in the chronic phase. These results suggest that although both strains cause lesions in the digestive tract, the Y strain is associated with early control of the lesion, while the Be-78 strain results in progressive gut lesions in this model.Item Trypanosoma cruzi : genetic diversity influences the profile of immunoglobulins during experimental infection.(2009) Santos, Daniela Maria dos; Silva, André Talvani Pedrosa da; Guedes, Paulo Marcos da Matta; Coelho, George Luiz Lins Machado; Lana, Marta de; Bahia, Maria TerezinhaThe clonal evolution model postulated for Trypanosoma cruzi predicts a correlation between the phylogenetic divergence of T. cruzi clonal genotypes and their biological properties. In the present study, the linkage between phylogenetic divergence of the parasite and IgG, IgG1, IgG2a and IgG2b response has been evaluated during the acute and chronic phases of the experimental infection. Eight laboratory-cloned stocks representative of this phylogenetic diversity and including the lineages T. cruzi I (genotypes 19 and 20), T. cruzi II (genotype 32) and T. cruzi (genotype 39) have been studied. The results showed that the pattern of humoral immune response was correlated with T. cruzi genotype, and that stocks included in genotype 20 were responsible for the high IgG response in the acute and chronic phases. Moreover, T. cruzi I lineage was more efficient in over-expressing all subclasses of specific anti-parasite IgG than either T. cruzi II or T. cruzi lineages. Curiously, the alteration in the pattern of antibodies induced by Benznidazole treatment was related to the phase of the infection but not to the genotype of the parasite. The data suggest that genotypes of T. cruzi are able to drive levels/subclasses of specific IgG, hence giving rise to further concerns about the sensitivity of serological assays in the diagnosis of human Chagas disease.