DEFAR - Departamento de Farmácia
URI permanente desta comunidadehttp://www.hml.repositorio.ufop.br/handle/123456789/530
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Resultados da Pesquisa
Item Activity of the new triazole derivative albaconazole against Trypanosoma (Schizotrypanum) cruzi in dog hosts.(2004) Guedes, Paulo Marcos da Matta; Urbina, Julio Alberto; Lana, Marta de; Afonso, Luís Carlos Crocco; Veloso, Vanja Maria; Tafuri, Washington Luiz; Coelho, George Luiz Lins Machado; Chiari, Egler; Bahia, Maria TerezinhaAlbaconazole is an experimental triazole derivative with potent and broad-spectrum antifungal activity and a remarkably long half-life in dogs, monkeys, and humans. In the present work, we investigated the in vivo activity of this compound against two strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas’ disease, using dogs as hosts. The T. cruzi strains used in the study were previously characterized (murine model) as susceptible (strain Berenice-78) and partially resistant (strain Y) to the drugs currently in clinical use, nifurtimox and benznidazole. Our results demonstrated that albaconazole is very effective in suppressing the proliferation of the parasite and preventing the death of infected animals. Furthermore, the parasitological, PCR, serological, and proliferative assay results indicated parasitological cure indices of 25 and 100% among animals inoculated with T. cruzi strain Y when they were treated with albaconazole at 1.5 mg/kg of body weight/day for 60 and 90 days, respectively. On the other hand, although albaconazole given at 1.5 mg/kg/day was very effective in suppressing the proliferation of the parasite in animals infected with the Berenice-78 T. cruzi strain, no parasitological cure was observed among them, even when a longer treatment period (150 doses) was used. In conclusion, our results demonstrate that albaconazole has trypanocidal activity in vivo and is capable of inducing radical parasitological cure, although natural resistance to this compound was also indicated. Furthermore, the compound can be used in long-term treatment schemes (60 to 150 days) with minimal toxicity and thus represents a potentially useful candidate for the treatment of human Chagas’ disease.Item Trypanosoma cruzi high infectivity in vitro is related to cardiac lesions during long-term infection in beagle dogs.(2007) Guedes, Paulo Marcos da Matta; Veloso, Vanja Maria; Caliari, Marcelo Vidigal; Carneiro, Cláudia Martins; Souza, Sheler Martins de; Lana, Marta de; Chiari, Egler; Bahia, Maria Terezinha; Galvão, Lúcia Maria da CunhaTrypanosoma cruzi is a hemoflagelate parasite associated with heart dysfunctions causing serious problems in Central and South America. Beagle dogs develop the symptoms of Chagas disease in humans, and could be an important experimental model for better understanding the immunopathogenic mechanisms involved in the chagasic infection. In the present study we investigated the relation among biological factors inherent to the parasite (trypomastigote polymorphism and in vitro infectivity) and immunoglobulin production, inflammation, and fibrosis in the heart of Beagle dogs infected with either T. cruzi Y or Berenice-78 strains. In vitro infectivity of Vero cells as well as the extension of cardiac lesions in infected Beagle was higher for Y strain when compared to Berenice-78 strain. These data suggested that in vitro infectivity assays may correlate with pathogenicity in vivo. In fact, animals infected with Y strain, which shows prevalence of slender forms and high infectivity in vitro, presented cardiomegaly, inflammation, and fibrosis in heart area. Concerning the immunoglobulin production, no statistically significant difference was observed for IgA, IgM or IgG levels among T. cruzi infected animals. However, IgA together IgM levels have shown to be a good marker for the acute phase of Chagas disease.Item Benznidazole therapy during acute phase of chagas disease reduces parasite load but does not prevent chronic cardiac lesions.(2008) Caldas, Ivo Santana; Silva, André Talvani Pedrosa da; Caldas, Sérgio; Carneiro, Cláudia Martins; Lana, Marta de; Guedes, Paulo Marcos da Matta; Bahia, Maria TerezinhaThe goals of this study were to evaluate the efficacy of benznidazole (Bz) treatment in decreasing of the parasitic load during the acute phase of experimental Chagas disease and to analyze its influence in the development of cardiac chronic alterations in mice inoculated with drug-resistant Trypanosoma cruzi strains. Our results showed that the early Bz treatment (started at 4th day of infection) was efficient in reducing the parasite load in animals from both acute and chronic phase of the infection. Moreover, this reduction in the parasite load could not be associated with the intensity of the cardiac chronic lesions. The histopathological evaluation of cardiac tissue of Bz-treated mice showed three different patterns of response: (1) presence of a small number of inflammatory cells and fibrotic area similar to noninfected mice; (2) similar intensity of inflammatory infiltrate and smaller fibrotic area in relation to nontreated animals; (3) similar intensity of inflammatory infiltrated and fibrosis area among the Bz-treated and nontreated animals. Each specific pattern was obtained with different T. cruzi strain, suggesting that the pattern of the heart lesions in chronic phase of Bz-treated animals was T. cruzi strain dependent but not related with drug resistance levels.Item Effects of ravuconazole treatment on parasite load and immune response in dogs experimentally infected with trypanosoma cruzi.(2010) Diniz, Lívia de Figueiredo; Caldas, Ivo Santana; Guedes, Paulo Marcos da Matta; Crepalde, Geovam Pereira; Lana, Marta de; Carneiro, Cláudia Martins; Silva, André Talvani Pedrosa da; Urbina, Julio Alberto; Bahia, Maria TerezinhaIn this work, we investigated the in vivo activity of ravuconazole against the Y and Berenice-78 Trypanosoma cruzi strains using acutely infected dogs as hosts. Ravuconazole was well tolerated, as no significant side effects were observed during the treatment using 6.0 mg/kg twice a day (12 mg/kg/day) for up to 90 days. In all treated animals, parasitemia was permanently suppressed by the first day of treatment, independently of the parasite strain. Cultures of blood obtained posttreatment were negative for 90% of the animals, confirming that the drug induced a marked reduction in the parasite load. The results of PCR tests for T. cruzi in blood performed 1 month posttreatment were consistently negative for three of five and two of five animals infected with the Y and Berenice-78 strains, respectively. All ravuconazole-treated dogs consistently had negative serological test results during and until 30 days after treatment, regardless of the therapeutic scheme used. However, after the end of treatment, an increase in specific antibody levels was observed in all treated animals, although the antibody levels were always significantly lower than those of the nontreated control dogs. Despite being unable to induce a parasitological cure, ravuconazole treatment led to significant reductions in the levels of gamma interferon expression and lesions in cardiac tissues in animals infected with the Y strain, while the level of interleukin-10 mRNA expression increased. We conclude that ravuconazole has potent suppressive but not curative activity in the canine model of acute Chagas' disease, probably due to its unfavorable pharmacokinetic properties (half-life, 8.8 h). The longer half-life of ravuconazole in humans (4 to 8 days) makes it a promising drug for assessment for use as chemotherapy in human Chagas' disease.Item 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 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.