EFAR - Escola de Farmácia
URI permanente desta comunidadehttp://www.hml.repositorio.ufop.br/handle/123456789/451
Notícias
O curso de Farmácia em Ouro Preto foi criado em 1839, sendo a mais antiga Escola de Farmácia da América Latina.
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12 resultados
Resultados da Pesquisa
Item The effect of benznidazole dose among the efficacy outcome in the murine animal model. A quantitative integration of the literature.(2020) Molina, Israel; Melo, Luísa Helena Perin de; Aviles, Augusto Sao; Vieira, Paula Melo de Abreu; Fonseca, Kátia da Silva; Cunha, Lucas Maciel; Carneiro, Cláudia MartinsDespite more than 100 years since it was firstly described Chagas disease, only two drugs are available to treat Chagas disease: Nifurtimox launched by Bayer in 1965 and benznidazole launched by Roche in 1971. Drug discovery initiatives have been looking for new compounds as an alternative to these old drugs. Although new platforms have been used with the latest technologies, a critical step on that process still relies on the in vivo model. Unfortunately, to date, available animal models have limited predictive value and there is no standardization. With the aim to better understand the role of benznidazole, the current standard of care of Chagas disease, we performed this review. We intend to analyze the influence of the experimental design of the most used animal model, the murine model, in the assessment of the efficacy endpoint.Item Pharmacokinetic and tissue distribution of benznidazole after oral administration in mice.(2017) Melo, Luísa Helena Perin de; Silva, Rodrigo Moreira da; Fonseca, Kátia da Silva; Cardoso, Jamille Mirelle de Oliveira; Mathias, Fernando Augusto Siqueira; Reis, Levi Eduardo Soares; Molina, Israel; Oliveira, Rodrigo Corrêa de; Vieira, Paula Melo de Abreu; Carneiro, Cláudia MartinsSpecific chemotherapy using benznidazole (BNZ) for Chagas disease during the chronic stage is controversial due to its limited efficacy and toxic effects. Although BNZ has been used to treat Chagas disease since the 1970s, few studies about the biodistribution of this drug exist. In this study, BNZ tissue biodistribution in a murine model and its pharmacokinetic profile in plasma were monitored. A bioanalytical high-performance liquid chromatography method with a UV detector (HPLC-UV) was developed and validated according to the European Medicines Agency for quantification of BNZ in organs and plasma samples prepared by liquidliquid extraction using ethyl acetate. The developed method was linear in the BNZ concentration, which ranged from 0.1 to 100.0 g/ml for plasma, spleen, brain, colon, heart, lung, and kidney and from 0.2 to 100.0 g/ml for liver. Validation assays demonstrated good stability for BNZ under all conditions evaluated. Pharmacokinetic parameters confirmed rapid, but low, absorption of BNZ after oral administration. Biodistribution assays demonstrated different maximum concentrations in organs and similar times to maximum concentration and mean residence times, with means of 40 min and 2.5 h, respectively. Therefore, the biodistribution of BNZ is extensive, reaching organs such as the heart and colon, which are the most relevant organs affected by Trypanosoma cruzi infection, and also the spleen, brain, liver, lungs, and kidneys. Simultaneous analyses of tissues and plasma indicated high BNZ metabolism in the liver. Our results suggest that low bioavailability, instead of inadequate biodistribution, coulItem 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 Different infective forms trigger distinct immune response in experimental Chagas disease.(2012) Vieira, Paula Melo de Abreu; Franscisco, Amanda Fortes; Machado, Evandro Marques de Menezes; Nogueira, Nívia Carolina; Fonseca, Kátia da Silva; Reis, Alexandre Barbosa; Carvalho, Andréa Teixeira de; Martins Filho, Olindo Assis; Tafuri, Washington Luiz; Carneiro, Cláudia MartinsAlthough metacyclic and blood trypomastigotes are completely functional in relation to parasite-host interaction and/or target cell invasion, they differ in the molecules present on the surface. Thus, aspects related to the variability that the forms of T. cruzi interacts with host cells may lead to fundamental implications on the immune response against this parasite and, consequently, the clinical evolution of Chagas disease. We have shown that BT infected mice presented higher levels of parasitemia during all the acute phase of infection. Moreover, the infection with either MT or BT forms resulted in increased levels of total leukocytes, monocytes and lymphocytes, specifically later for MT and earlier for BT. The infection with BT forms presented earlier production of proinflammatory cytokine TNF-a and later of IFN-c by both T cells subpopulations. This event was accompanied by an early cardiac inflammation with an exacerbation of this process at the end of the acute phase. On the other hand, infection with MT forms result in an early production of IFN-c, with subsequent control in the production of this cytokine by IL-10, which provided to these animals an immunomodulatory profile in the end of the acute phase. These results are in agreement with what was found for cardiac inflammation where animals infected with MT forms showed intense cardiac inflammation later at infection, with a decrease in the same at the end of this phase. In summary, our findings emphasize the importance of taking into account the inoculums source of T. cruzi, since vectorial or transfusional routes of T. cruzi infection may trigger distinct parasite-host interactions during the acute phase that may influence relevant biological aspects of chronic 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 Follow-up of experimental chronic Chagas’ disease in dogs : use of polymerase chain reaction (PCR) compared with parasitological and serological methods.(2002) Araújo, Flávio Marcos Gomes de; Bahia, Maria Terezinha; Magalhães, Neuza Maria de; Martins Filho, Olindo Assis; Veloso, Vanja Maria; Carneiro, Cláudia Martins; Tafuri, Washington Luiz; Lana, Marta deIn this study, the polymerase chain reaction (PCR) was compared with parasitological and serological methods to detect the infection in dogs, 5–12 years after experimental infection with Trypanosoma cruzi. The ability of parasitological methods to identify a positive animal was 22 and 11% by hemoculture and xenodiagnosis/xenoculture, respectively. On the other hand, the serological tests, including conventional serology and anti-live trypomastigote antibodies (ALTA) were positive in all infected dogs. Despite its low sensitivity, if considering only one reaction, the PCR analysis showed 100% of positivity, demonstrating the presence of parasite kDNA in all infected dogs. To identify a positive dog required at least two blood samples and up to nine repeated reactions using the same sample. Serial blood sample collection, ranging from 1 to 9, revealed that the percentage of dogs with positive PCR ranged from 67 to 100%. These findings suggested that, although the PCR is useful to detect the parasite in infected hosts, it should not be used isolated for the diagnosis of Chagas’ disease and warn for the necessity of serial blood collection and re-tests. Moreover, these data validate once more the dog as a model for Chagas’ disease since they demonstrate the permanence of infection by PCR, parasitological and serological methods, reaching relevant requisites for an ideal model to study this disease.Item Further genetic characterization of the two Trypanosoma cruzi Berenice strains (Be-62 and Be-78) isolated from the first human case of Chagas disease (Chagas, 1909).(2006) Cruz, Ruth Elizabeth; Macedo, Andréa Mara; Barnabé, Christian; Freitas, Jorge Marcelo de; Chiari, Egler; Veloso, Vanja Maria; Carneiro, Cláudia Martins; Bahia, Maria Terezinha; Tafuri, Washington Luiz; Lana, Marta deWe describe here an extension of a previous genetic characterization of Trypanosoma cruzi strains (Be-62 and Be-78) isolated from the patient Berenice, the first human case of Chagas disease [Chagas, C., 1909. Nova Tripanom´ıase humana. Estudos sobre morfologia e o ciclo evolutivo do Schizotrypanum cruzi, n. gen., n. sp., agente etiol´ojico da nova entidade morbida do homem. Mem. Inst. Oswaldo Cruz 1, 159–218]. We wanted to verify the composition of T. cruzi populations originated from these two isolates. In the present work, 22 enzymatic loci (MLEE), nine RAPD primers and 7 microsatellite loci were analyzed. Clones from both strains were also characterized to verify whether these strains are mono or polyclonal. Be-62 and Be-78 strains were different in 3 out of 22 enzymatic systems, in 3 out of 9 RAPD primers tested and in all microsatellite loci investigated. However, our data suggests that both strains are phylogenetically closely related, belonging to genetic group 32 from Tibayrenc and Ayala [Tibayrenc, M., Ayala, F.J., 1988. Isoenzime variability in Trypanosoma cruzi, the agent of Chagas’ disease: genetical, taxonomical, and epidemiological significance. Evolution 42, 277–292], equivalent to zymodeme 2 and T. cruzi II major lineage which, in Brazil, comprises parasites from the domestic cycle of the disease. Microsatellite analyses showed differences betweenthe parental strains but suggested that both populations are monoclonal since each strain and their respective clones showed the same amplification products.Item Trypanosoma cruzi : effect of benznidazole therapy combined with the iron chelator desferrioxamine in infected mice.(2008) Francisco, Amanda Fortes; Vieira, Paula Melo de Abreu; Arantes, Jerusa Marilda; Pedrosa, Maria Lúcia; Martins, Helen Rodrigues; Silva, Maísa; Veloso, Vanja Maria; Lana, Marta de; Bahia, Maria Terezinha; Tafuri, Washington Luiz; Carneiro, Cláudia MartinsIron chelators have been employed in various studies aimed at evaluating the relationship between the iron status of the host and the development of infection. In the present study, the effects of benznidazole (BZ) therapy in combination with the iron chelator desferrioxamine (DFO) on the development of infection in mice inoculated with Trypanosoma cruzi Y strain have been investigated. Infected mice treated with DFO presented lower levels of parasitemia compared with infected untreated animals. Therapy with BZ for 21 days, with or without DFO, led to decreased parasitemia and reduced mortality, but BZ in combination with DFO treatment for 35 days (BZ/DFO-35) gave 0% mortality. All infected groups presented lower levels of iron in the liver, but serum iron concentrations were greater in DFO-35 and BZ/DFO-35, whereas hemoglobin levels were higher in BZ/DFO-35 and lower in DFO-35 compared with other treated groups. The percentage cure, determined from negative hemoculture and PCR results in animals that had survived for 60 days post-infection, was 18% for BZ and BZ/DFO-35, 42% for BZ combined with DFO for 21 days, and 67% for DFO-35. The results demonstrate that modification in iron stores increases BZ efficacy.Item Trypanosoma cruzi : desferrioxamine decreases mortality and parasitemia in infected mice through a trypanostatic effect.(2011) Arantes, Jerusa Marilda; Francisco, Amanda Fortes; Vieira, Paula Melo de Abreu; Silva, Maísa; Araújo, Márcio Sobreira Silva; Carvalho, Andréa Teixeira de; Pedrosa, Maria Lúcia; Carneiro, Cláudia Martins; Tafuri, Washington Luiz; Martins Filho, Olindo Assis; Santos, Silvana Maria ElóiDesferrioxamine (DFO) is a potent iron chelator that is also known to modulate inflammation and act as an efficient antioxidant under normal conditions and under oxidative stress. Many in vitro and in vivo studies have shown the efficacy of DFO in the treatment of viral, bacterial and protozoan infections. DFO is known to reduce the intensity of Trypanosoma cruzi infections in mice even during a course of therapy that is not effective in maintaining anaemia or low iron levels. To further clarify these findings, we investigated the action of DFO on mouse T. cruzi infection outcomes and the direct impact of DFO on parasites. Infected animals treated with DFO (5 mg/animal/day) for 35 days, beginning 14 days prior to infection, presented lower parasitemia and lower cumulative mortality rate. No significant effect was observed on iron metabolism markers, erythrograms, leukograms or lymphocyte subsets. In the rapid method for testing in vivo T. cruzi susceptibility, DFO also induced lower parasitemia. In regard to its direct impact on parasites, DFO slightly inhibited the growth of amastigotes and trypomastigotes in fibroblast culture. Trypan blue staining showed no effects of DFO on parasite viability, and only minor apoptosis in trypomastigotes was observed. Nevertheless, a clear decrease in parasite mobility was detected. In conclusion, the beneficial actions of DFO on mice T. cruzi infection seem to be independent of host iron metabolism and free of significant haematological side effects. Through direct action on the parasite, DFO has more effective trypanostatic than trypanocidal properties.Item Differential impact of metacyclic and blood trypomastigotes on parasitological, serological and phenotypic features triggered during acute Trypanosoma cruzi infection in dogs.(2007) Carneiro, Cláudia Martins; Martins Filho, Olindo Assis; Reis, Alexandre Barbosa; Veloso, Vanja Maria; Araújo, Flávio Marcos Gomes de; Bahia, Maria Terezinha; Lana, Marta de; Coelho, George Luiz Lins Machado; Gazzinelli, Giovanni; Oliveira, Rodrigo Corrêa de; Tafuri, Wagner LuizDifferential impact of metacyclic and blood trypomastigotes on parasitological, serological and phenotypic features triggered during acute Trypanosoma cruzi infection in dogs A detailed follow-up investigation of the major parasitological, serological and phenotypic features in dogs experimentally infected with metacyclic (MT) and blood (BT) trypomastigotes of Trypanosoma cruzi strain Berenice-78, typifying vectorial and transfusional transmission of human Chagas disease, has been conducted. Although there were no changes with respect to the window of patent-parasitaemia, significant differences between MT- and BT-infected dogs in both the prepatent period (days 23 and 19, respectively) and the day of maximum parasitaemia (days 26 and 22, respectively) were recorded. A progressive enhancement in the level of T. cruzi -specific antibodies accompanied infection by both MT and BT forms, although higher IgG titres developed on days 14 and 21 following infection with MT forms. Higher Thy-1 + /CD21 + and lower CD4 + /CD8 + cell ratios, occasioned by increased levels of Thy-1 + and CD8 + T-cells and reduced frequencies of CD4 + T-cells and CD21 + B-lymphocytes, were observed in both MT- and BT-infected animals. The reduced frequency of CD14 + leukocytes was revealed as the most relevant phenotypic feature intrinsic to T. cruzi infection independent of inoculum source. BT-specific phenotypic features included an early reduction