EFAR - Escola de Farmácia
URI permanente desta comunidadehttp://www.hml.repositorio.ufop.br/handle/123456789/451
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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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Item New miconazole-based azoles derived from eugenol show activity against Candida spp. and Cryptococcus gattii by inhibiting the fungal ergosterol biosynthesis.(2023) Péret, Vinícius Augusto Campos; Reis, Rúbia Castro Fernandes Melo; Braga, Saulo Fehelberg Pinto; Benedetti, Monique Dias; Caldas, Ivo Santana; Carvalho, Diogo Teixeira; Santana, Luiz Felipe de Andrade; Johann, Susana; Souza, Thiago Belarmino deThis work describes the design, synthesis and antifungal activity of new imidazoles and 1,2,4-triazoles derived from eugenol and dihydroeugenol. These new compounds were fully characterized by spectroscopy/spectro- metric analyses and the imidazoles 9, 10, 13 e 14 showed relevant antifungal activity against Candida sp. and Cryptococcus gattii in the range of 4.6–75.3 μM. Although no compound has shown a broad spectrum of antifungal activity against all evaluated strains, some azoles were more active than either reference drugs employed against specific strains. Eugenol-imidazole 13 was the most promising azole (MIC: 4.6 μM) against Candida albicans being 32 times more potent than miconazole (MIC: 150.2 μM) with no relevant cytotoxicity (selectivity index >28). Notably, dihydroeugenol-imidazole 14 was twice as potent (MIC: 36.4 μM) as miconazole (MIC: 74.9 μM) and more than 5 times more active than fluconazole (MIC: 209.0 μM) against alarming multi-resistant Candida auris. Furthermore, in vitro assays showed that most active compounds 10 and 13 altered the fungal ergosterol biosynthesis, reducing its content as fluconazole does, suggesting the enzyme lanosterol 14α-demethylase (CYP51) as a possible target for these new compounds. Docking studies with CYP51 revealed an interaction between the imidazole ring of the active substances with the heme group, as well as insertion of the chlorinated ring into a hydrophobic cavity at the binding site, consistent with the behavior observed with control drugs miconazole and fluconazole. The increase of azoles-resistant isolates of Candida species and the impact that C. auris has had on hospitals around the world reinforces the importance of discovery of azoles 9, 10, 13 e 14 as new bioactive compounds for further chemical optimization to afford new clinically antifungal agents.Item Synthesis, activity, and molecular modeling studies of 1,2,3‐ triazole derivatives from natural phenylpropanoids as new trypanocidal agents.(2019) Souza, Thiago Belarmino de; Caldas, Ivo Santana; Paula, Favero Reisdorfer; Rodrigues, Camila Coelho; Carvalho, Diogo Teixeira; Dias, Danielle FerreiraThe search for compounds with new structural scaffolds is an important tool to the discovery of new drugs against Chagas disease. We report herein the synthesis of 1,2,3‐triazoles obtained from eugenol and di‐hydroeugenol and their in vitro and in vivo trypanocidal activity. These derivatives were obtained by a three‐step objective route and were suitably characterized by 1H and 13C nuclear magnetic resonance spectroscopy and high‐resolution mass spectrometry. Two compounds (9 and 10 ) showed activity against epimastigote forms of Trypanosoma cruzi (Y strain) in the range 42.8–88.4 μM and were weakly toxic to cardiomyoblast cells (H9c2 cells). The triazole 10 was the most active derivative and could reduce more than 50% of parasitemia after a 100‐mg/kg oral treatment of mice infected with T. cruzi . Molecular docking studies suggested this compound could act as a trypanocidal agent by inhibiting cruzain, an essential enzyme for T. cruzi metabolism, usually inhibited by triazole compounds.Item Retinol-binding protein 4 and insulin resistance are related to body fat in primary and secondary schoolchildren : the Ouro Preto study.(2014) Castro, Ana Paula Pereira; Cândido, Ana Paula Carlos; Nicolato, Roney Luiz de Carvalho; Caldas, Ivo Santana; Coelho, George Luiz Lins MachadoPurpose Evidence suggests that plasma retinol-binding protein 4 (RBP4) and insulin resistance are related to body fat (BF). We aimed to assess the relationship between RBP4 and insulin resistance with obesity in a mixed (skin color) cohort of the Brazilian population. Methods A nested case–control study was conducted in 227 schoolchildren aged 7–14 years. Schoolchildren with a high BF percentage (% BF, C 30 for girls and C 25 for boys) were identified as the obese group (n = 137), and those with lower values were identified as the non-obese group (n = 90). Percentage of body fat (% BF) was determined by tetrapolar bioimpedance (Quantum II, RJL System), RBP4 by enzyme-linked immunosorbent assay (Immunology Consultants Laboratory), plasma fasting insulin by chemiluminescent immunoassay (Access Immunoassay System) and insulin resistance by the homeostasis model insulin resistance (IRHOMA) index. Serum lipid profile and arterial blood pressure were evaluated. Results The significant independent risk factors associated with obesity were as follows: male sex, increased serum LDL-C, RBP4 and IRHOMA. Among children with higher RBP4, the association with obesity increased significantly (from 3.1 to 8.5) in the presence of insulin resistance, when compared to higher RBP4 and non-insulin resistance. Conclusion IRHOMA and RBP4 showed significant associations with obesity and traditional CVD risk factors. They might therefore be used as a marker for CVD risk and have clinical implications in the development of comorbidities associated with obesity.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 Trypanosoma cruzi : blood parasitism kinetics and their correlation with heart parasitism intensity during long-term infection of Beagle dogs.(2008) Veloso, Vanja Maria; Guedes, Paulo Marcos da Matta; Andrade, Isabel Mayer de; Caldas, Ivo Santana; Martins, Helen Rodrigues; Carneiro, Cláudia Martins; Coelho, George Luiz Lins Machado; Lana, Marta de; Galvão, Lúcia Maria da Cunha; Bahia, Maria Terezinha; Chiari, EglerThe goals of the present study were to evaluate the kinetics of blood parasitism by examination of fresh blood, blood culture (BC) and PCR assays and their correlation with heart parasitism during two years of infection in Beagle dogs inoculated with the Be-78, Y and ABC Trypanosoma cruzi strains. Our results showed that the parasite or its kDNA is easily detected during the acute phase in all infected animals. On the other hand, a reduced number of positive tests were verified during the chronic phase of the infection. The frequency of positive tests was correlated with T. cruzi strain. The percentage of positive BC and blood PCR performed in samples from animals inoculated with Be-78 and ABC strains were similar and significantly larger in relation to animals infected with the Y strain. Comparison of the positivity of PCR tests performed using blood and heart tissue samples obtained two years after infection showed two different patterns associated with the inoculated T. cruzi strain: (1) high PCR positivity for both blood and tissue was observed in animals infected with Be-78 or ABC strains; (2) lower and higher PCR positivity for the blood and tissue, respectively, was detected in animals infected with Y strains. These data suggest that the sensitivity of BC and blood PCR was T. cruzi strain dependent and, in contrast, the heart tissue PCR revealed higher sensitivity regardless of the parasite stock.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.