Navegando por Autor "Andrade, Isabel Mayer de"
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Item Avaliação in vivo da atividade anti-Trypanosoma cruzi de derivados nitroimidazólicos.(Programa de Pós-Graduação em Ciências Biológicas. Núcleo de Pesquisas em Ciências Biológicas, Pró-Reitoria de Pesquisa e Pós Graduação, Universidade Federal de Ouro Preto., 2011) Andrade, Isabel Mayer de; Bahia, Maria TerezinhaO objetivo deste estudo foi avaliar a atividade anti-Trypanosoma cruzi de compostos nitroimidazólicos usando quatro ensaios seqüenciais: (i) a avaliação da eficácia de uma dose única de cada composto em reduzir a parasitemia e mortalidade, (ii) a determinação da dose efetiva de cada novo composto usando um esquema terapêutico rápido, por 7 dias, (iii) avaliação da eficácia dos composto em induzir cura em camundongos infectados pela cepa Y, que é moderadamente resistente ao Benznidazol (Bz) e (iv) avaliação da eficácia em induzir cura em camundongos infectados com cepas resistentes ao Bz (cepas VL-10 e Colombiana). Os animais foram infectados com a cepa Y e tratados com Fexinidazol (Fex), DNDi-IM2, DNDi-IM3, DNDi-IM4 e com a droga de referência (Bz). Nossos resultados mostraram que para todos os nitroimidazóis avaliados, uma única dose de 500 mpk (mg/kg) foi eficiente em suprimir ou reduzir a carga parasitária e mortalidade de camundongos infectados pela cepa Y. No segundo esquema de tratamento foi observada uma relação entre a dose do composto avaliado e a resposta terapêutica. O tratamento com 300mpk/dia foi capaz de induzir maior (Fex e DNDi-IM3) similar (DNDi-IM2) ou menor (DNDi-IM4) redução dos níveis de parasitemia, quando comparados com o tratamento com Bz. Em seguida, para verificar a eficácia de cada composto avaliado em induzir cura parasitológica em camundongos infectados pela cepa Y, os animais foram tratados por 20 dias. Confirmando os resultados anteriores, o composto DNDi-IM4 não foi eficiente em induzir cura nos animais infectados pela cepa Y. O DNDi-IM2 induziu 33,3% de cura, sendo o Bz induziu 60,1% de cura. Diferentemente, o tratamento com 300mpk do Fex e do DNDi-IM3 induziu cura parasitológica em 80% e 100% dos camundongos, respectivamente. Considerando, que o Fex demonstrou alta atividade tripanocida, este composto foi utilizado para o tratamento de animais infectados com as cepas VL-10 e Colombiana, resistentes ao Bz. O tratamento com Fex induziu cura em 89% e 78% dos animais infectados pelas cepas VL-10 e Colombiana, respectivamente, sendo que o Bz não foi capaz de induzir cura em nenhum dos animais. O Fex ainda induziu 70% de cura em animais infectados com a cepa VL-10 quando administrado no curso da infecção crônica. Adicionalmente, o tratamento com Fex foi eficaz em reduzir a miocardite em todos os animais infectados com as cepas VL-10 e Colombiana, mesmo nos animais não curados. De maneira geral, nossos resultados mostraram que todos os nitroimidazois avaliados apresentaram atividade anti-T. cruzi, mas com as diferenças individuais na sua eficácia.Item Benznidazole and Posaconazole in experimental Chagas disease: positive interaction in concomitant and sequential treatments.(2013) Diniz, Lívia de Figueiredo; Urbina, Julio Alberto; Andrade, Isabel Mayer de; Mazzeti, Ana Lia; Martins, Tassiane Assíria Fontes; Caldas, Ivo Santana; Silva, André Talvani Pedrosa da; Ribeiro, Isabela; Bahia, Maria TerezinhaBackground: Current chemotherapy for Chagas disease is unsatisfactory due to its limited efficacy, particularly in the chronic phase, with frequent side effects that can lead to treatment discontinuation. Combined therapy is envisioned as an ideal approach since it may improve treatment efficacy whilst decreasing toxicity and the likelihood of resistance development. We evaluated the efficacy of posaconazole in combination with benznidazole on Trypanosoma cruzi infection in vivo. Methods and Findings: Benznidazole and posaconazole were administered individually or in combination in an experimental acute murine infection model. Using a rapid treatment protocol for 7 days, the combined treatments were more efficacious in reducing parasitemia levels than the drugs given alone, with the effects most evident in combinations of sub-optimal doses of the drugs. Subsequently, the curative action of these drug combinations was investigated, using the same infection model and 25, 50, 75 or 100 mg/kg/day (mpk) of benznidazole in combination with 5, 10 or 20 mpk of posaconazole, given alone or concomitantly for 20 days. The effects of the combination treatments on parasitological cures were higher than the sum of such effects when the drugs were administered separately at the same doses, indicating synergistic activity. Finally, sequential therapy experiments were carried out with benznidazole or posaconazole over a short interval (10 days), followed by the second drug administered for the same period of time. It was found that the sequence of benznidazole (100 mpk) followed by posaconazole (20 mpk) provided cure rates comparable to those obtained with the full (20 days) treatments with either drug alone, and no cure was observed for the short treatments with drugs given alone. Conclusions: Our data demonstrate the importance of investigating the potential beneficial effects of combination treatments with marketed compounds, and showed that combinations of benznidazole with posaconazole have a positive interaction in murine models of Chagas disease.Item Benznidazole microcrystal preparation by solvent change precipitation and in vivo evaluation in the treatment of Chagas disease.(2011) Maximiano, Flávia Pires; Paula, Lívia Maria de; Figueiredo, Vivian Paulino; Andrade, Isabel Mayer de; Silva, André Talvani Pedrosa da; Barreto, Lívia Cristina Lira de Sá; Bahia, Maria Terezinha; Cunha Filho, Marcílio Sérgio Soares daBenznidazole (BNZ) is traditionally used to treat Chagas disease. Despite its common use, BNZ has a poor water solubility and a variable bioavailability. The purpose of this study was to prepare BNZ microcrystals by solvent change precipitation and to study the effects of BNZ micronisation on therapeutic efficiency using a murine model of Chagas disease. The solvent change precipitation procedure was optimised in order to obtain stable and homogeneous particles with a small particle size, high yield and fast dissolution rate. The thermal and crystallographic analysis showed no polymorphic change in the microcrystals, and microscopy confirmed a significant reduction in particle size. A marked improvement in the drug dissolution rate was observed for micronised BNZ particles and BNZ tablets in comparison with untreated BNZ and commercial Rochagan_. In vivo studies showed a significant increase in the therapeutic efficacy of the BNZ microparticles, corroborating the dissolution results.Item Benznidazole/Itraconazole combination treatment enhances anti-Trypanosoma cruzi activity in experimental Chagas disease.(2015) Martins, Tassiane Assíria Fontes; Diniz, Lívia de Figueiredo; Mazzeti, Ana Lia; Nascimento, Álvaro Fernando da Silva do; Caldas, Sérgio; Caldas, Ivo Santana; Andrade, Isabel Mayer de; Ribeiro, Isabela; Bahia, Maria TerezinhaThe nitroheterocyclic drugs nifurtimox and benznidazole are first-line drugs available to treat Chagas disease; however, they have limitations, including long treatment courses and toxicity. Strategies to overcome these limitations include the identification of new drugs with specific target profiles, re-dosing regimens for the current drugs, drug repositioning and combination therapy. In this work, we evaluated combination therapy as an approach for optimization of the current therapeutic regimen for Chagas disease. The curative action of benznidazole/itraconazole combinations was explored in an established infection of the mice model with the T. cruzi Y strain. The activities of the benznidazole/itraconazole combinations were compared with the results from those receiving the same dosage of each individual drug. The administration of benznidazole/itraconazole in combination eliminated parasites from the blood more efficiently than each drug alone. Here, there was a significant reduction of the number of treatment days (number of doses) necessary to induce parasitemia suppression with the benznidazole/itraconazole combination, as compared to each compound administered alone. These results clearly indicate the enhanced effects of these drugs in combination, particularly at the dose of 75 mg/kg, as the effects observed with the drug combinations were four times more effective than those of each drug used alone. Moreover, benznidazole/itraconazole treatment was shown to prevent or decrease the typical lesions associated with chronic experimental Chagas disease, as illustrated by similar levels of inflammatory cells and fibrosis in the cardiac muscle tissue of healthy and treated mice. These results emphasize the importance of exploring the potential of combination treatments with currently available compounds to specifically treat Chagas disease.Item Fexinidazole : a potential new drug candidate for Chagas disease.(2012) Bahia, Maria Terezinha; Andrade, Isabel Mayer de; Martins, Tassiane Assíria Fontes; Nascimento, Álvaro Fernando da Silva do; Diniz, Lívia de Figueiredo; Caldas, Ivo Santana; Silva, André Talvani Pedrosa da; Trunz, Bernadette Bourdin; Torreele, Els; Ribeiro, IsabelaBackground: New safe and effective treatments for Chagas disease (CD) are urgently needed. Current chemotherapy options for CD have significant limitations, including failure to uniformly achieve parasitological cure or prevent the chronic phase of CD, and safety and tolerability concerns. Fexinidazole, a 2-subsituted 5-nitroimidazole drug candidate rediscovered following extensive compound mining by the Drugs for Neglected Diseases initiative and currently in Phase I clinical study for the treatment of human African trypanosomiasis, was evaluated in experimental models of acute and chronic CD caused by different strains of Trypanosoma cruzi. Methods and Findings: We investigated the in vivo activity of fexinidazole against T. cruzi, using mice as hosts. The T. cruzi strains used in the study were previously characterized in murine models as susceptible (CL strain), partially resistant (Y strain), and resistant (Colombian and VL-10 strains) to the drugs currently in clinical use, benznidazole and nifurtimox. Our results demonstrated that fexinidazole was effective in suppressing parasitemia and preventing death in infected animals for all strains tested. In addition, assessment of definitive parasite clearance (cure) through parasitological, PCR, and serological methods showed cure rates of 80.0% against CL and Y strains, 88.9% against VL-10 strain, and 77.8% against Colombian strain among animals treated during acute phase, and 70% (VL-10 strain) in those treated in chronic phase. Benznidazole had a similar effect against susceptible and partially resistant T. cruzi strains. Fexinidazole treatment was also shown to reduce myocarditis in all animals infected with VL-10 or Colombian resistant T. cruzi strains, although parasite eradication was not achieved in all treated animals at the tested doses. Conclusions: Fexinidazole is an effective oral treatment of acute and chronic experimental CD caused by benznidazolesusceptible, partially resistant, and resistant T. cruzi. These findings illustrate the potential of fexinidazole as a drug candidate for the treatment of human CD.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.