Browsing by Author "Murta, Silvane Maria Fonseca"
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Item Avaliação da atividade anti-Trypanosoma cruzi in vitro e in vivo do composto silibinina isolado e associado ao benznidazol.(2019) Torchelsen, Fernanda Karoline Vieira da Silva; Lana, Marta de; Silva, Glenda Nicioli da; Murta, Silvane Maria Fonseca; Brandão, Geraldo Célio; Lana, Marta deA doença de Chagas (DC) é uma doença parasitária endêmica na América Latina e encontrada em diversos países no mundo. Seu tratamento é feito com o benznidazol (BZ) e o nifurtimox (NF), ambos fármacos com baixa eficácia terapêutica na maoria dos pacientes em fase crônica tardia da DC, e que causam vários efeitos colaterais. A busca por novos fármacos para a DC é estimulada entre produtos naturais e em estratégias como associação de fármacos. A silibinina (SLB) é um composto natural capaz de inibir a proteína de efluxo (Pgp) nas membranas celulares, induzir a morte de microrganismos, além de possuir atividade anti-inflamatória. Ainda não há na literatura relato de sua atividade em T. cruzi. Neste trabalho foi avaliada a atividade in vitro e in vivo de SLB e de SLB associada a BZ (SLB+BZ) frente a cepa Y de T. cruzi. Foi realizado ensaio de citotoxicidade pelo método de MTT em células VERO (24h), que revelou IC50 de 250,22 µM para a SLB. A atividade tripanocida avaliada por método com resazurina em epimastigotas (24h) mostrou que a SLB 25 µM inibiu o crescimento dos parasitos. O ensaio em amastigotas revelou índice de seletividade de 3,13, além de mostrar a maior porcentagem de inibição (> 90%) quando a SLB foi usada na associação de SLB100+BZ10µM, em comparação com SLB (100; 25; 6,25 µM) ou BZ (10; 5; 2,5 µM) isolados. No ensaio in vivo, camundongos Swiss comprovadamente infectados IP com 10.000 tripomastigotas sanguíneos foram tratados por via oral por 20 dias consecutivos com SLB50, SLB150, SLB50+BZ25, SLB50+BZ50, SLB50+BZ100, SLB150+BZ25, SLB150+BZ50, SLB150+BZ100, BZ25, BZ50 e BZ100 mg/kg/dia. Os animais foram avaliados diariamente na fase aguda (parasitemia) e aos 90, 180 e 240 dias após tratamento por hemocultura, qPCR de eluato sanguíneo e sorologia (ELISA). Após a eutanásia, foram feitas, além das avaliações anteriores, a qPCR do tecido cardíaco. Os resultados in vivo demonstraram que a SLB em monoterapia não foi capaz de controlar a parasitemia e a mortalidade dos animais. As avaliações parasitológicas mostraram 100% de negatividade na maioria dos grupos de animais tratados com combinação de drogas ou doses menores de BZ, enquanto a sorologia foi positiva em todos os animais não sendo constatada cura pelo critério clássico. Entretanto verificamos que os grupos experimentais tratados com BZ em menores doses e que os tratados com BZ em menores doses quando associado a SLB apresentaram maior negatividade nos exames parasitológicos, porém sem diferenças significativas entre os demais grupos. Análise histopatológica cardíaca será feita para avaliar se houve redução da inflamação/fibrose entre os grupos tratados com a associação SLB+BZ versus BZ.Item Avaliação do tratamento com benznidazol, itraconazol e sua associação na fase aguda da doença de Chagas experimental no modelo cão.(2017) Cunha, Eleonora Lima Alves; Lana, Marta de; Lana, Marta de; Silva, André Talvani Pedrosa da; Murta, Silvane Maria FonsecaA doença de Chagas (DCh) e seu tratamento permanecem negligenciados e ainda constitui um sério problema de saúde pública na América Latina. O benznidazol (BZ) é atualmente o único fármaco disponível no Brasil para o tratamento da DCh, apresentando efeitos colaterais graves, limitada e variável eficácia terapêutica, especialmente na fase crônica da doença. Após os ensaios clínicos feitos no Brasil demonstrarem que os derivados azólicos de primeira geração não promoveram cura parasitológica e nem impediram a progressão da DCh em humanos, os estudos de associação de fármacos desta classe de compostos com BZ passaram a ser estimulados. Nesse sentido, o objetivo do presente estudo foi avaliar a ação terapêutica do BZ, itraconazol (ITRA) e de sua associação (BZ+ITRA), em cães infectados com cepa VL-10 do Trypanosoma cruzi (T. cruzi) tratados durante a fase aguda da infecção e seu impacto na evolução clínica da doença. O modelo cão foi utilizado por ser considerado ideal para o estudo da DCh e seu tratamento, pois reproduzem as fases aguda e crônica da doença e a manifestação clínica mais importante, a cardiopatia chagásica crônica. Para tal, 20 cães jovens sem raça definida foram inoculados via IP com 2000 tripomastigotas sanguíneas de T. cruzi/kg, e divididos em 4 grupos: I – tratados com BZ: 7 mg/kg em duas doses diárias; II – tratados com ITRA: 6 mg/kg/dia; III – tratados com BZ+ITRA na mesma posologia da monoterapia; IV – grupo controle infectado não tratado. Os animais foram tratados a partir do primeiro dia de parasitemia patente por 60 dias consecutivos. Foram realizados exames de sangue a fresco, hemocultura, reação em cadeia da polimerase (PCR) em eluato de sangue, sorologia convencional (ELISA), PCR quantitativa e histopatologia de tecido cardíaco. Após 18 meses das repetidas avaliações dos animais, foi possível observar uma melhor atividade terapêutica da associação de BZ+ITRA do que nos grupos tratados com ITRA e BZ em monoterapia. De acordo com o critério de cura estabelecido pelo Ministério da Saúde (2016), o cão B8, tratado com BZ+ITRA, apresentou na sua última avaliação resultados negativos nos testes parasitológicos e na ELISA, sugerindo estar curado. Já o cão B4 tratado com ITRA e o cão B7 tratados com BZ+ITRA, apresentaram avaliações parasitológicas negativas, exceto sorologia convencional. Contudo, para a melhor compreensão da cura efetiva dos animais ainda seriam necessárias mais avaliações a longo prazo ou técnicas alternativas.Item Design, synthesis, molecular modelling, and in vitro evaluation of tricyclic coumarins against Trypanosoma cruzi.(2019) Coelho, Gleicekelly Silva; Andrade, Josimara Souza; Xavier, Viviane Flores; Sales Júnior, Policarpo Ademar; Araújo, Bárbara Caroline Rodrigues de; Fonseca, Kátia da Silva; Caetano, Melissa Soares; Murta, Silvane Maria Fonseca; Vieira, Paula Melo de Abreu; Carneiro, Cláudia Martins; Taylor, Jason GuyChagas disease is caused by infection with the parasite protozoan Trypanosoma cruzi and affects about 8 million people in 21 countries in Latin America. The main form of treatment of this disease is still based on the use of two drugs, benznidazole and nifurtimox, which both present low cure rates in the chronic phase and often have serious side-effects. Herein, we describe the synthesis of tricyclic coumarins that were obtained via NHC organocatalysis and evaluation of their trypanocidal activity. Molecular docking studies against trypanosomal enzyme triosephosphate isomerase (TIM) were carried out, as well as a theoretical study of the physicochemical parameters. The tricyclic coumarins were tested in vitro against the intracellular forms of Trypanosoma cruzi. Among the 18 compounds tested, 10 were more active than the reference drug benznidazole. The trypanocidal activity of the lead compound was rationalized by molecular docking study which suggested the strong interaction with the enzyme TIM by T. cruzi and therefore indicating a possible mode of action. Furthermore, the selectivity index of eight tricyclic coumarins with high anti-T. cruzi activity was above 50 and thus showing that these lead compounds are viable candidates for further in vivo assays.Item Experimental and clinical treatment of Chagas disease : a review.(2017) Sales Júnior, Policarpo Ademar; Molina, Israel; Murta, Silvane Maria Fonseca; Sánchez Montalvá, Adrián; Salvador, Fernando; Oliveira, Rodrigo Corrêa de; Carneiro, Cláudia MartinsChagas disease (CD) is caused by the protozoan parasite Trypanosoma cruzi that infects a broad range of triatomines and mammalian species, including man. It afflicts 8 million people in Latin America, and its incidence is increasing in nonendemic countries owing to rising international immigration and nonvectorial transmission routes such as blood donation. Since the 1960s, the only drugs available for the clinical treatment of this infection have been benznidazole (BZ) and nifurtimox (NFX). Treatment with these trypanocidal drugs is recommended in both the acute and chronic phases of CD. These drugs have low cure rates mainly during the chronic phase, in addition both drugs present side effects that may result in the interruption of the treatment. Thus, more efficient and better-tolerated new drugs or pharmaceutical formulations containing BZ or NFX are urgently needed. Here, we review the drugs currently used for CD chemotherapy, ongoing clinical assays, and most-promising new experimental drugs. In addition, the mechanism of action of the commercially available drugs, NFX and BZ, the biodistribution of the latter, and the potential for novel formulations of BZ based on nanotechnology are discussed. Taken together, the literature emphasizes the urgent need for new therapies for acute and chronic CD.Item In vitro evaluation of synthetic flavones against Trypanosoma cruzi.(2021) Andrade, Josimara Souza; Abreu, Leonardo Gomes de; Sales Júnior, Policarpo Ademar; Murta, Silvane Maria Fonseca; Taylor, Jason GuyChagas disease is caused by infection of the parasite protozoan Trypanosoma cruzi and affects about 8 million people in 21 countries in Latin America. Treatment of this disease is still based on the use of benznidazole or nifurtimox, which both present low cure rates in the chronic phase and often have many undesirable side effects. Herein, we describe the synthesis of flavones and evaluation of their trypanocidal activity. The flavones were tested to in vitro against T. cruzi and amongst the 13 compounds tested, 6 of these demonstrated some modest trypanocidal activity in vitro. Enhancements in anti T. cruzi activity were noted for flavones bearing either nitro or methoxy substituents. Moreover, very low cytotoxicities were maintained for flavones with methoxy groups which suggests that this functional group favors more selective trypanocidal compounds. Finally, structural modification at position 3 of the dihydropyrone ring provided the most active flavone, which suggests that the introduction of different functionalities at this position could yield promising new compounds with trypanocidal properties.Item Influence of the long-term Trypanosoma cruzi infection in vertebrate host on the genetic and biological diversity of the parasite.(2005) Veloso, Vanja Maria; Romanha, Alvaro José; Lana, Marta de; Murta, Silvane Maria Fonseca; Carneiro, Claudia Martins; Alves, Cíntia Fontes; Borges, Erika Carime; Tafuri, Washington Luiz; Coelho, George Luiz Lins Machado; Chiari, Egler; Bahia, Maria TerezinhaThe influence of the long-term Trypanosoma cruzi infection in vertebrate host on the biological and genetic properties of the parasite was evaluated. Four T. cruzi isolates obtained from different chronic chagasic dogs infected with Berenice-78 T. cruzi strain during 2 and 7 years were comparatively analyzed. The long-term T. cruzi infection has led to alterations in parasitemia, virulence and pathogenicity of Be-78 strain for mice. These biological parameters varied from low to high in realation to the parental strain. Randomly amplified polymorphic DNA and isoenzyme profiles detected two distinct genetic groups of parasites. The first group included the parental strain and two T. cruzi isolates, and the second group the two other isolates. Interestingly, the isolates of the second group showed a reversibility of the genetic profile to the parental strain after 25 passages in mice. No correlation between the genetic groups and biological properties of the isolates was observed. Our findings confirmed the population heterogeneity of the Be-78 strain, and showed how differently it responds to the long-term infection in the same vertebrate hosts.Item Synthesis of 3,5-Diarylisoxazole derivatives and evaluation of in vitro trypanocidal activity.(2017) Souza, Aline Aparecida Nunes de; Xavier, Viviane F.; Coelho, Gleicekelly Silva; Sales Júnior, Policarpo Ademar; Romanha, Alvaro José; Murta, Silvane Maria Fonseca; Carneiro, Claudia Martins; Taylor, Jason GuyChagas disease is included in the neglected tropical diseases list and is endemic to 21 Latin American countries. The two drugs currently available for treating Chagas disease are nifurtimox and benznidazole and both result in many significant side effects. The study describes the synthesis and biological evaluation of 3,5-disubstituted isoxazoles. Isoxazoles were obtained by reaction of flavones and hydroxylamine and either alkylated at the free hydroxyl group and/or nitrated at the isoxazole ring. These compounds were evaluated for their in vitro anti-Trypanosoma cruzi activity against trypomastigote and amastigote forms of the parasite in T. cruzi-infected cell lineages. Benznidazole was used as a reference compound for the in vitro assay and mammalian L929 cells were employed to evaluate cytotoxicity. A majority of the compounds tested were very active and the most active isoxazole against amastigote and trypomastigotes of T. cruzi was slightly more potent than the current medicine benznidazole.Item Synthesis of xylitan derivatives and preliminary evaluation of in vitro trypanocidal activity.(2016) Elias, Paula Regina; Coelho, Gleicekelly Silva; Xavier, Viviane Flores; Sales Júnior, Policarpo Ademar; Romanha, Alvaro José; Murta, Silvane Maria Fonseca; Carneiro, Claudia Martins; Camilo, Nilton Soares; Hilário, Flaviane Francisco; Taylor, Jason GuyA series of novel xylitan derivatives derived from xylitol were synthesized using operationally simple procedures. A xylitan acetonide was the key intermediate used to prepare benzoate, arylsulfonate esters and 1,2,3-triazole derivatives of xylitan. These compounds were evaluated for their in vitro anti-Trypanosoma cruzi activity against trypomastigote and amastigote forms of the parasite in T. cruzi-infected cell lineages. Benznidazole was used as positive control against T. cruzi and cytotoxicity was determined in mammalian L929 cells. The arylsulfonate xylitan derivative bearing a nitro group displayed the best activity of all the compounds tested, and was slightly more potent than the reference drug benznidazole. The importance of the isopropylidene ketal moiety was established and the greater lipophilicity of these compounds suggests enhancement in cell penetration.Item Trypanocidal activity and increased solubility of benznidazole incorporated in PEG 4000 and its derivatives.(2021) Sousa, Lucas Resende Dutra; Azevedo, Maria Luíza Schaefer; Rocha, Dayana F.; Andrade, Ângela Leão; Amparo, Tatiane Roquete; Santos, Orlando David Henrique dos; Seibert, Janaína Brandão; Pereira, Luciano Rodrigues; Vieira, Paula Melo de Abreu; Carneiro, Cláudia Martins; Barboza, Ana Paula Moreira; Neves, Bernardo Ruegger Almeida; Sales Junior, Policarpo Ademar Molina; Murta, Silvane Maria Fonseca; Novack, Kátia Monteiro; Santos, Viviane Martins Rebello dosSelecting a polymer depends on its characteristics, the properties of the drug and of the remaining ingredients in the formulation. The drug, when incorporated into a polymeric matrix, can show several advantages when compared with its conventional form. In this context, this work describes the preparation and characterization of polyethylene glycol (PEG 4000) and its derivative particles loaded with benznidazole, as well as evaluates their trypanocidal activity. In this work, reactions to modify the PEG 4000 polymer and the subsequent incorporation of the benznidazole were made. The nuclear magnetic resonance (NMR) analysis confirmed the efficiency in modifying the PEG chains. The morphology of polymeric films was observed by atomic force microscopy (AFM) and showed considerable changes on the film organization. The acetylation of PEG favored the stability of the system and an increase in the zeta potential from -14.83 to -25.54 mV was observed. Although encapsulation efficiency values between 30.14 and 39.48% were found, the enhanced benznidazole dissolution profile by microparticles enables the use of lower drug concentrations. This fact can be proven by the increased trypanocidal effect of benznidazole when encapsulated in BP3 microparticles. Finally, the high selectivity of the formulations for trypanocidal action guarantees their safety as an alternative for the treatment of the Chagas disease.Item Trypanocidal activity of flavanone derivatives.(2020) Diogo, Gabriela Maciel; Andrade, Josimara Souza; Sales Júnior, Policarpo Ademar; Murta, Silvane Maria Fonseca; Santos, Viviane Martins Rebello dos; Taylor, Jason GuyChagas disease, also known as American trypanosomiasis, is classified as a neglected disease by the World Health Organization. For clinical treatment, only two drugs have been on the market, Benznidazole and Nifurtimox, both of which are recommended for use in the acute phase but present low cure rates in the chronic phase. Furthermore, strong side effects may result in discontinuation of this treatment. Faced with this situation, we report the synthesis and trypanocidal activity of 3-benzoyl-flavanones. Novel 3-benzoyl-flavanone derivatives were prepared in satisfactory yields in the 3-step synthetic procedure. According to recommended guidelines, the whole cell-based screening methodology was utilized that allowed for the simultaneous use of both parasite forms responsible for human infection. The majority of the tested compounds displayed promising anti-Trypanosoma cruzi activity and the most potent flavanone bearing a nitrofuran moiety was more potent than the reference drug, Benznidazole.