Benznidazole Treatment: Time- and Dose-Dependence Varies with the Trypanosoma cruzi Strain

Trypanosoma cruzi; Benznidazol; Estratègies terapèutiquesTrypanosoma cruzi; Benznidazol; Estrategias terapéuticasTrypanosoma cruzi; Benznidazole; Therapeutic strategiesAs the development of new drugs for Chagas disease is not a priority due to its neglected disease status, an option for increasing treatment adherence is to explore alternative treatment regimens, which may decrease the incidence of side effects. Therefore, we evaluated the efficacy of different therapeutic schemes with benznidazole (BNZ) on the acute and chronic phases of the disease, using mice infected with strains that have different BNZ susceptibilities. Our results show that the groups of animals infected by VL-10 strain, when treated in the chronic phase with a lower dose of BNZ for a longer period of time (40 mg/kg/day for 40 days) presented better treatment efficacy than with the standard protocol (100 mg/kg/day for 20 days) although the best result in the treatment of the animals infected by the VL-10 strain was with100 mg/kg/day for 40 days. In the acute infection by the Y and VL-10 strains of T. cruzi, the treatment with a standard dose, but with a longer time of treatment (100 mg/kg/day for 40 days) presented the best results. Given these data, our results indicate that for BNZ, the theory of dose and time proportionality does not apply to the phases of infection.Funding was provided by the Universidade Federal de Ouro Preto (UFOP), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), research fellowships from CNPq (Carneiro CM, Correa-Oliveira R), CAPES—Science Without Borders and Senior Research Visitor (Molina I, Correa-Oliveira R), and BERENICE (Collaborative Project supported by the European Commission under the Health Innovation Work Programme of the 7th Framework Programme). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Benznidazole Treatment : Time- and Dose-Dependence Varies with the Trypanosoma cruzi Strain

As the development of new drugs for Chagas disease is not a priority due to its neglected disease status, an option for increasing treatment adherence is to explore alternative treatment regimens, which may decrease the incidence of side effects. Therefore, we evaluated the efficacy of different therapeutic schemes with benznidazole (BNZ) on the acute and chronic phases of the disease, using mice infected with strains that have different BNZ susceptibilities. Our results show that the groups of animals infected by VL-10 strain, when treated in the chronic phase with a lower dose of BNZ for a longer period of time (40 mg/kg/day for 40 days) presented better treatment efficacy than with the standard protocol (100 mg/kg/day for 20 days) although the best result in the treatment of the animals infected by the VL-10 strain was with100 mg/kg/day for 40 days. In the acute infection by the Y and VL-10 strains of T. cruzi, the treatment with a standard dose, but with a longer time of treatment (100 mg/kg/day for 40 days) presented the best results. Given these data, our results indicate that for BNZ, the theory of dose and time proportionality does not apply to the phases of infectio

Efeito do polimorfismo biol?gico e molecular do Trypanosoma cruzi sobre a resposta imune e as altera??es teciduais no cora??o e c?lon de camundongos na fase cr?nica da infec??o.

Programa de P?s-Gradua??o em Ci?ncias Biol?gicas. N?cleo de Pesquisas em Ci?ncias Biol?gicas, Pr?-Reitoria de Pesquisa de P?s Gradua??o, Universidade Federal de Ouro Preto.V?rios fatores atuam na patog?nese da doen?a de Chagas (DCh), alguns s?o inerentes ao Trypanosoma cruzi, enquanto outros est?o relacionados ao hospedeiro. Estudos demonstram uma associa??o entre o desenvolvimento de distintas formas cl?nicas e o tropismo tecidual de diferentes linhagens do T. cruzi, apontando o polimorfismo gen?tico como fator cr?tico para o progn?stico da doen?a. Dados pr?vios do nosso grupo de pesquisa demonstraram que um isolado da cepa Berenice-78 (Be-78is) tem caracter?sticas histopatol?gicas semelhantes ? cepa Be-62, bem como parasitemia semelhante ? Be-78 parental, na fase aguda da DCh. Diante disso, esse trabalho teve como objetivo avaliar o efeito do polimorfismo biol?gico e molecular do T. cruzi sobre o processo inflamat?rio e as altera??es da matriz extracelular no cora??o e c?lon de camundongos ao longo da fase cr?nica da infec??o experimental. Para isso 80 camundongos BALB/c foram divididos em quatro grupos experimentais: NI (n?o infectados), cepa Be-62, isolado Be-78is e cepa Be-78 parental, os animais foram eutanasiados aos 90 dias ap?s a infec??o (DAI). Os dados obtidos neste trabalho, mostram que os animais infectados pela cepa Be-78 parental mantiveram a carga parasit?ria no cora??o ao longo da infec??o, se comparado aos dados da fase aguda (Nogueira-Paiva, 2015) no entanto, aos 90DAI, o processo inflamat?rio, exuberante na fase aguda foi capaz de gerar dano tecidual reparado com uma discreta fibrose, sugerindo na fase cr?nica recente, uma situa??o de equil?brio entre parasito-hospedeiro, que pode estar relacionada ? presen?a de amastigotas quiescentes, incapazes de gerar est?mulo antig?nico necess?rio ? inflama??o, portanto, ?protegidas? do efeito citot?xico da resposta imune celular. Em contrapartida, os animais infectados pelo isolado Be-78is apresentavam um histotropismo preferencial para o c?lon e uma resposta imune aparentemente controlada no cora??o, demonstraram, aos 90DAI, neste ?rg?o, carga parasit?ria maior que a observada na fase aguda (Nogueira-Paiva, 2015) que embora, inferior em rela??o ? cepa parental, acompanhada de processo inflamat?rio que foi importante no controle do parasitismo tecidual. Em detrimento do processo inflamat?rio sustentado na fase cr?nica, nenhuma altera??o na express?o de laminina e conexina 43 foi observado nos animais infectados em rela??o os animais n?o infectados, o que pode estar relacionado ao aumento da citocina IL-10 encontrado nos animais infectados pelo isolado Be-78is que foi capaz de imunomodular o efeito citot?xico da resposta inflamat?ria. Assim, podemos concluir que no cora??o, o isolado Be-78is parece apresentar um perfil atrasado em rela??o ? cepa Be-78 parental, podendo estar relacionado a uma patogenicidade inferior ou at? mesmo por apresentar uma infec??o mais silenciosa, sendo necess?rias an?lises mais tardias que poderiam evidencia melhor as les?es causadas nos casos cl?nicos na DCh.Several factors acting on the pathology of Chagas disease (DCh), some are inherent to Trypanosoma cruzi, while others are related to the host. Studies show an association between the development of different clinical forms and the geographical distribution of different T. cruzi strains, pointing to genetic polymorphism as a critical factor for disease prognosis. Data from our research group demonstrated that Be-78 has histopathological features similar to Be62, as well as the parental parasitemia of Be-78 in the acute phase of DCh. Therefore, this study aimed to evaluate the effect of T. cruzi biological and molecular polymorphism on the inflammatory process and extracellular matrix changes in the heart and colon of mice during the chronic phase of experimental infection. For this, 80 BALB/c mice were divided into three experimental groups: NI (uninfected), strain Be-62, parental Be-78is and Be-78 isolates, euthanized 90 days after infection (DAI). The data obtained in this work show that the animals infected with the parental Be-78 strain maintained the parasitic load on the heart throughout the infection, compared to the data from the acute phase (Nogueira-Paiva, 2015), however, at 90DAI, the process inflammatory, exuberant in the acute phase was able to generate tissue damage repaired with mild fibrosis, suggesting in the recent chronic phase, a situation of balance between host parasite, which may be related to the presence of quiescent amastigotes, unable to generate antigenic stimulus necessary for inflammation, therefore, ?protected? from the cytotoxic effect of the cellular immune response. In contrast, the animals infected by the Be-78is isolate had a preferential histotropism for the colon and an apparently controlled immune response in the heart, demonstrated, at 90DAI, in this organ, a greater parasitic load than that observed in the acute phase (Nogueira-Paiva, 2015) which, although inferior to the parental strain, accompanied by an inflammatory process that was important in the control of tissue parasitism. To the detriment of the inflammatory process sustained in the chronic phase, no change in the expression of laminin and connexin43 was observed in infected animals compared to non-infected animals, which may be related to the increase in the cytokine IL-10 found in animals infected by the isolate Be -78is that was able to immunomodulate the cytotoxic effect of the inflammatory response. Thus, we can conclude that in the heart, the Be-78is isolate appears to show a delayed profile in relation to the parental Be-78 strain, which may be related to a lower pathogenicity or even to have a quieter infection, requiring later analyzes that could better evidence the injuries caused in clinical cases in DCh