Browsing by Author "Molina, Israel"

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    Course of serological tests in treated subjects with chronic Trypanosoma cruzi infection : a systematic review and meta-analysis of individual participant data.
    (2018) Sguassero, Yanina; Roberts, Karen N.; Harvey, Guillermina B.; Comandé, Daniel; Cuesta, Cristina B.; Aguiar, Camila; Castro, Ana M. de; Danesi, Emmaría; Andrade, Ana L. de; Lana, Marta de; Escribà, Josep M.; Fabbro, Diana L.; Fernandes, Cloé Duarte; Flores Chávez, María; Hasslocher Moreno, Alejandro Marcel; Jackson, Yves Laurent; Assis, Girley Francisco Machado de; Maldonado, Marisel; Meira, Wendell Sérgio Ferreira; Molina, Israel; Monje Rumi, María Mercedes; Martín, Catalina Muñoz-San; Murcia, Laura; Castro, Cleudson Nery de; Negrette, Olga Sánchez; Segovia, Manuel; Silveira, Celeste Aída Nogueira; Solari, Aldo; Steindel, Mário; Streiger, Mirtha Leonor; Bilbao, Ninfa Vera de; Zulantay, Inés; Sosa Estani, Sergio
    Objective To determine the course of serological tests in subjects with chronic Trypanosoma cruzi infection treated with anti-trypanosomal drugs. Methods A systematic review and meta-analysis was conducted using individual participant data. Survival analysis and the Cox proportional hazards regression model with random effects to adjust for covariates were applied. The protocol was registered in the PROSPERO database (http://www.crd.york.ac.uk/PROSPERO; CRD42012002162). Results A total of 27 studies (1296 subjects) conducted in eight countries were included. The risk of bias was low for all domains in 17 studies (63.0%). Nine hundred and thirteen subjects were assessed (149 seroreversion events, 83.7% censored data) for enzyme-linked immunosorbent assay (ELISA), 670 subjects (134 events, 80.0% censored) for indirect immunofluorescence assay (IIF), and 548 subjects (99 events, 82.0% censored) for indirect hemagglutination assay (IHA). A higher probability of seroreversion was observed within a shorter time span in subjects aged 1–19 years compared to adults. The chance of seroreversion also varied according to the country where the infection might have been acquired. For instance, the pooled adjusted hazard ratio between children/adolescents and adults for the IIF test was 1.54 (95% confidence interval 0.64–3.71) for certain countries of South America (Argentina, Bolivia, Chile, and Paraguay) and 9.37 (95% confidence interval 3.44–25.50) for Brazil. Conclusions The disappearance of anti-T. cruzi antibodies was demonstrated along the course of follow-up. An interaction between age at treatment and country setting was found.
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    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 Martins
    Chagas 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.
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    Low-dose of benznidazole promotes therapeutic cure in experimental chronic Chagas' disease with absence of parasitism in blood, heart and colon.
    (2020) Melo, Luísa Helena Perin de; Fonseca, Kátia da Silva; Carvalho, Thaís Vieira de; Carvalho, Lívia Mendes; Madeira, João Vitor; Medeiros, Luciana da Fonseca; Molina, Israel; Oliveira, Rodrigo Corrêa de; Carneiro, Cláudia Martins; Vieira, Paula Melo de Abreu
    Studies suggest that the dose of the standard benznidazole (BNZ) treatment regimen might be too high. We investigated the efficacy of BNZ 20 and 40 mg/kg/day compared with standard dose (100 mg/kg/day) to induce cure in mice infected with Trypanosoma cruzi Y strain in the acute and chronic phases of Chagas' disease. Our findings indicate that an experimental treatment with a BNZ low-dose (40 mg/kg/day) is similarly effective as the usual dose in the chronic mice model (100% of cure). In addition, the treatment in the chronic model of Chagas' disease presented better results than the acute model and colon appears to be a key tissue when it comes to evaluating treatment efficacy compared to blood and heart. Therefore, our data suggest the reconsideration of the current therapy, mainly in the chronic phase of the disease.
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    Novas estratégias para o tratamento da doença de Chagas com benznidazol : eficácia, farmacocinética, farmacocinética populacional e relação farmacocinética/farmacodinâmica no modelo camundongo.
    (2019) Melo, Luísa Helena Perin de; Oliveira, Rodrigo Corrêa de; Vieira, Paula Melo de Abreu; Molina, Israel; Vieira, Paula Melo de Abreu; Azeredo, Francine Johansson; Bahia, Maria Terezinha; Lana, Marta de; Moraes, Natália Valadares de; Oliveira, Rodrigo Corrêa de
    O presente estudo avaliou a eficácia, farmacocinética (PK), biodistribuição (BD), dose proporcionalidade (DP), farmacocinética populacional (POPPK) e a relação entre a farmacocinética/farmacodinâmica (PK/PD) de novas estratégias terapêuticas com benznidazol (BNZ) em camundongos Swiss. O estudo foi dividido em dois capítulos. O capítulo I determina a eficácia de diferentes abordagens terapêuticas utilizando BNZ frente à infecção com diferentes cepas do Trypanosoma cruzi. O capítulo II analisa a PK e a BD do BNZ, utilizando-se da POPPK desse fármaco em camundongos sadios. No capítulo I foi avaliada a eficácia terapêutica do BNZ em três abordagens: na Abordagem I a eficácia do tratamento com BNZ nas doses de 40 e 20 mg/kg/dia por 20 dias durante a infecção aguda (IA) e crônica (IC) pela cepa Y; na Abordagem II a eficácia do tratamento com complexos nanoconjugados de benznidazol:ciclodextrina (BNZ:HPβCD) nas doses de 40 e 20 mg/kg/dia por 20 dias durante a IA pela cepa Y e na Abordagem III a eficácia do tratamento com BNZ nas doses de 100 e 40 mg/kg/dia por 20 e 40 dias durante a IA pela cepa Y e durante a IA e IC pelas cepas Be-78 e VL-10. Nas duas primeiras abordagens, os resultados mostram que o tratamento durante a IA pela cepa Y com as doses de 40 e 20 mg/kg/dia de BNZ e BNZ:HPβCD é capaz de suprimir a parasitemia e prevenir a mortalidade, mas não demonstra capacidade de cura. Por outro lado, o tratamento com BNZ 40 mg/kg/dia por 20 dias durante a IC curou 100% dos camundongos. Na terceira sequência de experimentos, os animais infectados pela cepa Be-78 e tratados com BNZ 100 mg/kg/dia por 20 dias ou 40 dias e BNZ 40 mg/kg/dia por 40 dias na IA apresentaram porcentagem de cura semelhantes (100 e 87%). Já na IC, o tratamento com BNZ 100 mg/kg/dia por 20 dias e BNZ 40 mg/kg/dia por 40 dias mostrou 75 e 86% de cura, respectivamente. Os camundongos na IA pela cepa Y apresentaram falha terapêutica quando tratados com BNZ em dose reduzida e eficácia de 75 e 87% quando tratados com a dose de 100 mg/kg/dia por 20 e 40 dias, respectivamente. Por fim, o tratamento com BNZ 100 mg/kg/dia por 40 dias em camundongos infectados pela cepa VL-10 possibilitou a cura de 12% na IA e 62% na IC. Na dose de 40 mg/kg/dia por 40 dias (IC), o tratamento apresentou 25% de cura. Dessa forma, a primeira parte desse trabalho demonstrou que a IC mostra-se ser mais facilmente tratável e a resposta terapêutica ao BNZ parece não ser dose-dependente. No capítulo II foi realizado um estudo de PK, BD, DP e POPPK dos tratamentos com BNZ nas doses de 100 e 40 mg/kg/dia por 20 e 40 dias e 200 mg/kg/dia por 20 dias. Amostras de sangue, cérebro, cólon, coração e fígado foram coletadas em 0,16; 0,33; 0,5; 1; 2; 3; 6 e 12 h após a administração oral do fármaco. A análise de POPPK foi realizada empregando o programa NONMEN v.7. O modelo monocompartimental com absorção de primeira ordem e eliminação linear foi o que melhor descreveu a PK do BNZ. A ASC e Cmax são doseproporcionais, confirmando a linearidade na PK do BNZ. O BNZ se distribui de maneira ampla sendo encontrado, em todos os órgãos analisados, com exceção do fígado. A exposição ao BNZ no cérebro, cólon e coração são dose–proporcionais. A razão de penetração tecidual foi de 4˗26% dependendo do tratamento realizado, o que permite inferir uma limitada e errática BD do fármaco. O modelo não-linear de efeitos mistos demonstrou ser preciso e com capacidade preditiva adequada para análise de POPPK do BNZ. A dose e tempo de tratamento não influenciam os parâmetros farmacocinéticos populacionais do BNZ em camundongos. O clearance sofre influência alométrica da co-variável peso. Não foi possível estabelecer uma relação direta entre a PK/PD.
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    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 Martins
    Specific 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, coul
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    Population pharmacokinetics and biodistribution of benznidazole in mice.
    (2020) Melo, Luísa Helena Perin de; Pinto, Leonardo Santos Ribeiro; Nardotto, Glauco Henrique Balthazar; Fonseca, Kátia da Silva; Paiva, Beatriz Oliveira; Mendes, Thaís Fernanda Rodrigues Bastos; Molina, Israel; Oliveira, Rodrigo Corrêa de; Vieira, Paula Melo de Abreu; Carneiro, Cláudia Martins
    Objectives: To evaluate the population pharmacokinetics of different benznidazole treatment regimens and the drug’s biodistribution in mice. Methods: Two hundred mice were divided into five groups according to benznidazole dosing regimens: (1) 100 mg/kg/day for 20 days; (2) 100 mg/kg/day for 40 days; (3) 200 mg/kg/day for 20 days; (4) 40 mg/kg/day for 20 days; or (5) 40 mg/kg/day for 40 days. The mice were euthanized and blood, heart, liver, colon and brain were collected. Samples were prepared by liquid-liquid extraction and analysed by HPLC-diode-array detection. The pharmacokinetic analysis of benznidazole was evaluated via non-linear mixed-effects modelling using the NONMEN program. Results: Our results demonstrate that mouse weight allometrically influences benznidazole clearance; the AUC curve and the highest plasma concentration are dose proportional; benznidazole does not influence its own metabolism; its tissue distribution is limited; and the standard treatment regimen for Chagas’ disease in mice (100 mg/kg/day for 20 days) is inadequate from a pharmacokinetic standpoint, as are the other regimens tested in this study (100 mg/kg/day for 40 days, 200 mg/kg/day for 20 days and 40 mg/kg/day for 20 or 40 days). Conclusions: Benznidazole reformulations that allow better tissue penetration and plasma and tissue exposure should be evaluated to enable higher cure rates in both animals and patients. The population pharmacokinetic model developed here can allow optimization of the dosing regimen of benznidazole to treat experimental Chagas’ disease. Determining appropriate treatment regimens in animals allows translation of these to clinical studies.
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    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 Martins
    Despite 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.