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Mem. Inst. Oswaldo Cruz ; 114: e190017, 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1012676


BACKGROUND Only benznidazole (Bnz) (1) and nifurtimox (Nfx) (2) are licensed for the treatment of Chagas disease although their safety and efficacy profile are far from ideal. Farmanguinhos from Fiocruz has developed seven nitroimidazole compounds (4-10) analogs of megazol (3). OBJECTIVES To evaluate whether the genotoxic effect of 3 was abolished in the seven nitroimidazoles (4-10) analogs using the in vitro alkaline comet assay (CA) and the in vitro cytokinesis-block micronucleus assay (CBMN) in whole human blood cells (WHBC) and correlate this effect with their trypanocidal activity using bloodstream trypomastigote forms of Trypanosoma cruzi. METHODS The toxicity of 3-10 to WHBC in the in vitro CA was determined using the fluorescein diacetate/ethidium bromide assay. DNA damage in the in vitro CA was evaluated according to tail size in four classes (0-3) and methyl methane-sulfonate (MMS) was used as a positive control. The cytotoxicity of 3-10 to WHBC in the CBMN was measured using the cytokinesis-block proliferation index and the replication index. The number of the micronucleate cells in 2,000 binucleate cells by experimental group was determined. Mitomycin C and N-deacetyl-N-methylcolchicine were used as positive controls. FINDINGS Compound 3 showed a significant DNA strand break effect through the in vitro CA and highly significant clastogenic and/or aneugenic effect in the CBMN. Compounds 5, 6, 8, 9 and 10 showed negative results in the CBMN and positive results in the in vitro CA, while the inverse effect was observed for 4 and 7. MAIN CONCLUSIONS Compound 10 was the most promising to proceed with the development as a drug candidate in the treatment of Chagas disease showing absence of chromosomal cytogenetic damage and high activity against T. cruzi, about two times higher than 3 and the clinical drug 1.

Tripanossomicidas/uso terapêutico , Tripanossomicidas/farmacologia , Nitroimidazóis/uso terapêutico , Técnicas In Vitro/métodos , Testes de Mutagenicidade/métodos
J. bras. pneumol ; 44(2): 153-160, Mar.-Apr. 2018. tab
Artigo em Inglês | LILACS | ID: biblio-893913


ABSTRACT Multidrug-resistant and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively) continue to represent a challenge for clinicians and public health authorities. Unfortunately, although there have been encouraging reports of higher success rates, the overall rate of favorable outcomes of M/XDR-TB treatment is only 54%, or much lower when the spectrum of drug resistance is beyond that of XDR-TB. Treating M/XDR-TB continues to be a difficult task, because of the high incidence of adverse events, the long duration of treatment, the high cost of the regimens used, and the drain on health care resources. Various trials and studies have recently been undertaken (some already published and others ongoing), all aimed at improving outcomes of M/XDR-TB treatment by changing the overall approach, shortening treatment duration, and developing a universal regimen. The objective of this review was to summarize what has been achieved to date, as far as new and repurposed drugs are concerned, with a special focus on delamanid, bedaquiline, pretomanid, clofazimine, carbapenems, and linezolid. After more than 40 years of neglect, greater attention has recently been paid to the need for new drugs to fight the "white plague", and promising results are being reported.

RESUMO A tuberculose multirresistente (TB-MDR, do inglês multidrug-resistant) e a extensivamente resistente (TB-XDR, do inglês extensively drug-resistant) continuam representando um desafio para os clínicos e as autoridades de saúde pública. Infelizmente, embora haja relatos encorajadores de taxas de sucesso maiores, a taxa global de desfechos favoráveis do tratamento da TB-MDR/XDR é de apenas 54%, ou muito menor quando o espectro de resistência aos fármacos vai além do da TB-XDR. O tratamento da TB-MDR/XDR continua sendo uma tarefa difícil, em razão da alta incidência de eventos adversos, do longo tempo de tratamento, do alto culto dos esquemas utilizados e da drenagem dos recursos de saúde. Diversos ensaios e estudos foram realizados recentemente (alguns já publicados e outros em andamento), todos visando a melhorar os desfechos do tratamento da TB-MDR/XDR por meio da alteração da abordagem geral, redução do tempo de tratamento e desenvolvimento de um esquema universal. O objetivo desta revisão foi resumir o que se conseguiu até o momento, no que se refere a novos fármacos e fármacos repropostos, dando foco especial para delamanid, bedaquilina, pretomanida, clofazimina, carbapenêmicos e linezolida. Após mais de 40 anos de negligência, recentemente foi dada mais atenção á necessidade de novos fármacos para se combater a "praga branca", e resultados promissores estão sendo relatados.

Humanos , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Reposicionamento de Medicamentos , Antituberculosos/uso terapêutico , Oxazóis/uso terapêutico , Ensaios Clínicos como Assunto , Diarilquinolinas/uso terapêutico , Nitroimidazóis/uso terapêutico , Antituberculosos/classificação
Mem. Inst. Oswaldo Cruz ; 113(3): 153-160, Mar. 2018. graf
Artigo em Inglês | LILACS | ID: biblio-894905


BACKGROUND The current chemotherapy for Chagas disease is based on monopharmacology with low efficacy and drug tolerance. Polypharmacology is one of the strategies to overcome these limitations. OBJECTIVES Study the anti-Trypanosoma cruzi activity of associations of benznidazole (Bnz) with three new synthetic T. cruzi-triosephosphate isomerase inhibitors, 2, 3, and 4, in order to potentiate their actions. METHODS The in vitro effect of the drug combinations were determined constructing the corresponding isobolograms. In vivo activities were assessed using an acute murine model of Chagas disease evaluating parasitaemias, mortalities and IgG anti-T. cruzi antibodies. FINDINGS The effect of Bnz combined with each of these compounds, on the growth of epimastigotes, indicated an additive action or a synergic action, when combining it with 2 or 3, respectively, and an antagonic action when combining it with 4. In vivo studies, for the two chosen combinations, 2 or 3 plus one fifth equivalent of Bnz, showed that Bnz can also potentiate the in vivo therapeutic effects. For both combinations a decrease in the number of trypomastigote and lower levels of anti-T. cruzi IgG-antibodies were detected, as well clear protection against death. MAIN CONCLUSIONS These results suggest the studied combinations could be used in the treatment of Chagas disease.

Triose-Fosfato Isomerase/química , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/imunologia , Nitroimidazóis/farmacologia , Anticorpos Antiprotozoários , Sinergismo Farmacológico , Quimioterapia Combinada
Biosci. j. (Online) ; 33(5): 1351-1361, sept./oct. 2017. graf, tab
Artigo em Inglês | LILACS | ID: biblio-966384


Secnidazole, a 5-nitroimidazole, is a drug used in the treatment against protozoa, and several bacterial infections. This study purpose was to develop and validate a UV spectrophotometric method to determine secnidazole in pharmaceutical tablet dosage forms once there is no method reported in the pharmacopoeia yet. The quantification was performed using methanol as solvent at 325 nm (maximum wavelength) and three kinds of products marketed in Brazil (reference, generic and similar tablets) containing 1g of secnidazole. The method obeyed Beer's law in the concentration range of 4 - 20 µgmL-1 respectively. The method was validated according to the International Conference on Harmonization (ICH) and Brazil National Health Surveillance Agency (ANVISA) guidelines, showing accuracy, precision, selectivity, robustness and linearity. Tests such as weight range, friability, disintegration, hardness and dissolution were carried out to check tablets' quality and all the trials showed to be in accordance with the general test guidelines of the Brazilian Pharmacopoeia. The dissolution test was carried out and the developed method was applied. The method developed is suitable for the estimation of secnidazole in tablets without any interference from the excipients and can be used for routine in quality control. Still, it's a simple, fast and low cost method.

Secnidazol, um nitroimidazólico, é um fármaco utilizado no tratamento para protozoários, e várias infecções bacterianas. Este trabalho propôs o desenvolvimento e validação de um método espectrofotométrico na região do ultravioleta para a determinação de Secnidazol na forma farmacêutica de comprimidos, uma vez que não há nenhum método relatado nas farmacopeias. A quantificação foi realizada utilizando metanol como solvente a 325 nm (máximo de comprimento de onda) e usando três tipos de produtos comercializados no Brasil (de referência, genéricos e comprimidos similares) contendo 1g de Secnidazol. O método obedeceu a lei de Beer no intervalo de concentração de 4 - 20 µgmL-1, respectivamente. O método foi validado de acordo com a Conferência Internacional de Harmonização (ICH) e diretrizes da Agência Nacional de Vigilância Sanitária do Brasil (ANVISA), apresentando exatidão, precisão, seletividade, robustez e linearidade. Testes como variação de peso, friabilidade, desintegração, dureza e dissolução foram realizados para verificar a qualidade de comprimidos e mostrou-se de acordo com os testes gerais da Farmacopeia Brasileira. O teste de dissolução realizado e o método desenvolvido pode ser aplicado. O método desenvolvido é adequado para a estimativa de secnidazole em comprimidos sem qualquer interferência dos excipientes e pode ser usado para a rotina de controlo de qualidade. Ainda, é um método simples, rápido e de baixo custo.

Controle de Qualidade , Infecções Bacterianas , Anti-Infecciosos , Antibacterianos , Nitroimidazóis
Mem. Inst. Oswaldo Cruz ; 112(3): 224-235, Mar. 2017. tab, graf
Artigo em Inglês | LILACS | ID: biblio-841775


Chagas cardiomyopathy is the most frequent and most severe manifestation of chronic Chagas disease, and is one of the leading causes of morbidity and death in Latin America. Although the pathogenesis of Chagas cardiomyopathy is incompletely understood, it may involve several mechanisms, including parasite-dependent myocardial damage, immune-mediated myocardial injury (induced by the parasite itself and by self-antigens), and microvascular and neurogenic disturbances. In the past three decades, a consensus has emerged that parasite persistence is crucial to the development and progression of Chagas cardiomyopathy. In this context, antiparasitic treatment in the chronic phase of Chagas disease could prevent complications related to the disease. However, according to the results of the BENEFIT trial, benznidazole seems to have no benefit for arresting disease progression in patients with chronic Chagas cardiomyopathy. In this review, we give an update on the main pathogenic mechanisms of Chagas disease, and re-examine and discuss the results of the BENEFIT trial, together with its limitations and implications.

Humanos , Animais , Masculino , Feminino , Pessoa de Meia-Idade , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/genética , Cardiomiopatia Chagásica/etiologia , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Doença Crônica , Ensaios Clínicos como Assunto , Resultado do Tratamento , Progressão da Doença
Braz. j. med. biol. res ; 50(9): e6188, 2017. graf
Artigo em Inglês | LILACS | ID: biblio-888993


PA-824 is a novel bicyclic nitroimidazole anti-tuberculosis (TB) drug. Cordyceps sinensis (Berk.) Sacc. (CS) was proven to be a good immunomodulatory compound. This research aimed to investigate the effect of CS on PA-824 in Mycobacterium tuberculosis (M.tb) infected mice (female CBA/J mice, 6 to 8 weeks of age and 20±2 g of weight). Mice were randomly assigned to 4 groups: PA-824, CS, PA-824+CS, and control. To verify the effect of PA-824 and CS on M.tb, after drug administration, mice lungs were harvested and bacterial colony formations were measured. Cells were isolated from infected lungs and spleens to analyze the percentage of CD4+ T cells (CD11a positive). Lung cells were cultured to detect the secretion of interferon-γ (IFN-γ) and interleukin-10 (IL-10) by ELISA. IFN-γ and IL-10 double-positive CD4+ cells in peripheral blood were measured by flow cytometry. The expression levels of IL-2 and IL-10 in mice lungs were analyzed by real-time PCR and western blot. Results showed that PA-824 combined with CS led to the lowest lung colony-forming units (CFU) counts among treated groups. Furthermore, this beneficial outcome might be associated with the decreased CD11a on CD4+ cells in mice lungs and spleens. Moreover, the suppressed secretion of IFN-γ and IL-10, and IL-10 expressions, as well as the decreased IFN-γ and IL-10 double-positive CD4+ cells in blood, could also be associated with the positive effect. However, no significant effect on IL-2 production was found. The combination of PA-824 and CS had more effective bacteriostatic and immunomodulatory effects on M.tb infected mice than PA-824 alone. In conclusion, CS has the potential to be an effective adjuvant in TB treatment.

Animais , Masculino , Camundongos , Antibacterianos/farmacologia , Cordyceps/química , Interleucina-10/imunologia , Mycobacterium tuberculosis/imunologia , Nitroimidazóis/farmacologia , Western Blotting , Modelos Animais de Doenças , Citometria de Fluxo , Imunomodulação/efeitos dos fármacos , Imunomodulação/imunologia , Camundongos Endogâmicos CBA , Mycobacterium tuberculosis/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Tuberculose Pulmonar/imunologia
Mem. Inst. Oswaldo Cruz ; 111(6): 365-371, June 2016. tab, graf
Artigo em Inglês | LILACS | ID: lil-784247


This study aimed to evaluate well-documented diagnostic antigens, named B13, 1F8 and JL7 recombinant proteins, as potential markers of seroconversion in treated chagasic patients. Prospective study, involving 203 patients treated with benznidazole, was conducted from endemic areas of northern Argentina. Follow-up was possible in 107 out of them and blood samples were taken for serology and PCR assays before and 2, 3, 6, 12, 24 and 36 months after treatment initiation. Reactivity against Trypanosoma cruzi lysate and recombinant antigens was measured by ELISA. The rate of decrease of antibody titers showed nonlinear kinetics with an abrupt drop within the first three months after initiation of treatment for all studied antigens, followed by a plateau displaying a low decay until the end of follow-up. At this point, anti-B13, anti-1F8 and anti-JL7 titers were relatively close to the cut-off line, while anti-T. cruzi antibodies still remained positive. At baseline, 60.8% (45/74) of analysed patients tested positive for parasite DNA by PCR and during the follow-up period in 34 out of 45 positive samples (75.5%) could not be detected T. cruzi DNA. Our results suggest that these antigens might be useful as early markers for monitoring antiparasitic treatment in chronic Chagas disease.

Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Anticorpos Antiprotozoários/sangue , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Antígenos de Protozoários/imunologia , Argentina , Doença de Chagas/sangue , Doença Crônica , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Seguimentos , Estudos Prospectivos , Fatores de Tempo
Mem. Inst. Oswaldo Cruz ; 111(3): 218-221, Mar. 2016. tab, graf
Artigo em Inglês | LILACS | ID: lil-777373


Pharmacological treatment of Chagas disease with benznidazole (BNZ) is effective in children in all stages, but it is controversial in chronically infected adults. We report the pharmacokinetics and pharmacodynamics in six adult patients with Chagas disease treated with the new BNZ formulation (ABARAX®) in doses between 2.5-5.5 mg/Kg/day. All but one patient had plasmatic BNZ concentrations within the expected range. All patients finalised treatment with nondetectable Trypanosoma cruziquantitative polymerase chain reaction, which remained nondetectable at the six month follow-up. Our data suggests parasitological responses with the new BNZ and supports the hypothesis that treatment protocols with lower BNZ doses may be effective.

Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/farmacocinética , Tripanossomicidas/farmacocinética , Trypanosoma cruzi/efeitos dos fármacos , Química Farmacêutica , Doença de Chagas/metabolismo , Seguimentos , Nitroimidazóis/administração & dosagem , Nitroimidazóis/sangue , Reação em Cadeia da Polimerase em Tempo Real , Tripanossomicidas/administração & dosagem , Tripanossomicidas/sangue , Trypanosoma cruzi/isolamento & purificação
Rev. Inst. Med. Trop. Säo Paulo ; 57(6): 531-535, Nov.-Dec. 2015. graf
Artigo em Inglês | LILACS, Sec. Est. Saúde SP, SESSP-IIERPROD, Sec. Est. Saúde SP | ID: lil-770117


The reactivation of Chagas disease in HIV infected patients presents high mortality and morbidity. We present the case of a female patient with confirmed Chagasic meningoencephalitis as AIDS-defining illness. Interestingly, her TCD4+ lymphocyte cell count was 318 cells/mm3. After two months of induction therapy, one year of maintenance with benznidazol, and early introduction of highly active antiretroviral therapy (HAART), the patient had good clinical, parasitological and radiological evolution. We used a qualitative polymerase chain reaction for the monitoring of T. cruzi parasitemia during and after the treatment. We emphasize the potential value of molecular techniques along with clinical and radiological parameters in the follow-up of patients with Chagas disease and HIV infection. Early introduction of HAART, prolonged induction and maintenance of antiparasitic therapy, and its discontinuation are feasible, in the current management of reactivation of Chagas disease.

A reativação da doença de Chagas em pacientes com a infecção pelo HIV apresenta uma alta morbidade e mortalidade. Neste relato, apresentamos caso confirmado de meningoencefalite chagásica, como doença definidora de aids, em paciente com 318 linfócitos T-CD4+/mm3. Após 2 meses de tratamento seguido de um ano de profilaxia secundária com benzonidazol e início precoce de terapia antirretroviral (HAART), a paciente apresentou boa evolução clínica, parasitológica e radiológica. Utilizamos a reação em cadeia da polimerase qualitativa do T. cruzi, para monitorização da parasitemia por T. cruzi durante e após o tratamento. Ressaltamos o valor potencial das técnicas moleculares associadas aos parâmetros clínicos e radiológicos nos pacientes com doença de Chagas e infecção pelo HIV. A introdução precoce da terapia antirretroviral, a terapia antiparasitária prolongada, manutenção e descontinuação da mesma, são desafios atuais, embora possíveis, no manejo da reativação da doença de Chagas na era das terapias antirretrovirais de alta eficácia.

Humanos , Feminino , Adulto , Infecções Oportunistas Relacionadas com a AIDS , Doença de Chagas/complicações , Imunossupressores/uso terapêutico , Meningoencefalite , Nitroimidazóis/uso terapêutico , Infecções Oportunistas Relacionadas com a AIDS/complicações , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/parasitologia , Síndrome de Imunodeficiência Adquirida/complicações , Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida/parasitologia , Terapia Antirretroviral de Alta Atividade , Doença de Chagas/virologia , Meningoencefalite/tratamento farmacológico , Meningoencefalite/parasitologia , Meningoencefalite , Meningoencefalite/virologia , Prevenção Secundária/métodos , Taxa de Sobrevida , Fatores de Tempo , Tripanossomicidas/uso terapêutico
Rev. Soc. Bras. Med. Trop ; 48(5): 629-632, Sept.-Oct. 2015. tab, graf
Artigo em Inglês | LILACS | ID: lil-763335


ABSTRACTA woman had been followed since 1957 for acute phase Chagas disease. Parasitological and serological tests were positive, and treatment included benznidazole in 1974. Following treatment, parasitological test results were negative and conventional serology remained positive until 1994, with subsequent discordant results (1995-1997). The results became consistently negative since 1999. She had an indeterminate chronic form until 1974. Only two minor and transitory nonspecific alterations on electrocardiogram were noted, with the last nine records normal until June 2014. This case confirms the possibility of curing chronic disease and suggests the benefit of specific treatments for preventing long-term morbidity.

Idoso , Feminino , Humanos , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/administração & dosagem , Tripanossomicidas/administração & dosagem , Doença Aguda , Doença Crônica , Seguimentos , Fatores de Tempo , Trypanosoma cruzi/imunologia
Mem. Inst. Oswaldo Cruz ; 110(4): 492-499, 09/06/2015. tab, graf
Artigo em Inglês | LILACS | ID: lil-748858


Nitroimidazoles exhibit high microbicidal activity, but mutagenic, genotoxic and cytotoxic properties have been attributed to the presence of the nitro group. However, we synthesised nitroimidazoles with activity against the trypomastigotes of Trypanosoma cruzi, but that were not genotoxic. Herein, nitroimidazoles (11-19) bearing different substituent groups were investigated for their potential induction of genotoxicity (comet assay) and mutagenicity (Salmonella/Microsome assay) and the correlations of these effects with their trypanocidal effect and with megazol were investigated. The compounds were designed to analyse the role played by the position of the nitro group in the imidazole nucleus (C-4 or C-5) and the presence of oxidisable groups at N-1 as an anion receptor group and the role of a methyl group at C-2. Nitroimidazoles bearing NO2 at C-4 and CH3 at C-2 were not genotoxic compared to those bearing NO 2 at C-5. However, when there was a CH3 at C-2, the position of the NO2 group had no influence on the genotoxic activity. Fluorinated compounds exhibited higher genotoxicity regardless of the presence of CH3 at C-2 or NO2 at C-4 or C-5. However, in compounds 11 (2-CH3; 4-NO2; N-CH2OHCH2Cl) and 12 (2-CH3; 4-NO2; N-CH2OHCH2F), the fluorine atom had no influence on genotoxicity. This study contributes to the future search for new and safer prototypes and provide.

Animais , Camundongos , Dano ao DNA/efeitos dos fármacos , Nitroimidazóis/química , Nitroimidazóis/toxicidade , Salmonella/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Ensaio Cometa , Relação Dose-Resposta a Droga , Testes de Mutagenicidade , Relação Estrutura-Atividade
Mem. Inst. Oswaldo Cruz ; 110(4): 507-509, 09/06/2015. tab
Artigo em Inglês | LILACS | ID: lil-748867


It is currently unknown whether treatment of Chagas disease decreases the risk of congenital transmission from previously treated mothers to their infants. In a cohort of women with Chagas disease previously treated with benznidazole, no congenital transmission of the disease was observed in their newborns. This finding provides support for the treatment of Chagas disease as early as possible.

Adolescente , Adulto , Criança , Feminino , Humanos , Gravidez , Adulto Jovem , Doença de Chagas/transmissão , Transmissão Vertical de Doença Infecciosa , Nitroimidazóis/uso terapêutico , Complicações Parasitárias na Gravidez , Tripanossomicidas/uso terapêutico , Estudos de Coortes , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Prevenção Primária , Complicações Parasitárias na Gravidez/tratamento farmacológico , Trypanosoma cruzi
Mem. Inst. Oswaldo Cruz ; 110(3): 433-444, 05/2015. tab, graf
Artigo em Inglês | LILACS | ID: lil-745976


Benznidazole (BZ) is one of the two drugs used for Chagas disease treatment. Nevertheless therapeutic failures of BZ have been reported, which were mostly attributed to variable drug susceptibility among Trypanosoma cruzi strains. ATP-binding cassette (ABC) transporters are involved in a variety of translocation processes and some members have been implicated in drug resistance. Here we report the characterisation of the first T. cruzi ABCG transporter gene, named TcABCG1, which is over-expressed in parasite strains naturally resistant to BZ. Comparison of TcABCG1 gene sequence of two TcI BZ-resistant strains with CL Brener BZ-susceptible strain showed several single nucleotide polymorphisms, which determined 11 amino acid changes. CL Brener transfected with TcI transporter genes showed 40-47% increased resistance to BZ, whereas no statistical significant increment in drug resistance was observed when CL Brener was transfected with the homologous gene. Only in the parasites transfected with TcI genes there was 2-2.6-fold increased abundance of TcABCG1 transporter protein. The analysis in wild type strains also suggests that the level of TcABCG1 transporter is related to BZ natural resistance. The characteristics of untranslated regions of TcABCG1 genes of BZ-susceptible and resistant strains were investigated by computational tools.

Animais , Humanos , Transportadores de Cassetes de Ligação de ATP/genética , Resistência a Medicamentos/genética , Nitroimidazóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/genética , DNA de Protozoário/genética , Genótipo , Proteínas de Membrana Transportadoras/genética , Testes de Sensibilidade Parasitária , Filogenia
Mem. Inst. Oswaldo Cruz ; 110(3): 414-421, 05/2015. tab, graf
Artigo em Inglês | LILACS | ID: lil-745978


The aim of this review is to describe the contributions of the knowledge of T-cell responses to the understanding of the physiopathology and the responsiveness to etiological treatment during the chronic phase of Chagas disease. T-helper (Th)1 and interleukin (IL)-10 Trypanosoma cruzi-specific T-cells have been linked to the asymptomatic phase or to severe clinical forms of the disease, respectively or vice versa, depending on the T. cruzi antigen source, the patient’s location and the performed immunological assays. Parasite-specific T-cell responses are modulated after benznidazole (BZ) treatment in chronically T. cruzi-infected subjects in association with a significant decrease in T. cruzi-specific antibodies. Accumulating evidence has indicated that treatment efficacy during experimental infection with T. cruzi results from the combined action of BZ and the activation of appropriate immune responses in the host. However, strong support of this interaction in T. cruzi-infected humans remains lacking. Overall, the quality of T-cell responses might be a key factor in not only disease evolution, but also chemotherapy responsiveness. Immunological parameters are potential indicators of treatment response regardless of achievement of cure. Providing tools to monitor and provide early predictions of treatment success will allow the development of new therapeutic options.

Humanos , Doença de Chagas/imunologia , Nitroimidazóis/uso terapêutico , Linfócitos T/imunologia , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/imunologia , Antígenos de Protozoários/imunologia , Doença Crônica , Doença de Chagas/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos
Mem. Inst. Oswaldo Cruz ; 110(3): 422-432, 05/2015. tab
Artigo em Inglês | LILACS | ID: lil-745981


The definition of a biomarker provided by the World Health Organization is any substance, structure, or process that can be measured in the body, or its products and influence, or predict the incidence or outcome of disease. Currently, the lack of prognosis and progression markers for chronic Chagas disease has posed limitations for testing new drugs to treat this neglected disease. Several molecules and techniques to detect biomarkers in Trypanosoma cruzi-infected patients have been proposed to assess whether specific treatment with benznidazole or nifurtimox is effective. Isolated proteins or protein groups from different T. cruzi stages and parasite-derived glycoproteins and synthetic neoglycoconjugates have been demonstrated to be useful for this purpose, as have nucleic acid amplification techniques. The amplification of T. cruzi DNA using the real-time polymerase chain reaction method is the leading test for assessing responses to treatment in a short period of time. Biochemical biomarkers have been tested early after specific treatment. Cytokines and surface markers represent promising molecules for the characterisation of host cellular responses, but need to be further assessed.

Humanos , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Biomarcadores/sangue , Doença Crônica
Recife; s.n; 2015. 73 p. ilus.
Tese em Português | LILACS | ID: lil-772858


Atualmente o Brasil apresenta 3 milhões de indivíduos portadores da cardiomiopatia chagásica. Porém, tratamento etiológico com o fármaco Benzonidazol (BZ) na fase crônica da doença ainda não está elucidado. Acredita-se que a recomendação do BZ nessa fase, pode prevenir ou retardar a evolução clínica da cardiomiopatia na Doença Chagas (DC). Assim o objetivo do estudo é avaliar a produção de quimiocinas e expressão de seus receptores em Células mononucleares do sangue periférico - PBMC (de portadores crônicos da doença de Chagas) submetidas in vitro ao tratamento com BZ, após a infecção com T.cruzi. Foram selecionados 11 pacientes na fase crônica da doença. Amostras de sangue desses pacientes foram coletadas para obtenção de PBMC, em que foram cultivadas em placas de cultivo na concentração de 106 células/ml por poço. Após a adesão das células aderentes (principalmente macrófagos), as células não aderentes (principalmente linfócitos) foram removidas e as formas tripomastigotas foram adicionadas ao cultivo para infecção das células aderentes. Subsequente a incubação, as células não aderentes foram adicionadas novamente ao cultivo juntamente com o fármaco Bz (1µg/mL), ficando um co-cultivo de células aderentes infectadas com T.cruzi, células não aderentes e o BZ (C+T+BZ). As placas de cultura foram incubadas por períodos de 24h e 5 dias. Para uma análise fidedigna da ação do BZ nas células aderentes e não aderentes foi necessário a criação dos controles: células (C), células e tripomastigotas (C+T) e células e o BZ (C+BZ). Após o cultivo, foram coletados os sobrenadantes das culturas, para avaliação da produção de quimiocinas (CCL2, CXL9, CXL10, CCL5 e CXCL8) por CBA (Cytometric Bead Array). Posteriormente foi realizada a imunofenotipagem...

Humanos , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Receptores de Quimiocinas , Trypanosoma cruzi , Tripanossomicidas/uso terapêutico , Células Cultivadas , Doença Crônica , Nitroimidazóis/administração & dosagem , Tripanossomicidas/administração & dosagem
Int. j. high dilution res ; 14(3): 10-19, 2015.
Artigo em Inglês | LILACS | ID: lil-783288


Although several diseases are treated by toxic drugs, their side effects may hamper adherence to the therapy. The aim of this study is to evaluate the effect of the association of ponderal benznidazole (BZ) with its ultra-high diluted (UHD) formula on clinical and parasitological parameters of mice infected by Trypanosoma cruzi (T. cruzi). 24 non-isogenic Swiss mice were divided into groups: CI – infected animals treated with 7% alcohol; BZp – infected animals treated with BZ (500 mg/ kg) from the beginning of infection; BZp+d – infected animals treated with ponderal BZ and with UHD BZ, which started to be administered four days after the beginning of treatment with ponderal BZ; CNI - group of non-treated and non-infected animals. The UHD medicine was prepared according to Phamacopoeia until 30x. The different treatment schedules were statistically compared through parasitological and clinical parameters. The group BZp+d displayed more favorable clinical evolution than the group BZp, with improvement of mass gain, feed conversion and water intake, presenting data approximated to CNI group. The significant increase of the body temperature of BZp+d group indicates an activation of the immune system which was not observed in the other groups. Moreover, the anti-parasitic effect of the ponderal drug was maintained in all parasitological parameters of this group. By reducing the side effects and maintaining the action of the ponderal drug, the combination of toxic drugs with their UHD formula could be considered a way of improving efficacy of the treatment...

A infecção por Trypanossoma cruzi é um problema de saúde pública e o único medicamento disponível no Brasil é o benznidazol (BZ), com efeitos limitados e tóxicos. Estudos anteriores com BZ na dose de 200 mg/kg indicaram que a administração de BZ diluído (30d) controla os efeitos tóxicos da droga em dose ponderal, sem alterar a sua ação terapêutica. Sob essa perspectiva e considerando a ação do BZ dose dependente, aumentar a quantidade de droga administrada significaria uma melhora na eficácia do tratamento. Portanto, este trabalho teve como objetivo avaliar o efeito do BZ ponderal (BZP), na dose de 500 mg/kg associado com BZ diluído (BZD) nos parâmetros clínicos de camundongos infectados por T. cruzi. Em estudo cego, controlado e randomizado, foram utilizados 23 camundongos suíços, machos, com 8 semanas divididos em grupos: CNI - Não infectados e não tratados; CI - Infectados e tratados com álcool 7 %; BZP - Infectados tratados com BZ (500 mg/kg de peso/ animal) a partir do início da infecção; BZP + BZD - Infectados e tratados com a associação de BZP e BZD. Os medicamentos foram administrados por gavagem (0,2 mL/ dia/ animal). O BZP foi administrado a partir da constatação da infecção. O BZ diluído foi preparado de acordo com a Farmacopeia Homeopática Brasileira e administrado 4 dias após o início do tratamento com BZP. Os parâmetros clínicos, avaliados diariamente, incluíram: peso, consumo de ração e água, temperatura e quantidade de excretas. A análise clínica apontou melhores resultados nos grupos BZP e BZP + BZD, mostrando melhor evolução de peso, consumo de ração, água e excretas quando comparado aos grupos não tratados (p< 0.05)...

Animais , Ratos , Altas Potências , Homeopatia , Nitroimidazóis/administração & dosagem , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/parasitologia , Toxicidade/efeitos adversos
Rev. Soc. Bras. Med. Trop ; 47(3): 397-400, May-Jun/2014. tab
Artigo em Inglês | LILACS | ID: lil-716410


This report describes the case of a patient with acute Chagas disease in Tocantins, Brazil, who was unaware of her pregnancy during benznidazole treatment. She presented with impaired cardiac function during the acute phase (pericarditis and incomplete right bundle-branch block) that resolved favorably after benznidazole therapy. Serological results also became negative, as determined by hemagglutination assays, enzyme-linked immunosorbent assays, and immunofluorescence assays. The child was born without sequelae and showed no evidence of congenital Trypanosoma cruzi infection at birth or 24 days later.

Feminino , Humanos , Recém-Nascido , Gravidez , Adulto Jovem , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Complicações Parasitárias na Gravidez/tratamento farmacológico , Tripanossomicidas/uso terapêutico , Doença Aguda , Doença de Chagas/congênito