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1.
Mem. Inst. Oswaldo Cruz ; 117: e210034, 2022. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1386352

ABSTRACT

As a result of globalization and constant migratory flows, Chagas disease is now present in almost all continents. The management and treatment of the disease is often influenced by the economic and social context of the societies that host patients. In this manuscript, we aim to provide a comparative review of approaches to patients with Chagas disease in the Americas and Europe.

2.
Mem. Inst. Oswaldo Cruz ; 117: e220019, 2022. graf
Article in English | LILACS-Express | LILACS | ID: biblio-1365154

ABSTRACT

Chagas disease (CD), caused by infection by the protozoan parasite Trypanosoma cruzi, presents as main clinical manifestation the chronic chagasic cardiomyopathy (CCC). CCC afflicts millions of people, mostly in Latin America, and vaccine and effective therapy are still lacking. Comprehension of the host/parasite interplay in the chronic phase of T. cruzi infection may unveil targets for rational trait-based therapies to improve CCC prognosis. In the present viewpoint, I critically summarise a collection of data, obtained by our network of collaborators and other groups on CCC and preclinical studies on pathogenesis, targeting identification for intervention and the use of drugs with immunomodulatory properties to improve CCC. In the last two decades, models combining mouse lineages and T. cruzi strains allowed replication of crucial clinical, histopathological, and immunological traits of CCC. This condition includes conduction changes (heart rate changes, arrhythmias, atrioventricular blocks, prolongation of the QRS complex and PR and corrected QT intervals), ventricular dysfunction and heart failure, CD8-enriched myocarditis, tissue remodeling and progressive fibrosis, and systemic inflammatory profile, resembling "cytokine storm". Studies on Chagas' heart disease pathogenesis begins to unveil the molecular mechanisms underpinning the inflammation-related cardiac tissue damage, placing IFNγ, TNF and NFκB signaling as upstream regulators of miRNAs and mRNAs associated with critical biological pathways as cell migration, inflammation, tissue remodeling and fibrosis, and mitochondrial dysfunction. Further, data on preclinical trials using hypothesis-based tools, targeting parasite and inflammation-related alterations, opened paths for multi-therapeutic approaches in CCC. Despite the long path taken using experimental CD models replicating relevant aspects of CCC and testing new therapies and therapeutic schemes, these findings may get lost in translation, as conceptual and economical challenges, underpinning the valley of death across preclinical and clinical trials. It is hoped that such difficulties will be overcome in the near future.

3.
Article in English | LILACS-Express | LILACS | ID: biblio-1360790

ABSTRACT

ABSTRACT The present study aimed to establish a population pharmacokinetic (PopPK) modeling of benznidazole (BZD) in Brazilian patients with chronic Chagas disease. This was part of a Brazilian prospective cohort study with eight patients diagnosed with Chagas disease during the beginning of BZD treatment up to the 60th day. On the 15th day of treatment, a blood sampling was collected and analyzed. A one-compartment PK model was developed using Pmetrics. Patients with an average age of 50.3 (SD: 6.2) years old, 6 female patients and 2 males, 70.2 kg (14.2), receiving a 5 mg/Kg/day dose were included. PK parameters estimated for CL, V and Ka were 6.27 L/h, 38.97 L and 1.66 h-1, respectively. This is the first study to establish a population pharmacokinetic modeling of BZD in Brazilian patients with chronic Chagas disease. Therefore, further studies are needed to obtain the complete characterization of BZD pharmacokinetics.

4.
Braz. J. Pharm. Sci. (Online) ; 56: e18034, 2020. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1089207

ABSTRACT

Chagas disease is a serious public health problem in Latin America and, due to migration, in other non-endemic regions. Benznidazole (BNZ) is first choice drug in pediatric therapeutics. However, little is known regarding its metabolism in humans. The aim of the study was to isolate and identify products of human BZN metabolism in urine samples obtained from a pediatric Chagas patient and a healthy adult volunteer both treated with BZN. Urine samples were collected after dose of BNZ. Urine was treated with β-glucuronidase followed by an extraction procedure under two different pH conditions and a HPLC/UV and MS/MS identification of BZN and its metabolites. BZN (m/z 260.09847) was identified in all urine extracts. Peaks from each extracted chromatograms were selected for MS and MS/MS identification. Three compounds structurally related to BZN were identified: BZN-Na+ (m/z 283.08009), N-amine-BZN (m/z 230.12307) and N-hydroxi-amine-BZN (m/z 246.11702). BNZ-Na+ was identified in all extracts, but N-amine-BZN and N-hydroxi-amine-BZN were only observed in those extracts treated with β-glucuronidase. This is the first experimental report showing elimination of BZN N-reduced metabolites in urine. As they were released after treatment with β-glucuronidase it can be suggested that glucuronization plays a role in BNZ metabolism and renal elimination.

5.
Rev. Soc. Bras. Med. Trop ; 53: e20190477, 2020. tab, graf
Article in English | LILACS | ID: biblio-1057272

ABSTRACT

Abstract INTRODUCTION: Benznidazole (BZL) and Nifurtimox (NFX) are the pharmacological treatment for acute phase Chagas Disease (CD); however, therapy resistance and residual mortality development remain important unresolved issues. Posaconazole (POS) has shown a trypanocidal effect in vivo and in vitro. Thus, this study aimed at comparing the T. Cruzi parasitic load-reducing effect of the combination of BZL+POS against that of monotherapy with either, during acute phase CD, in an experimental murine model. METHODS Nineteen Wistar rats were randomly allocated to four groups and inoculated with the trypomastigotes of T. cruzi strain´s JChVcl1. The rats were administered anti-parasites from day 20-29 post-infection. The Pizzi and Brener method was used for parasitemia measurement. Longitudinal data analysis for the continuous outcome of repeated measures was performed using parasitemia as the outcome measured at days 20, 22, 24, 27, and 29 post-infection. RESULTS All four groups had similar parasitic loads (p=0.143) prior to therapy initiation. Among the three treatment groups, the BZL+POS (n=5) group showed the highest mean parasitic load reduction (p=0.000) compared with the control group. Likewise, the BZL+POS group rats showed an earlier therapeutic effect and were the only ones without parasites in their myocardial samples. CONCLUSIONS: Treatment of acute phase CD with BZL+POS was more efficacious at parasitemia and myocardial injury reduction, compared with monotherapy with either.


Subject(s)
Animals , Rats , Triazoles/administration & dosage , Trypanocidal Agents/administration & dosage , Chagas Disease/drug therapy , Parasitemia/drug therapy , Nitroimidazoles/administration & dosage , Acute Disease , DNA, Protozoan , Rats, Wistar , Disease Progression , Disease Models, Animal , Drug Therapy, Combination , Parasite Load
6.
Rev. Soc. Bras. Med. Trop ; 53: e20190150, 2020. tab
Article in English | LILACS | ID: biblio-1057268

ABSTRACT

Abstract INTRODUCTION: Benznidazole is used for treating Chagas disease (CD). This cross-sectional study aimed to characterize the adverse drug reactions (ADRs) of benznidazole at a public hospital in Brazil's Federal District. METHODS: Medical records were analyzed and ADRs were categorized by type, intensity, seriousness, and causality. RESULTS: Of the 62 patients who started benznidazole treatment for CD, 41 (66%) presented with 105 ADRs; 23 (37%) discontinued the treatment. Most reactions were classified as probable (81%), severe (63%), serious (67%), and dose-dependent (56%). CONCLUSIONS: The high incidence of ADRs because of treatment withdrawal revealed the need for safer alternatives for CD treatment.


Subject(s)
Humans , Male , Female , Adult , Trypanocidal Agents/adverse effects , Chagas Disease/drug therapy , Drug-Related Side Effects and Adverse Reactions/epidemiology , Nitroimidazoles/adverse effects , Socioeconomic Factors , Trypanocidal Agents/therapeutic use , Severity of Illness Index , Brazil/epidemiology , Hemagglutination Tests , Incidence , Cross-Sectional Studies , Drug-Related Side Effects and Adverse Reactions , Hospitals, Public , Middle Aged , Nitroimidazoles/therapeutic use
7.
Acta bioquím. clín. latinoam ; 53(2): 209-215, jun. 2019. ilus, graf, tab
Article in Spanish | LILACS | ID: biblio-1019255

ABSTRACT

La enfermedad de Chagas afecta aproximadamente a 10 millones de personas en Sudamérica y 1,5 millones en la Argentina. La transmisión congénita es la más importante en áreas urbanas. Existen dos drogas aprobadas para el tratamiento: nifurtimox (Laboratorios Bayer) y benznidazol (BNZ) (Laboratorios Roche, LAFEPE y Elea) que fueron desarrolladas hace más de 40 años y cuya farmacología y metabolismo en humanos han sido poco estudiados. La información disponible es virtualmente inexistente en niños y mujeres embarazadas. Se busca aportar estudios sistemáticos hacia una farmacoterapéutica racional en niños ya que empíricamente ha demostrado gran efectividad. Se desarrollaron métodos bioanalíticos aplicables a matrices biológicas como plasma, orina y leche materna para las drogas madres y la identificación de metabolitos en muestras de pacientes bajo terapéutica. La farmacocinética poblacional pediátrica descripta aquí para BNZ es concluyente respecto de sus diferencias con la farmacocinética en adultos. Se identificaron tres compuestos presentados como metabolitos del BNZ. La transferencia de dicho fármaco a la leche materna no supone riesgo para el lactante. Estos resultados brindan información para mejorar los protocolos de tratamiento existentes buscando una farmacoterapéutica adaptada a la edad y un uso más seguro de los fármacos en niños y eventualmente en adultos.


Chagas disease affects approximately 10 million people in South America and 1.5 million in Argentina. Congenital transmission is most important in urban areas. There are two drugs approved for treatment: nifurtimox (Bayer) and benznidazole (BNZ) (Roche, LAFEPE, Elea),developed more than 40 years ago. Their pharmacology and metabolism in humans have been seldom studied. The information available on children and pregnant women is virtually non-existent. The aim of this study is to provide systematic studies towards a rational pharmacotherapeutic sin children, which has been empirically proven to be highly effective. Bioanalytical methods were developed for plasma, urine and breast milk for parent drugs and for the identification of their metabolites in samples of patients under treatment. The pediatric population pharmacokinetics described here for BNZ is conclusive about their differences from adult pharmacokinetics. Three compounds presented as BNZ metabolites were identified. The transfer of this drug to the breast milk does not present a risk to the infant. These evidences offer information to improve the existing treatment protocols, seeking a pharmacotherapy adapted to the age and a safer use of the drugs in children and eventually in adults.


A doença de Chagas afeta aproximadamente 10 milhões de pessoas na América do Sul e 1,5 milhão na Argentina. A transmissão congênita é a mais importante em áreas urbanas. Existem dois medicamentos aprovados para o tratamento: nifurtimox (Laboratórios Bayer) e benznidazol (BNZ) (Laboratórios Roche, LAFEPE e Elea), desenvolvidas há mais de 40 anos, e sua farmacologia e seu metabolismo em humanos têm sido pouco estudados. A informação disponível é praticamente inexistente em crianças e mulheres grávidas. O objetivo é fornecer estudos sistemáticos para uma farmacoterapêutica racional em crianças visto que foram comprovadas empiricamente como sendo altamente eficazes. Métodos bioanalíticos aplicáveis a matrizes biológicas como plasma, urina e leite materno para fármacos-mãe e para a identificação de metabólitos em amostras de pacientes em tratamento terapêutico foram desenvolvidos. A farmacocinética da população pediátrica aqui descrita para BNZ é conclusiva em relação às suas diferenças com a farmacocinética de adultos. Três compostos apresentados como metabólitos do BNZ foram identificados. A transferência do referido medicamento para o leite materno não representa risco para o lactente. Essas evidências oferecem informações para melhorar os protocolos de tratamento existentes, buscando uma farmacoterapia adaptada à idade e um uso mais seguro dos medicamentos em crianças e eventualmente em adultos.


Subject(s)
Humans , Male , Female , Toxicology , Chagas Disease/diagnosis , Chagas Disease/drug therapy , Lactation/drug effects , Chagas Disease/etiology , Chagas Disease/ethnology , Pharmacologic Actions , Metabolic Side Effects of Drugs and Substances
8.
Rev. Soc. Bras. Med. Trop ; 51(2): 133-140, Mar.-Apr. 2018. tab
Article in English | LILACS | ID: biblio-897057

ABSTRACT

Abstract Chagas disease is a protozoan infection that was identified over a century ago. No drugs are available to treat the indeterminate and determinate chronic phases of the disease. Success of a drug design is dependent on correct biological evaluation. Concerning new drug designs for Chagas disease, it is essential to first identify the most effective, existing, experimental chronic protocols that can be used for comparison purposes. Here, we present a literature review regarding experimental models with chronic Chagas disease to evaluate the efficacy of benznidazole (BZN). We searched literature published in PubMed and Web of Science databases, using these keywords: animal model, BZN, Chagas disease, T. cruzi, and chronic phase, with no timeframe limitations. We excluded articles involving acute phase animal models and/or those without BZN treatment. The selected studies were conducted using different BZN concentrations (10mg-100mg) involving several different periods (5-70 days). Concentrations and durations of use are directly related to side effects, but do not prevent chronic tissue lesions. BZN use during the late/chronic phases of Chagas disease is unable to eliminate amastigote forms present in infected tissues. This study suggests the administration of a lower BZN concentration (<100mg/kg/day) during the chronic phase of the animal model, as this had been reported to result in fewer side effects.


Subject(s)
Animals , Trypanocidal Agents/administration & dosage , Chagas Disease/drug therapy , Dose-Response Relationship, Drug , Nitroimidazoles/administration & dosage , Chronic Disease , Disease Models, Animal , Mice
9.
Rev. Soc. Bras. Med. Trop ; 51(1): 52-56, Jan.-Feb. 2018. graf
Article in English | LILACS, SES-SP, SESSP-IDPCPROD, SES-SP | ID: biblio-897053

ABSTRACT

Abstract INTRODUCTION: Approximately seven to eight million people worldwide have Chagas disease. In Brazil, benznidazole is the most commonly used active drug against Trypanosoma cruzi; however, its efficacy is limited, and side effects are frequent. Recent studies suggest that amiodarone may be beneficial in the treatment of this disease, by exerting anti-T. cruzi action. This study evaluated changes in T. cruzi cell count in in vitro cultures subjected to different doses of benznidazole, amiodarone, and their combination. METHODS: T. cruzi (Y strain) cultures containing approximately 100,000 cells were treated with either 100mg, 50mg, 25mg, 12.5mg, or 10mg of benznidazole, amiodarone, or their combination. On the 4th day, cell count was compared to the baseline data. RESULTS: On the 4th day, no parasites were observed in any of the treated cultures. CONCLUSIONS: Benznidazole and amiodarone were equally effective in eliminating T. cruzi in culture. The combination of the two drugs was also equally effective, but our data cannot demonstrate synergism, as similar results were obtained when the drugs were tested individually or in combination. It is suggested that this study be repeated with other T. cruzi strains to determine whether similar results can be obtained again.


Subject(s)
Animals , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Parasitic Sensitivity Tests , Amiodarone/pharmacology , Nitroimidazoles/pharmacology , Trypanocidal Agents/administration & dosage , Dose-Response Relationship, Drug , Drug Combinations , Amiodarone/administration & dosage , Mice , Nitroimidazoles/administration & dosage
10.
Mem. Inst. Oswaldo Cruz ; 113(9): e180162, 2018. graf
Article in English | LILACS | ID: biblio-1040603

ABSTRACT

Eukaryotic initiation factor 5A (eIF5A) is a conserved protein with an essential role in translation elongation. Using one and two-dimensional western blotting, we showed that the eIF5A protein level was 2-fold lower in benznidazole (BZ)-resistant (BZR and 17LER) Trypanosoma cruzi populations than in their respective susceptible counterparts (BZS and 17WTS). To confirm the role of eIF5A in BZ resistance, we transfected BZS and 17WTS with the wild-type eIF5A or mutant eIF5A-S2A (in which serine 2 was replaced by alanine). Upon overexpressing eIF5A, both susceptible lines became approximately 3- and 5-fold more sensitive to BZ. In contrast, the eIF5A-S2A mutant did not alter its susceptibility to BZ. These data suggest that BZ resistance might arise from either decreasing the translation of proteins that require eIF5A, or as a consequence of differential levels of precursors for the hypusination reactions (e.g., spermidine and trypanothione), both of which alter BZ's effects in the parasite.


Subject(s)
Humans , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/enzymology , Drug Resistance/genetics , Peptide Initiation Factors/metabolism , RNA-Binding Proteins/metabolism , Nitroimidazoles/pharmacology , Trypanosoma cruzi/genetics , Gene Expression , Peptide Initiation Factors/analysis , Peptide Initiation Factors/drug effects , RNA-Binding Proteins/analysis , RNA-Binding Proteins/drug effects
11.
Rev. Soc. Bras. Med. Trop ; 50(3): 296-300, May-June 2017. tab
Article in English | LILACS | ID: biblio-896973

ABSTRACT

Abstract After more than one century since its discovery, Chagas disease is still extremely prevalent in 21 Latin American countries. Chagas disease is one of the most concerning public health problems in Latin America; the overall cost of CD treatment is approximately 7 billion United States dollars per year and it has a strong social impact on populations. Little progress has been made regarding the access to diagnosis and treatment at the primary health care level, calling into question the current policies to ensure the right to health and access to essential medications. In this article, diverse dimensions of access to treatment for Chagas disease are reviewed, illustrating the present state of benznidazole medication in relation to global production capacity, costs, and needs. The findings are based on an investigation requested by Médecins Sans Frontières Brazil through a consultancy in 2015, aiming to estimate the current costs of benznidazole production.


Subject(s)
Humans , Trypanocidal Agents/therapeutic use , Drug Costs/statistics & numerical data , Chagas Disease/drug therapy , Health Services Accessibility , Nitroimidazoles/therapeutic use , Trypanocidal Agents/economics , Brazil , Chagas Disease/economics , Health Services Needs and Demand , Latin America , Nitroimidazoles/economics
12.
Mem. Inst. Oswaldo Cruz ; 112(3): 224-235, Mar. 2017. tab, graf
Article in English | LILACS | ID: biblio-841775

ABSTRACT

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.


Subject(s)
Humans , Animals , Male , Female , Middle Aged , Trypanocidal Agents/therapeutic use , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/genetics , Chagas Cardiomyopathy/etiology , Chagas Cardiomyopathy/parasitology , Chagas Cardiomyopathy/drug therapy , Nitroimidazoles/therapeutic use , Chronic Disease , Clinical Trials as Topic , Treatment Outcome , Disease Progression
13.
Rev. Soc. Bras. Med. Trop ; 50(1): 145-147, Jan.-Feb. 2017. graf
Article in English | LILACS | ID: biblio-842820

ABSTRACT

Abstract Benznidazole, drug of choice for Chagas disease (CD), has been associated with a high incidence of adverse reactions that can become serious, necessitating discontinuation of the drug. We describe the case of a Bolivian patient living in Spain for 9 years, who, following treatment with benznidazole for CD in indeterminate chronic phase, presented with fever, skin lesions, digestive symptoms, general malaise, and laboratory abnormalities. After the discontinuation of benznidazole and, the intake of antihistamines and systemic corticosteroids, the patient presented a complete resolution of the symptoms. Optimization of dose strategies and development of more effective, and better-tolerated drugs is advisable.


Subject(s)
Humans , Female , Trypanocidal Agents/adverse effects , Drug-Related Side Effects and Adverse Reactions , Nitroimidazoles/adverse effects , Trypanocidal Agents/therapeutic use , Chagas Disease/drug therapy , Middle Aged , Nitroimidazoles/therapeutic use
14.
Rev. Soc. Bras. Med. Trop ; 49(6): 713-720, Dec. 2016. tab, graf
Article in English | LILACS | ID: biblio-829676

ABSTRACT

Abstract: INTRODUCTION: Chagas disease currently affects 5.7 million people in Latin America and is emerging in non-endemic countries. There is no consensus concerning the efficacy of trypanocidal therapy for patients with the chronic form of the disease. We evaluated cardiac function and sociodemographic, clinical, and serologic characteristics of a group of asymptomatic Trypanosoma cruzi-seropositive former blood donors, and compared the effects of benznidazole treatment applied for different lengths of time. METHODS: Blood donors who screened positive for T. cruzi between 1998 and 2002 were recruited 10 years later for follow-up (n = 244); 46 individuals had received treatment. Three subjects had terminated treatment prematurely. The remaining 43 individuals were divided into two groups: individuals who had received benznidazole therapy for 50-60 days (n = 28; BT ≤60 group) or more than 60 days (n = 15; BT >60). Serologic assays, biochemical tests, electrocardiographic, echocardiographic, and clinical examinations were performed on all participants. Parasite loads were determined by qualitative and quantitative polymerase chain reaction. RESULTS: Parasitemia was significantly reduced in the BT ≤60 and BT >60 groups compared with the untreated group. There were no differences in epidemiologic profiles or clinical, biochemical, electrocardiographic, or echocardiographic data between any of the groups. CONCLUSIONS: Despite elimination or significant reduction in parasitemia in patients with chronic Chagas disease who received benznidazole, there was no clinical difference between those who were treated for >60 days and those treated for a shorter duration. Furthermore, the adverse effects of benznidazole appear to be less severe than previous reports would suggest.


Subject(s)
Humans , Male , Female , Adult , Trypanocidal Agents/administration & dosage , Blood Donors , Chagas Disease/drug therapy , Parasitemia/parasitology , Nitroimidazoles/administration & dosage , Time Factors , Clinical Protocols , Polymerase Chain Reaction , Chronic Disease , Cross-Sectional Studies , Treatment Outcome , Chagas Disease/parasitology , Asymptomatic Infections , Parasite Load , Middle Aged
15.
Rev. Soc. Bras. Med. Trop ; 49(6): 721-727, Dec. 2016. tab, graf
Article in English | LILACS | ID: biblio-829672

ABSTRACT

Abstract INTRODUCTION: Geographical, epidemiological, and environmental differences associated with therapeutic response to Chagas etiological treatment have been previously discussed. This study describes high seroconversion rates 72 months after benznidazole treatment in patients under 16 years from a project implemented by Doctors without Borders in Guatemala. METHODS: An enzyme-linked immunosorbent assay was used to detect Trypanosoma cruzi IgG antibodies in capillary blood samples from patients 72 months after treatment. Fisher's exact test was used to establish association between characteristics, such as sex, age, and origin of patients, and final seroconversion. Kappa index determined concordance between laboratory tests. The level of significance was set to 5%. RESULTS: Ninety-eight patients, aged 6 months to 16 years, were available for follow-up. Sex and origin were not associated with seroconversion. Individuals older than 13 were more prone to maintain a positive result 72 months after treatment, although results were not highly significant. Laboratory tests presented elevated Kappa concordance (95% CI) = 0.8290 (0.4955-1), as well as high (97%) seroconversion rates. CONCLUSIONS: The high seroconversion rate found in this study emphasizes the importance of access to diagnosis, treatment, and follow-up of individuals affected by Chagas disease. Moreover, it contradicts the idea that it is not possible to achieve a cure with the currently available drugs. This study strongly supports expanding programs for patients infected with T. cruzi in endemic and non-endemic countries.


Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Child , Adolescent , Trypanocidal Agents/therapeutic use , Trypanosoma cruzi/immunology , Antibodies, Protozoan/blood , Chagas Disease/drug therapy , Nitroimidazoles/therapeutic use , Enzyme-Linked Immunosorbent Assay , Chronic Disease , Treatment Outcome , Chagas Disease/immunology , Seroconversion , Guatemala
16.
Mem. Inst. Oswaldo Cruz ; 111(6): 365-371, June 2016. tab, graf
Article in English | LILACS | ID: lil-784247

ABSTRACT

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.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Young Adult , Antibodies, Protozoan/blood , Chagas Disease/drug therapy , Nitroimidazoles/therapeutic use , Trypanocidal Agents/therapeutic use , Antigens, Protozoan/immunology , Argentina , Chagas Disease/blood , Chronic Disease , Cohort Studies , Enzyme-Linked Immunosorbent Assay , Follow-Up Studies , Prospective Studies , Time Factors
17.
Mem. Inst. Oswaldo Cruz ; 111(3): 218-221, Mar. 2016. tab, graf
Article in English | LILACS | ID: lil-777373

ABSTRACT

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.


Subject(s)
Adult , Female , Humans , Male , Middle Aged , Young Adult , Chagas Disease/drug therapy , Nitroimidazoles/pharmacokinetics , Trypanocidal Agents/pharmacokinetics , Trypanosoma cruzi/drug effects , Chemistry, Pharmaceutical , Chagas Disease/metabolism , Follow-Up Studies , Nitroimidazoles/administration & dosage , Nitroimidazoles/blood , Real-Time Polymerase Chain Reaction , Trypanocidal Agents/administration & dosage , Trypanocidal Agents/blood , Trypanosoma cruzi/isolation & purification
18.
Mem. Inst. Oswaldo Cruz ; 110(3): 433-444, 05/2015. tab, graf
Article in English | LILACS | ID: lil-745976

ABSTRACT

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.


Subject(s)
Animals , Humans , ATP-Binding Cassette Transporters/genetics , Drug Resistance/genetics , Nitroimidazoles/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/genetics , DNA, Protozoan/genetics , Genotype , Membrane Transport Proteins/genetics , Parasitic Sensitivity Tests , Phylogeny
19.
Mem. Inst. Oswaldo Cruz ; 110(3): 414-421, 05/2015. tab, graf
Article in English | LILACS | ID: lil-745978

ABSTRACT

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.


Subject(s)
Humans , Chagas Disease/immunology , Nitroimidazoles/therapeutic use , T-Lymphocytes/immunology , Trypanocidal Agents/therapeutic use , Trypanosoma cruzi/immunology , Antigens, Protozoan/immunology , Chronic Disease , Chagas Disease/drug therapy , T-Lymphocytes/drug effects , Trypanosoma cruzi/drug effects
20.
Mem. Inst. Oswaldo Cruz ; 110(1): 86-94, 03/02/2015. tab, graf
Article in English | LILACS | ID: lil-741617

ABSTRACT

Trypanosoma cruzi strains from distinct geographic areas show differences in drug resistance and association between parasites genetic and treatment response has been observed. Considering that benznidazole (BZ) can reduce the parasite burden and tissues damage, even in not cured animals and individuals, the goal is to assess the drug response to BZ of T. cruzi II strains isolated from children of the Jequitinhonha Valley, state of Minas Gerais, Brazil, before treatment. Mice infected and treated with BZ in both phases of infection were compared with the untreated and evaluated by fresh blood examination, haemoculture, polymerase chain reaction, conventional (ELISA) and non-conventional (FC-ALTA) serologies. In mice treated in the acute phase, a significant decrease in parasitaemia was observed for all strains. Positive parasitological and/or serological tests in animals treated during the acute and chronic (95.1-100%) phases showed that most of the strains were BZ resistant. However, beneficial effect was demonstrated because significant reduction (p < 0.05%) and/or suppression of parasitaemia was observed in mice infected with all strains (acute phase), associated to reduction/elimination of inflammation and fibrosis for two/eight strains. BZ offered some benefit, even in not cured animals, what suggest that BZ use may be recommended at least for recent chronic infection of the studied region.


Subject(s)
Humans , Drug Discovery , Industrial Waste/analysis , Nootropic Agents/isolation & purification , Plant Extracts/chemistry , Plant Shoots/chemistry , Stilbenes/isolation & purification , Vitis/chemistry , Agriculture/economics , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Benzofurans/analysis , Benzofurans/chemistry , Benzofurans/economics , Benzofurans/isolation & purification , Chromatography, High Pressure Liquid , France , Industrial Waste/economics , Molecular Structure , Neuroprotective Agents/chemistry , Neuroprotective Agents/economics , Neuroprotective Agents/isolation & purification , Neuroprotective Agents/pharmacology , Nootropic Agents/chemistry , Nootropic Agents/economics , Nootropic Agents/pharmacology , Protein Aggregation, Pathological , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Phenols/chemistry , Phenols/economics , Plant Extracts/economics , Protein Aggregates/drug effects , Spectrometry, Mass, Electrospray Ionization , Stereoisomerism , Stilbenes/analysis , Stilbenes/chemistry , Stilbenes/economics , Stilbenes/pharmacology
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