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Hepatic changes by benznidazole in a specific treatment for Chagas disease.

ABSTRACT: Chagas disease (Cd) is the third most common parasitic disease that causes damage to human health. Even a century after its description by Carlos Chagas and advances in its control, it remains a neglected disease. To eradicate the parasite or reduce the parasitic load, specific treatment for Trypanosoma cruzi (T. cruzi) is advisable; benznidazole (BNZ) is the drug that is currently prescribed. The purpose of this study is to report the adverse events (AE) due to the use of BNZ as a specific treatment for Cd, with a particular focus on hepatic changes. This was an observational, cross-sectional cohort study that included patients who were treated with BNZ. The medical records of patients who joined the Grupo de Estudo em doença de Chagas [Chagas Disease Study Group]/UNICAMP/Brazil and were treated with BNZ were reviewed for epidemiological, clinical, laboratory and AE parameters for the drug. The 204 patients who were assessed had an average age of 40.6 years ± 13.5 years, and 104 of them were women (50.98%). Fourteen (6.86%) individuals were in the acute phase of Cd, and 190 (93.13%) were in its chronic phase. AEs occurred in 85 patients (41.66%), 35 (41.17%) of whom had AEs related to the liver, characterized by an elevation of AST liver enzymes, ALT, alkaline phosphatase and gamma-glutamyltransferase (?GT). Other AEs that were observed included the following: 48 cases of cutaneous changes (56.47%), 8 cases of epigastric pain (9.41%), 7 cases of blood alteration (8.23%), and 3 cases of peripheral neuropathy (3.52%). Treatment was interrupted in 32 patients (37.64%) due to AD. Adverse events related to the liver secondary to the use of BNZ for Cd-specific treatment were frequent in this study and were characterized by an elevation of liver enzymes. Therefore, it is suggested that these enzymes be monitored during treatment with benznidazole.

SUBMITTER: Pavan TBS

PROVIDER: S-EPMC6054377 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Hepatic changes by benznidazole in a specific treatment for Chagas disease.

Pavan Tycha Bianca Sabaini TBS Silva Jamiro Wanderley da JWD Martins Luiz Cláudio LC Costa Sandra Cecília Botelho SCB Almeida Eros Antônio de EA

PloS one 20180720 7

Chagas disease (Cd) is the third most common parasitic disease that causes damage to human health. Even a century after its description by Carlos Chagas and advances in its control, it remains a neglected disease. To eradicate the parasite or reduce the parasitic load, specific treatment for Trypanosoma cruzi (T. cruzi) is advisable; benznidazole (BNZ) is the drug that is currently prescribed. The purpose of this study is to report the adverse events (AE) due to the use of BNZ as a specific trea ...[more]

PMID: 30028842

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Project description:The aim of the present study was to build a population pharmacokinetic (popPK) model to characterize benznidazole (BNZ) pharmacokinetics in adults with chronic Chagas disease. This study was a prospective, open-label, single-center clinical trial approved by the local ethics committee. Patients received BNZ at 2.5 mg/kg of body weight/12 h (Abarax, Elea Laboratory, Argentina) for 60 days. Plasma BNZ samples were taken several times during the study and analyzed by high-performance liquid chromatography with UV-visible detection (HPLC-UV). The popPK analysis was done with NONMEMv.7.3. Demographic and biological data were tested as covariates. Intraindividual, interoccasion, and residual variabilities were modeled. Internal and external validations were completed to assess the robustness of the model. Later on, simulations were performed to generate BNZ concentration-time course profiles for different dosage regimens. A total of 358 plasma BNZ concentrations from 39 patients were included in the analysis. A one-compartment PK model characterized by clearance (CL/F) and the apparent volume of distribution (V/F), with first-order absorption (Ka) and elimination, adequately described the data (CL/F, 1.73 liters/h; V/F, 89.6 liters; and Ka, 1.15 h(-1)). No covariates were found to be significant for CL/F and V/F. Internal and external validations of the final model showed adequate results. Data from simulations revealed that a dose of 2.5 mg/kg/12 h might lead to overexposure in most patients. A lower dose (2.5 mg/kg/24 h) was able to achieve trough BNZ plasma concentrations within the accepted therapeutic range of 3 to 6 mg/liter. In summary, we developed a population PK model for BNZ in adults with chronic Chagas disease. Dosing simulations showed that a BNZ dose of 2.5 mg/kg/24 h will adequately keep BNZ trough plasma concentrations within the recommended target range for the majority of patients. (This study has been registered at EudraCT under number 2011-002900-34 and at ClinicalTrials.gov under number NCT01755403.).

Project description:Chagas disease is caused by Trypanosoma cruzi. The persistence of the parasite is associated with the disease chronicity and the impairment of the cellular immune response. It has been reported that the CD4+CD8+ T cell population expands in chronic Chagas disease patients. Few studies have focused on this subset of cells, and very little is known about the impact of antiparasitic treatment on this population.Thirty-eight chronic Chagas disease patients (20 asymptomatic and 18 symptomatic) and twelve healthy controls were enrolled in this study. Peripheral blood mononuclear cells were stimulated with soluble T. cruzi antigens to analyze the production of cytokines and cytotoxic molecules by CD4+CD8+ T cells before and after benznidazole treatment. Additionally, expression and co-expression of five inhibitory receptors in these patients after treatment were studied using a multiparameter flow cytometry technique.The frequency of CD4+CD8+ T cells was higher in chronic Chagas disease patients compared with healthy donors. Furthermore, a higher ratio of CD4+CD8low/CD4+CD8high subpopulations was observed in chronic Chagas disease patients than in healthy donors. Additionally, CD4+CD8+ T cells from these patients expressed and co-expressed higher levels of inhibitory receptors in direct proportion to the severity of the pathology. Benznidazole treatment reduced the frequency of CD4+CD8+ T cells and decreased the ratio of CD4+CD8low/CD4+CD8high subpopulations. The co-expression level of the inhibitory receptor was reduced after treatment simultaneously with the enhancement of the multifunctional capacity of CD4+CD8+ T cells. After treatment, an increase in the frequency of T. cruzi antigen-specific CD4+CD8+ T cells expressing IL-2 and TNF-? was also observed.CD4+CD8+ T cells could play an important role in the control of T. cruzi infection since they were able to produce effector molecules for parasite control. Benznidazole treatment partially reversed the exhaustion process caused by T. cruzi infection in these cells with an improvement in the functional response of the T. cruzi antigen-specific CD4+CD8+ T cells.

Project description:Chagas disease is a neglected parasitic illness affecting approximately 8 million people, predominantly in Latin America. Benznidazole is the drug of choice for treatment, although its availability has been limited. A paucity of knowledge of the pharmacokinetic properties of this drug has contributed to its limited availability in several jurisdictions. The objective of this study was to conduct a systematic literature review and a Bayesian meta-analysis of pharmacokinetic studies to improve estimates of the basic pharmacokinetic properties of benznidazole. A systematic search of the Embase, Medline, LILACS, and SciELO (Scientific Electronic Library Online) databases was conducted. Eligible studies reported patient-level data from single-100-mg-dose pharmacokinetic evaluations of benznidazole in adults or otherwise provided data relevant to the estimation of pharmacokinetic parameters which could be derived from such studies. A Bayesian hierarchical model was used for analysis. Secondary data (i.e., data from studies that did not include patient-level, single-100-mg-dose data) were used for the generation of empirical priors for the Bayesian analysis. The systematic search identified nine studies for inclusion. Nine pharmacokinetic parameters were estimated, including the area under the concentration-time curve (AUC), the maximum concentration of drug in plasma (Cmax), the time to Cmax, the elimination rate constant (kel), the absorption rate constant (Ka), the absorption and elimination half-lives, the apparent oral clearance, and the apparent oral volume of distribution. The results showed consistency across studies. AUC and Cmax were 51.31 mg · h/liter (95% credible interval [CrI], 45.01, 60.28 mg · h/liter) and 2.19 mg/liter (95% CrI, 2.06, 2.33 mg/liter), respectively. Ka and kel were 1.16 h-1 (95% CrI, 0.59, 1.76 h-1) and 0.052 h-1 (95% CrI, 0.045, 0.059 h-1), respectively, with the corresponding absorption and elimination half-lives being 0.60 h (95% CrI, 0.38, 1.11 h) and 13.27 h (95% CrI, 11.79, 15.42 h), respectively. The oral clearance and volume of distribution were 2.04 liters/h (95% CrI, 1.77, 2.32 liters/h) and 39.19 liters (95% CrI, 36.58, 42.17 liters), respectively. A Bayesian meta-analysis was used to improve the estimates of the standard pharmacokinetic parameters of benznidazole. These data can inform clinicians and policy makers as access to this drug increases.

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Hepatic changes by benznidazole in a specific treatment for Chagas disease.

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Hepatic changes by benznidazole in a specific treatment for Chagas disease.

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