Dataset Information

Treatment With Suboptimal Dose of Benznidazole Mitigates Immune Response Molecular Pathways in Mice With Chronic Chagas Cardiomyopathy.

ABSTRACT: Chronic Chagas cardiomyopathy (CCC) is the most frequent and severe form of Chagas disease, a neglected tropical illness caused by the protozoan Trypanosoma cruzi, and the main cause of morbimortality from cardiovascular problems in endemic areas. Although efforts have been made to understand the signaling pathways and molecular mechanisms underlying CCC, the immunological signaling pathways regulated by the etiological treatment with benznidazole (Bz) has not been reported. In experimental CCC, Bz combined with the hemorheological and immunoregulatory agent pentoxifylline (PTX) has beneficial effects on CCC. To explore the molecular mechanisms of Bz or Bz+PTX therapeutic strategies, C57BL/6 mice chronically infected with the T. cruzi Colombian strain (discrete typing unit TcI) and showing electrocardiographic abnormalities were submitted to suboptimal dose of Bz or Bz+PTX from 120 to 150 days postinfection. Electrocardiographic alterations, such as prolonged corrected QT interval and heart parasite load, were beneficially impacted by Bz and Bz+PTX. RT-qPCR TaqMan array was used to evaluate the expression of 92 genes related to the immune response in RNA extracted from heart tissues. In comparison with non-infected mice, 30 genes were upregulated, and 31 were downregulated in infected mice. Particularly, infection upregulated the cytokines IFN-γ, IL-12b, and IL-2 (126-, 44-, and 18-fold change, respectively) and the T-cell chemoattractants CCL3 and CCL5 (23- and 16-fold change, respectively). Bz therapy restored the expression of genes related to inflammatory response, cellular development, growth, and proliferation, and tissue development pathways, most probably linked to the cardiac remodeling processes inherent to CCC, thus mitigating the Th1-driven response found in vehicle-treated infected mice. The combined Bz+PTX therapy revealed pathways related to the modulation of cell death and survival, and organismal survival, supporting that this strategy may mitigate the progression of CCC. Altogether, our results contribute to the better understanding of the molecular mechanisms of the immune response in the heart tissue in chronic Chagas disease and reinforce that parasite persistence and dysregulated immune response underpin CCC severity. Therefore, Bz and Bz+PTX chemotherapies emerge as tools to interfere in these pathways aiming to improve CCC prognosis.

SUBMITTER: Farani PSG

PROVIDER: S-EPMC8351877 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Chagas disease is a neglected disease that remains a public health threat, particularly in Latin America. The most important treatment options are nitroimidazole derivatives, such as nifurtimox and benznidazole (BZN). Some studies suggest that for adults seropositive to T. cruzi but without clinically evident chronic Chagas cardiomyopathy (CCC), a simple fixed-dose scheme of BZN could be equivalent to a weight-adjusted dose. We compared the efficacy and safety of a fixed dose of BZN with an adjusted dose for T. cruzi seropositive adults without CCC. We used the Cochrane methods, and reported according to the PRISMA statement. We included randomized controlled trials (RCTs) allocating participants to fixed and/or adjusted doses of BZN for T. cruzi seropositive adults without CCC. We searched (December 2019) Cochrane, MEDLINE, EMBASE, LILACS, Clinicaltrials.gov, and International Clinical Trials Registry Platform (ICTRP), and contacted Chagas experts. Selection, data extraction, and risk of bias assessment, using the Cochrane tool, were performed independently by pairs of reviewers. Discrepancies were solved by consensus within the team. Primary outcomes were parasite-related outcomes and efficacy or patient-related safety outcomes. We conducted a meta-analysis using RevMan 5.3 software and used GRADE summary of finding tables to present the certainty of evidence by outcome. We identified 655 records through our search strategy and 10 studies (four of them ongoing) met our inclusion criteria. We did not find any study directly comparing fixed vs adjusted doses of BZN, however, some outcomes allowed subgroup comparisons between fixed and adjusted doses of BZN against placebo. Moderate-certainty evidence suggests no important subgroup differences for positive PCR at one year and for three safety outcomes (drug discontinuation, peripheral neuropathy, and mild rash). The same effect was observed for any serious adverse events (low-certainty evidence). All subgroups showed similar effects (I2 0% for all these subgroup comparisons but 32% for peripheral neuropathy), supporting the equivalence of BZN schemes. We conclude that there is no direct evidence comparing fixed and adjusted doses of BZN. Based on low to very low certainty of evidence for critical clinical outcomes and moderate certainty of evidence for important outcomes, fixed and adjusted doses may be equivalent in terms of safety and efficacy. An individual patient data network meta-analysis could better address this issue.

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.).

Dataset Information

Treatment With Suboptimal Dose of Benznidazole Mitigates Immune Response Molecular Pathways in Mice With Chronic Chagas Cardiomyopathy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets