Pharmacokinetic and pharmacodynamic responses in adult patients with Chagas disease treated with a new formulation of benznidazole

Fory

Rev. Soc. Bras. Med. Trop.

2017

The pharmacological management of adults with chronic-phase Chagas disease is challenging despite it being the recent focus of extensive research. One of the challenges in the current clinical practice guidelines (CPGs) landscape is the existence of nonevidence-based recommendations for the use of laboratory tests in treatment monitoring. This study aimed to systematically assess the quality and consistency of recommendations of CPGs on the pharmacological management of adults with chronicphase Chagas disease. Systematic literature searches were conducted in MEDLINE, EMBASE, SciELO and Google to identify all published CPGs relevant to the pharmacological management of Chagas disease, between January 2010 and March 2016. Three independent reviewers assessed the quality of each CPG using the Appraisal of Guidelines Research and Evaluation (AGREE) II instrument. A total of fi ve CPGs were included and the overall quality of the guidelines for therapeutic drug monitoring of Chagas disease was moderate-to-low. There was considerable variation in the quality of the CPGs across the AGREE II domains. The domains of scope/purpose, stakeholder involvement, and clarity of presentation were rated well, and the domains of applicability and editorial independence received poor ratings. This review showed that the methodological quality of CPGs for Chagas disease was generally inappropriate, and there was no explicit link between the best available evidence and current recommendations.

Section: Discussionmentioning

confidence: 99%

Therapeutic drug monitoring of benznidazole and nifurtimox: a systematic review and quality assessment of published clinical practice guidelines

Fory

Rev. Soc. Bras. Med. Trop.

2017

Int J Experimental Path

“…Despite this, only two drugs remain available for treatment during the acute phase of Chagas disease: nifurtimox and benznidazole (BZN) . For both adults and children, these drugs have demonstrated limited action in the indeterminate form …”

Section: Introductionmentioning

confidence: 99%

“…2,3 For both adults and children, these drugs have demonstrated limited action in the indeterminate form. [4][5][6][7][8][9][10][11][12] Chung et al 13 obtained the hydroxymethylnitrofurazone (NFOH), as a synthetic intermediate aiming to obtain nitrofurazone (NF)-primaquine prodrugs. The NFOH exhibited trypanocidal activity against trypomastigotes and amastigote forms of T. cruzi using infected LLC-MK 2 cells.…”

Section: Introductionmentioning

confidence: 99%

Hydroxymethylnitrofurazone treatment in indeterminate form of chronic Chagas disease: Reduced intensity of tissue parasitism and inflammation—A histopathological study

Scarim

Andrade

Rosa

et al. 2018

Summary Hydroxymethylnitrofurazone (NFOH) is a nitrofurazone prodrug effective in vivo during acute infections, and it has less hepatotoxicity effect than the standard drug benznidazole (BZN) which has been used during short‐ and long‐term treatment. In the present study, we induced the indeterminate form of Chagas disease in mice with a Y strain of Trypanosoma cruzi and analysed the histopathological data about the effects of NFOH and BZN on different tissues, including the heart, skeletal muscle, liver, kidney, colon, spleen and brain. After infection, BALB/c mice were treated with NFOH (150 mg/kg) and BZN (60 mg/kg) for 60 days and then submitted to immunosuppression using dexamethasone (5 mg/kg) for 14 days. Two trained analysts, as part of a blind evaluation, examined the results using serial sections of 3 mm diameter in two different moments. The results showed reactivation of the disease only in the infected nontreated group (POS). After treatment, amastigote nests were found in the heart, colon, liver and skeletal muscle in the POS group and in the heart and liver of the BZN group. Interestingly, amastigote nests were not found in the NFOH and NEG groups. The histopathological analysis showed fewer tissue lesions and parasite infiltrates in the NFOH group when compared with the BZN and POS groups. We have not observed any increase in the levels of hepatocellular injury biomarkers (AST/ALT) in the NFOH group. These in vivo studies show the potential for NFOH as an effective and safe compound useful as an anti‐T. cruzi agent.

Antimicrob Agents Chemother

“…Of these, 12 were excluded: 1 because of an ineligible study design, 7 because the populations studied did not inform the primary analysis of interest (i.e., a single-dose pharmacokinetic analysis), 2 because the intervention of interest was not included, and 2 because the outcome of interest was not included. This resulted in a total of 9 studies that were included in the analysis (17)(18)(19)(20)(21)(22)(23)(24)(25). There were no single-dose PK studies of benznidazole in children.…”

Section: Evidence Basementioning

confidence: 99%

“…One was a published study (22); one was an unpublished trial report (17); and one was a Ph.D. thesis (20), which also remained unpublished and was obtained from the corresponding university archives with authorization for the purpose of this analysis. Three studies contained limited individual patient-level data from multidose studies (18,20,21). Of these, only the study by Raaflaub (21) provided data pertinent to the primary analyses.…”

Section: Evidence Basementioning

confidence: 99%

Systematic Review and Meta-analysis of the Pharmacokinetics of Benznidazole in the Treatment of Chagas Disease

Wiens

Kanters

Mills

et al. 2016

f 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 (C max ), the time to C max , the elimination rate constant (k el ), the absorption rate constant (K a ), the absorption and elimination half-lives, the appar-