Ideal benznidazole dose regimen in chronic chagasic patients: a systematic review

Frade, Virgínia Paula; Simões, Nathália Soares; Baldoni, Nayara Ragi; Sanches, Cristina; Oliveira, Cláudia Di Lorenzo

doi:10.1590/s1678-9946202062052

Cited by 4 publications

(2 citation statements)

References 36 publications

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“…Although several systematic reviews showed the same effect of interventions against placebos, none addressed the comparison between fixed and adjusted doses of BZN [52,53,56,58,61,62]. A systematic review conducted by Frade et al tried to evaluate the best dose regimen for BZN in adult patients with CD in the chronic phase [63]. The authors included 23 experimental or observational studies and concluded that there is no consensus regarding dose, treatment time or cure criteria, but suggested 5 mg/kg/day for 30 days instead of 60 days, based, mainly, on the frequency of adverse events.…”

Section: Discussionmentioning

confidence: 99%

Direct evidence gap on fixed versus adjusted‐dose benznidazole for adults with chronic Chagas disease without cardiomyopathy: Systematic review and individual patient data meta‐analysis

Ciapponi

Barreira²,

Perelli

et al. 2022

Tropical Med Int Health

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Objectives To determine the comparative efficacy and safety of a fixed dose of benznidazole (BZN) with an adjusted‐dose for Trypanosoma cruzi‐seropositive adults without cardiomyopathy. Methods We conducted a systematic review and individual participant data (IPD) meta‐analysis following Cochrane methods, and the PRISMA‐IPD statement for reporting. Randomised controlled trials (RCTs) allocating participants to fixed or adjusted doses of BZN for T. cruzi‐seropositive adults without cardiomyopathy were included. We searched (December 2021) Cochrane, MEDLINE, EMBASE, LILACS and trial registries and contacted Chagas experts. Selection, data extraction, risk of bias assessment using the Cochrane tool, and a GRADE summary of finding tables were performed independently by pairs of reviewers. We conducted a random‐effects IPD meta‐analysis using the one‐stage strategy, or, if that was impossible, the two‐stage strategy. Results Five RCTs (1198 patients) were included, none directly comparing fixed with adjusted doses of BZN. Compared to placebo, BZN therapy was strongly associated with negative qPCR and sustainable parasitological clearance regardless of the type of dose and subgroup analysed. For negative qPCR, the fixed/adjusted rate of odds ratios (RORF/A) was 8.83 (95% CI 1.02–76.48); for sustained parasitological clearance, it was 4.60 (95% CI 0.40–52.51), probably indicating at least non‐inferior effect of fixed doses, with no statistically significant interactions by scheme for global and most subgroup estimations. The RORF/A for treatment interruption due to adverse events was 0.44 (95% CI 0.14–1.38), probably indicating no worse tolerance of fixed doses. Conclusions We found no direct comparison between fixed and adjusted doses of BZN. However, fixed doses versus placebo are probably not inferior to weight‐adjusted doses of BZN versus placebo in terms of parasitological efficacy and safety. Network IPD meta‐analysis, through indirect comparisons, may well provide the best possible answers in the near future. Registration The study protocol was registered in PROSPERO (CRD42019120905).

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Section: Discussionmentioning

confidence: 99%

Direct evidence gap on fixed versus adjusted‐dose benznidazole for adults with chronic Chagas disease without cardiomyopathy: Systematic review and individual patient data meta‐analysis

Ciapponi

Barreira²,

Perelli

et al. 2022

Tropical Med Int Health

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“…The disease is characterized by an acute and a chronic phase, and approximately 30 to 40% of chronically infected individuals develop overt clinical forms, such as cardiac and digestive ones 2 . There are two drugs available to treat the disease, nifurtimox and benznidazole (BZD); the last is the drug of choice in Brazil 3 . Although BZD has been commercially available for over 50 years, few studies on its pharmacokinetics are found in the literature.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetic modeling of benznidazole in Brazilian patients with chronic Chagas disease

Frade

Moreira

Sabino

et al. 2022

Rev. Inst. Med. trop. S. Paulo

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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 60 th day. On the 15 th 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.

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New 2‐nitroimidazole‐N‐acylhydrazones, analogs of benznidazole, as anti‐Trypanosoma cruzi agents

Pitombeira,

Júnior,

Murta

et al. 2024

Archiv der Pharmazie

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Chagas disease is a neglected tropical parasitic disease caused by the protozoan Trypanosoma cruzi. Worldwide, an estimated 8 million people are infected with T. cruzi, causing more than 10,000 deaths per year. Currently, only two drugs, nifurtimox and benznidazole (BNZ), are approved for its treatment. However, both are ineffective during the chronic phase, show toxicity, and produce serious side effects. This work aimed to obtain and evaluate novel 2‐nitroimidazole‐N‐acylhydrazone derivatives analogous to BNZ. The design of these compounds used the two important pharmacophoric subunits of the BNZ prototype, the 2‐nitroimidazole nucleus and the benzene ring, and the bioisosterism among the amide group of BNZ and N‐acylhydrazone. The 27 compounds were obtained by a three‐step route in 57%–98% yields. The biological results demonstrated the potential of this new class of compounds, since eight compounds were potent and selective in the in vitro assay against T. cruzi amastigotes and trypomastigotes using a drug‐susceptible strain of T. cruzi (Tulahuen) (IC50 = 4.3–6.25 µM) and proved to be highly selective with low cytotoxicity on L929 cells. The type I nitroreductase (TcNTR) assay suggests that the new compounds may act as substrates for this enzyme.

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Ideal benznidazole dose regimen in chronic chagasic patients: a systematic review

Abstract: This is an open-access article distributed under the terms of the Creative Commons Attribution License.

Cited by 4 publications

References 36 publications

Direct evidence gap on fixed versus adjusted‐dose benznidazole for adults with chronic Chagas disease without cardiomyopathy: Systematic review and individual patient data meta‐analysis

Direct evidence gap on fixed versus adjusted‐dose benznidazole for adults with chronic Chagas disease without cardiomyopathy: Systematic review and individual patient data meta‐analysis

Population pharmacokinetic modeling of benznidazole in Brazilian patients with chronic Chagas disease

New 2‐nitroimidazole‐N‐acylhydrazones, analogs of benznidazole, as anti‐Trypanosoma cruzi agents

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