Toxicity of nifurtimox as second-line treatment after benznidazole intolerance in patients with chronic Chagas disease: when available options fail

Crespillo-Andújar, Clara; Chamorro-Tojeiro, Sandra; Norman, Francesca; Monge‐Maíllo, Begoña; López‐Vélez, Rogelio; Perez-Molina, José A.

doi:10.1016/j.cmi.2018.06.006

Cited by 34 publications

(20 citation statements)

References 13 publications

(22 reference statements)

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“…As the second-line treatment, nifurtimox also presents high rates of TD (26 out of 53 patients; 49.1%). This means that approximately 12.3% of patients are left with no other therapeutic options [15]. Some new drugs or combinations with benznidazole, have not demonstrated sufficient efficacy to substitute the current treatment regimens [14,16,17].…”

Section: Discussionmentioning

confidence: 99%

Comparison of the toxicity of two treatment schemes with benznidazole for chronic Chagas disease: a prospective cohort study in two Spanish referral centres

Crespillo-Andújar

López‐Vélez

Trigo

et al. 2020

Clinical Microbiology and Infection

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Objectives: Chagas disease (CD) treatment is limited to two therapeutic options: benznidazole (generally the first option in Spain) and nifurtimox. Both drugs present high rates of adverse reactions and treatment discontinuation and there is no consensus regarding the most effective administration schedule for benznidazole or how to prevent and manage treatment toxicity. We aim to compare the tolerability and treatment discontinuation rate between two different treatment schemes with benznidazole. Methods: This was a prospective observational study of adult patients with CD, enrolled from January 2014 to March 2018 in two referral centres in Madrid (Spain). Participants were treated either with benznidazole 5 mg/kg/day (full dose) over 60 days (benznidazole standard dose scheme (BSD)), or with an escalating dose lasting 5 days up to a maximum of 300 mg/day (benznidazole increasing dose scheme (BID)). Results: 471 patients were analysed: 201 in the BSD group and 270 in the BID group. There were no significant differences regarding age (40.4 (SD 8.7) vs 41 (SD 8.2) years), sex (74.1% (149/201) vs 68.5% (185/270) women), weight (69.4 (SD 12.8) vs 68.9 (SD 11) kg) or nationality (97.5% (196/201) vs 96.7% (261/270) Bolivians) between groups. There were also no differences in adverse reactions rate (55.2% (111/201) vs 55.6% (150/270)), number of adverse reactions per patient, adverse reactions type (except for arthralgias and myalgias which occurred more frequently in the BID group (0% (0/111) BSD vs 8% (12/ 150) BID; p 0.002)) and degree and time to first adverse reactions. There was significantly more treatment discontinuation (49.8% (100/201) vs 33.0% (89/270); p <0.001) in the BSD group, but not during the first 30 days of treatment (32.3% (65/201) vs 25.6% (69/270); p 0.08). Conclusion:The use of increasing doses of benznidazole for 5 days and a maximum dose of 300 mg, does not significantly improve drug tolerability. However, while the treatment discontinuation rates were similar during the first 30 days of treatment, it may improve the treatment completion rate at 60 days.

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Section: Discussionmentioning

confidence: 99%

Comparison of the toxicity of two treatment schemes with benznidazole for chronic Chagas disease: a prospective cohort study in two Spanish referral centres

Crespillo-Andújar

López‐Vélez

Trigo

et al. 2020

Clinical Microbiology and Infection

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“…However, the appearance of adverse effects, including hepatic and renal damage, anorexia, dermatitis, nervous and digestive problems, immunosuppression and teratogenicity after BNZ administration, is still a serious concern (Maya et al , 2007; Salomon, 2012; Bonney, 2014). As described, between 20 and 40% of patients must discontinue treatment due to such undesirable effects (Viotti et al , 2009; Vinuesa et al , 2017; Crespillo-Andújar et al , 2018). Taking all these considerations into account, it is imperative to develop chemotherapeutic alternatives to optimize the biological response and minimize the adverse effects, as strongly recommended by other researchers (Kratz et al , 2018; Ribeiro et al , 2020).…”

Section: Introductionmentioning

confidence: 99%

In vitro studies and preclinical evaluation of benznidazole microparticles in the acute Trypanosoma cruzi murine model

et al. 2020

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Chagas disease is a serious parasitic infection caused by Trypanosoma cruzi. Unfortunately, the current chemotherapeutic tools are not enough to combat the infection. The aim of this study was to evaluate the trypanocidal activity of benznidazole-loaded microparticles during the acute phase of Chagas infection in an experimental murine model. Microparticles were prepared by spray-drying using copolymers derived from esters of acrylic and methacrylic acids as carriers. Dissolution efficiency of the formulations was up to 3.80-fold greater than that of raw benznidazole. Stability assay showed no significant difference (P > 0.05) in the loading capacity of microparticles for 3 years. Cell cultures showed no visible morphological changes or destabilization of the cell membrane nor haemolysis was observed in defibrinated human blood after microparticles treatment. Mice with acute lethal infection survived 100% after 30 days of treatment with benznidazole microparticles (50 mg kg−1 day−1). Furthermore, no detectable parasite load measured by quantitative polymerase chain reaction and lower levels of T. cruzi-specific antibodies by enzyme-linked immunosorbent assay were found in those mice. A significant decrease in the inflammation of heart tissue after treatment with these microparticles was observed, in comparison with the inflammatory damage observed in both infected mice treated with raw benznidazole and untreated infected mice. Therefore, these polymeric formulations are an attractive approach to treat Chagas disease.

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“…For adult patients treated during the chronic phase, only 7-8% cure rate was obtained. It remains an alternative drug for patients with benznidazole intolerance [17]. Benznidazole is a nitroimidazole derivative, which has been reported to increase reductive stress and to covalently modify the parasite´s proteins and DNA.…”

Section: Introductionmentioning

confidence: 99%

In vitro susceptibility of Trypanosoma cruzi discrete typing units (DTUs) to benznidazole: A systematic review and meta-analysis

et al. 2021

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Background Chagas disease, a neglected tropical disease endemic to Latin America caused by the parasite Trypanosoma cruzi, currently affects 6–7 million people and is responsible for 12,500 deaths each year. No vaccine exists at present and the only two drugs currently approved for the treatment (benznidazole and nifurtimox), possess serious limitations, including long treatment regimes, undesirable side effects, and frequent clinical failures. A link between parasite genetic variability and drug sensibility/efficacy has been suggested, but remains unclear. Therefore, we investigated associations between T. cruzi genetic variability and in vitro benznidazole susceptibility via a systematic article review and meta-analysis. Methodology/Principal findings In vitro normalized benznidazole susceptibility indices (LC50 and IC50) for epimastigote, trypomastigote and amastigote stages of different T. cruzi strains were recorded from articles in the scientific literature. A total of 60 articles, which include 189 assays, met the selection criteria for the meta-analysis. Mean values for each discrete typing unit (DTU) were estimated using the meta and metaphor packages through R software, and presented in a rainforest plot. Subsequently, a meta-regression analysis was performed to determine differences between estimated mean values by DTU/parasite stage/drug incubation times. For each parasite stage, some DTU mean values were significantly different, e.g. at 24h of drug incubation, a lower sensitivity to benznidazole of TcI vs. TcII trypomastigotes was noteworthy. Nevertheless, funnel plots detected high heterogeneity of the data within each DTU and even for a single strain. Conclusions/Significance Several limitations of the study prevent assigning DTUs to different in vitro benznidazole sensitivity groups; however, ignoring the parasite’s genetic variability during drug development and evaluation would not be advisable. Our findings highlight the need for establishment of uniform experimental conditions as well as a screening of different DTUs during the optimization of new drug candidates for Chagas disease treatment.

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Toxicity of nifurtimox as second-line treatment after benznidazole intolerance in patients with chronic Chagas disease: when available options fail

Cited by 34 publications

References 13 publications

Comparison of the toxicity of two treatment schemes with benznidazole for chronic Chagas disease: a prospective cohort study in two Spanish referral centres

Comparison of the toxicity of two treatment schemes with benznidazole for chronic Chagas disease: a prospective cohort study in two Spanish referral centres

In vitro studies and preclinical evaluation of benznidazole microparticles in the acute Trypanosoma cruzi murine model

In vitro susceptibility of Trypanosoma cruzi discrete typing units (DTUs) to benznidazole: A systematic review and meta-analysis

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