Chagas cardiomyopathy: The potential effect of benznidazole treatment on diastolic dysfunction and cardiac damage in dogs chronically infected with Trypanosoma cruzi

Santos, Fabiane Matos dos; Mazzeti, Ana Lia; Caldas, Sérgio; Gonçalves, Karolina Ribeiro; Lima, Wanderson Geraldo de; Torres, Rosália Morais; Bahia, Maria Terezinha

doi:10.1016/j.actatropica.2016.05.007

Cited by 34 publications

(28 citation statements)

References 46 publications

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“…Indeed, when benznidazole is discontinued and the T. cruzi population returns to a level normally seen in the chronic phase, scarce as that may be, inflammation and endomysium fibrosis return. There is a similar result in canine models (36,37). While autoimmunity is still a possible component of the damage to the tissue, reactivity to self-antigen is not sufficient to induce inflammation and the expansion of cytotoxic T lymphocytes (CTLs); the parasite antigens are needed for that.…”

Section: Discussionmentioning

confidence: 80%

“…Many of these difficulties can be addressed in animal experimental models of CCC. In mouse and canine models of CCC, a reduction of the parasite load in the heart tissue by trypanocide treatment during the chronic phase results in reductions of inflammation and fibrosis (33)(34)(35)(36)(37)(38). Thus, autoimmunity is not sufficient to maintain inflammation when the amount of the parasite antigen is reduced.…”

Section: Discussionmentioning

confidence: 99%

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Low-Level Parasite Persistence Drives Vasculitis and Myositis in Skeletal Muscle of Mice Chronically Infected with Trypanosoma cruzi

et al. 2019

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In chronic Trypanosoma cruzi infection, the cause of Chagas disease, life-threatening inflammatory diseases develop over time in the heart, esophagus, and colon of some patients. C57BL/6 mice infected with the myotropic Colombiana strain of T. cruzi model many of the immunological and parasitological features of human infection but succumb to chronic paralyzing myositis and skeletal muscle vasculitis, not cardiomyopathy or gastrointestinal disease. Here we show that T cell depletion in the chronic phase of this model increased tissue parasitism to acutephase levels and induced neutrophilic skeletal muscle inflammation. Conversely, after daily treatment with the trypanocide benznidazole for 8 weeks during the chronic phase, viable parasites were no longer detectable, myositis completely resolved, vasculitis was ϳ80% reduced, fibrosis was reduced, and myofiber morphology normalized. After the drug was discontinued, parasitism rebounded, and immunopathology recurred. The parasite load was statistically strongly correlated with the severity of inflammation. Thus, both T cell immunity and trypanocidal pharmacotherapy suppress to very low levels, but do not cure, T. cruzi infection, which is necessary and possibly sufficient to induce crippling chronic skeletal muscle myositis and vasculitis in the model.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Low-Level Parasite Persistence Drives Vasculitis and Myositis in Skeletal Muscle of Mice Chronically Infected with Trypanosoma cruzi

et al. 2019

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“…Bz itself decreased NF‐kB and MAPK activation and liver inflammation in a mouse‐induced sepsis model (Ronco et al, 2011), probably through the induction of nuclear factor erythroid‐derived 2‐like and decreased expression and therefore localization of TLR4 in the membrane (Lambertucci et al, 2017), partly explaining its anti‐inflammatory action. However, it has been reported that although Bz decreases the parasitic load in animal models of CCC, it cannot reverse or improve the structural damage induced by the parasite and therefore does not prevent the development of cardiomyopathy (Santos et al, 2012, 2016). This evidence is complemented by studies in humans where Bz was unable to reverse cardiac alterations in previously treated patients (Molina et al, 2014; Morillo et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Notch receptor expression in Trypanosoma cruzi‐infected human umbilical vein endothelial cells treated with benznidazole or simvastatin revealed by microarray analysis

Campos‐Estrada

González‐Herrera

Greif

et al. 2020

Cell Biology International

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Chagas disease is a vector-borne disease caused by the protozoan parasite Trypanosoma cruzi. Current therapy involves benznidazole. Benznidazole and other drugs can modify gene expression patterns, improving the response to the inflammatory influx induced by T. cruzi and decreasing the endothelial activation or immune cell recruitment, among other effects. Here, we performed a microarray analysis of human umbilical vein endothelial cells (HUVECs) treated with benznidazole and the anti-inflammatory drugs acetylsalicylic acid or simvastatin and infected with T. cruzi. Parasitic infection produces differential expression of a set of genes in HUVECs treated with benznidazole alone or a combination with simvastatin or acetylsalicylic acid. The differentially expressed genes were involved in inflammation, adhesion, cardiac function, and remodeling. Notch1 and high mobility group B1 were genes of interest in this analysis due to their importance in placental development, cardiac development, and inflammation. Quantitative polymerase chain reaction confirmation of these two genes indicated that both are upregulated in the presence of benznidazole.

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“…In vivo activity of BZN has been evaluated, in both acute and chronic stages, against approximately 64 strains/clones infecting (most frequently) mice, rabbits, and dogs [36,38,39,41,[46][47][48][49][50][51]. Findings in animals suggest that BZN treatment is beneficial in both CD stages, but more efficacious in acute models of T. cruzi infection.…”

Section: In Vivo Studiesmentioning

confidence: 99%

Clinical and pharmacological profile of benznidazole for treatment of Chagas disease

Kratz

Bournissen

Forsyth

et al. 2018

Expert Review of Clinical Pharmacology

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Chagas disease (CD) is one of the most neglected public health problems in the Americas, where <1% of the estimated 6 million people with the infection have been diagnosed and treated. The goal of treatment is to eliminate the parasite, decrease the probability of cardiomyopathy and other complications during the chronic stage of infection, and interrupt the cycle of disease transmission by preventing congenital infection. Currently, only benznidazole (BZN) and nifurtimox are recognized by the World Health Organization as effective drugs for treatment of CD. In this paper, we provide an overview of the clinical pharmacology of BZN. Areas covered: This review covers the historical background, chemistry, mechanism of action, pharmacokinetics, preclinical research, resistance, clinical research, toxicology, adverse effects, and current regulatory status of BZN. Expert commentary: Ongoing investigations aim to optimize BZN therapy by adjusting the current standard regimen or by combining BZN with new chemical entities. These studies are assessing alternatives that improve safety while maintaining or increasing the efficacy of BZN. Timely diagnosis and antitrypanosomal treatment are critical components of programs to eliminate CD as a public health problem, and can dramatically reduce the heavy burden of morbidity and mortality caused by the disease.

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Chagas cardiomyopathy: The potential effect of benznidazole treatment on diastolic dysfunction and cardiac damage in dogs chronically infected with Trypanosoma cruzi

Cited by 34 publications

References 46 publications

Low-Level Parasite Persistence Drives Vasculitis and Myositis in Skeletal Muscle of Mice Chronically Infected with Trypanosoma cruzi

Low-Level Parasite Persistence Drives Vasculitis and Myositis in Skeletal Muscle of Mice Chronically Infected with Trypanosoma cruzi

Notch receptor expression in Trypanosoma cruzi‐infected human umbilical vein endothelial cells treated with benznidazole or simvastatin revealed by microarray analysis

Clinical and pharmacological profile of benznidazole for treatment of Chagas disease

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