Benznidazole and Chagas disease: can an old drug be the answer to an old problem?

Mady, Charles; Ianni, Bárbara Maria; Souza, José Leão de

doi:10.1517/13543784.17.10.1427

Cited by 21 publications

(10 citation statements)

References 31 publications

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“…The treatment of human Chagas' disease with the anti-T. cruzi drugs nifurtimox [4-(5-nitro-furylidenoamine)-tetrahydro-4-4-1,4-thiazine-1-1-dioxide] or benznidazole (N-benzyl-2-nitro-imidazoleacetamide) has had limited success (184,224,253,306,365,373). First, these nitroderivatives do not eradicate acute human T. cruzi infections, and an indication of parasite persistence is given by positive after-treatment immunological and nucleic acid tests (407).…”

Section: Progressive Chagas' Heart Disease In Drug-treated Casesmentioning

confidence: 99%

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

et al. 2011

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SUMMARY Acute Trypanosoma cruzi infections can be asymptomatic, but chronically infected individuals can die of Chagas' disease. The transfer of the parasite mitochondrial kinetoplast DNA (kDNA) minicircle to the genome of chagasic patients can explain the pathogenesis of the disease; in cases of Chagas' disease with evident cardiomyopathy, the kDNA minicircles integrate mainly into retrotransposons at several chromosomes, but the minicircles are also detected in coding regions of genes that regulate cell growth, differentiation, and immune responses. An accurate evaluation of the role played by the genotype alterations in the autoimmune rejection of self-tissues in Chagas' disease is achieved with the cross-kingdom chicken model system, which is refractory to T. cruzi infections. The inoculation of T. cruzi into embryonated eggs prior to incubation generates parasite-free chicks, which retain the kDNA minicircle sequence mainly in the macrochromosome coding genes. Crossbreeding transfers the kDNA mutations to the chicken progeny. The kDNA-mutated chickens develop severe cardiomyopathy in adult life and die of heart failure. The phenotyping of the lesions revealed that cytotoxic CD45, CD8 + γδ, and CD8α + T lymphocytes carry out the rejection of the chicken heart. These results suggest that the inflammatory cardiomyopathy of Chagas' disease is a genetically driven autoimmune disease.

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Section: Progressive Chagas' Heart Disease In Drug-treated Casesmentioning

confidence: 99%

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

et al. 2011

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“…Both of them are nitroheterocyclic compounds (Figure 1A), discovered in 1965 and in 1971, respectively [36]. Nifurtimox is a 5-nitrofuran derivative; benznidazole is a 2-nitroimidazole derivative.…”

Section: Current Clinical Etiological Treatment For Chagas Diseasementioning

confidence: 99%

Design or screening of drugs for the treatment of Chagas disease: what shows the most promise?

Lepesheva

2013

Expert Opinion on Drug Discovery

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Introduction Endemic in Latin America, Chagas disease is now becoming a serious global health problem, and yet has no financial viability for the pharmaceutical industry and remains incurable. In 2012, two antimycotic drugs inhibitors of fungal sterol 14α-demethylase (CYP51) – posaconazole and ravuconazole – entered clinical trials. Availability of the X-ray structure of the orthologous enzyme from the causative agent of the disease, protozoan parasite Trypanosoma cruzi, determined in complexes with posaconazole as well as with several experimental protozoa-specific CYP51 inhibitors opens an excellent opportunity to improve the situation. Areas covered This article summarizes the information available in PubMed and Google on the outcomes of treatment of the chronic Chagas disease. It also outlines the major features of the T. cruzi CYP51 structure and the possible structure-based strategies for rational design of novel T. cruzi specific drugs. Expert opinion There is no doubt that screenings for alternative drug-like molecules as well as mining the T. cruzi genome for novel drug targets are of great value and might eventually lead to groundbreaking discoveries. However, all newly identified molecules must proceed through the long, expensive and low-yielding drug optimization process, and all novel potential drug targets must be validated in terms of their essentiality and druggability. CYP51 is already a well-validated and highly successful target for clinical and agricultural antifungals. With minimal investments into the final stages of their development/trials, T. cruzi-specific CYP51 inhibitors can provide an immediate treatment for Chagas disease, either on their own or in combination with the currently available drugs.

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“…The etiological treatment used during early stages of Chagas disease is generally associated with high cure rates and good clinical outcome (Galvão et al 1993, Mady et al 2008. Analysis of the immunological changes following the etiological treatment of early Chagas disease has been recently performed (Sathler-Avelar et al 2006, 2008 (Sathler-Avelar et al 2008).…”

Section: The Impact Of Chagas Disease Etiological Treatment On Innatementioning

confidence: 99%

Innate immunity and regulatory T-cells in human Chagas disease: what must be understood?

Sathler-Avelar

Vitelli-Avelar

Teixeira-Carvalho

et al. 2009

Mem. Inst. Oswaldo Cruz

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Benznidazole and Chagas disease: can an old drug be the answer to an old problem?

Cited by 21 publications

References 31 publications

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

Design or screening of drugs for the treatment of Chagas disease: what shows the most promise?

Innate immunity and regulatory T-cells in human Chagas disease: what must be understood?

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