Recent Developments in the Chemotherapy of Chagas Disease

Docampo, Roberto

doi:10.2174/1381612013397546

Cited by 71 publications

(53 citation statements)

References 57 publications

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“…Among these are allopurinol, an antiuricemic hypoxanthine that is used to treat gout, and antifungals that inhibit ergosterol, such as ketoconazole, itraconazole and fluconazole [42][43][44][45][46] . These have not been shown to be effective in vivo, including during the acute phase of the disease.…”

Section: Drugs In Use and New Strategies For Treating Chagas Diseasementioning

confidence: 99%

Chagas disease: What is known and what should be improved: a systemic review

Coura

Borges-Pereira

2012

Rev. Soc. Bras. Med. Trop.

118

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This study consists of a broad review on what is known and what should be improved regarding knowledge of Chagas disease, not only through analysis on the main studies published on the topics discussed, but to a large extent based on experience of this subject, acquired over the past 50 years (1961-2011). Among the subjects covered, we highlight the pathogenesis and evolution of infection by Trypanosoma cruzi, drugs in use and new strategies for treating Chagas disease; the serological tests for the diagnosis and the controls of cure the infection; the regional variations in prevalence, morbidity and response to treatment of the disease; the importance of metacyclogenesis of T. cruzi in different species of triatomines and its capacity to transmit Chagas infection; the risks of adaptation of wild triatomines to human dwellings; the morbidity and need for a surveillance and control program for Chagas disease in the Amazon region and the need to prioritize initiatives for controlling Chagas disease in Latin America and Mexico and in non-endemic countries, which is today a major international dilemma. Finally, we raise the need for to create a new initiative for controlling Chagas disease in the Gran Chaco, which involves parts of Argentina, Bolivia and Paraguay.

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Section: Drugs In Use and New Strategies For Treating Chagas Diseasementioning

confidence: 99%

Chagas disease: What is known and what should be improved: a systemic review

Coura

Borges-Pereira

2012

Rev. Soc. Bras. Med. Trop.

118

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“…T. cruzi has been recognized as a significant cause of morbidity and mortality from Mexico to South America (4). Chagas' disease remains a problem because of limited therapeutic choices and adverse reactions to the two drugs available, nifurtimox and benznidazole (4,14). Therefore, it is important to identify enzymes and metabolic pathways in T. cruzi that might be potential targets for drug development.…”

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confidence: 99%

Formation and Remodeling of Inositolphosphoceramide during Differentiation of Trypanosoma cruzi from Trypomastigote to Amastigote

et al. 2003

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Differentiation of Trypanosoma cruzi trypomastigotes to amastigotes inside myoblasts or in vitro, at low extracellular pH, in the presence of [3 H]palmitic acid or [ 3 H]inositol revealed differential labeling of inositolphosphoceramide and phosphatidylinositol, suggesting that a remodeling process takes place in both lipids. Using 3 H-labeled inositolphosphoceramide and phosphatidylinositol as substrates, we demonstrated the association of at least five enzymatic activities with the membranes of amastigotes and trypomastigotes. These included phospholipase A 1 , phospholipase A 2 , inositolphosphoceramide-fatty acid hydrolase, acyltransferase, and a phospholipase C releasing either ceramide or a glycerolipid from the inositolphospholipids. These enzymes may be acting in remodeling reactions leading to the anchor of mature glycoproteins or glycoinositolphospholipids and helping in the transformation of the plasma membrane, a necessary step in the differentiation of slender trypomastigotes to round amastigotes. Synthesis of inositolphosphoceramide and particularly of glycoinositolphospholipids was inhibited by aureobasidin A, a known inhibitor of fungal inositolphosphoceramide synthases. The antibiotic impaired the differentiation of trypomastigotes at acidic pH, as indicated by an increased appearance of intermediate forms and a decreased expression of the Ssp4 glycoprotein, a characteristic marker of amastigote forms. Aureobasidin A was also toxic to differentiating trypomastigotes at acidic pH but not to trypomastigotes maintained at neutral pH. Our data suggest that inositolphosphoceramide is implicated in T. cruzi differentiation and that its metabolism could provide important targets for the development of antiparasitic therapies.

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“…The DHFR activity of the T. cruzi enzyme was measured in 50 mM Tris HCl buffer, pH 7.0, and that of the human enzyme was measured in 50 mM KH 2 PO 4 , 250 mM KCl, 5 mM ␤-mercaptoethanol (␤-ME), pH 7.3, under optimum conditions for each enzyme. The inhibitory activity of TMQ was determined by measuring reaction velocities at several fixed concentrations (5,10,15,20,25, and 30 M) of DHF and various concentrations (0, 6.55, 13.11, 19.66, and 26.22 nM) of TMQ. The concentration of NADPH was kept at 150 M. The reaction was initiated by adding 1 g of purified TcDHFR-TS or 3 g of hDHFR.…”

Section: Methodsmentioning

confidence: 99%