Login Register Cart 0
Review Article

New Approaches for the Treatment of Chagas Disease

Author(s): Ramendra Pati Pandey*, Marilda Savoia Nascimento, Catrin E. Moore, V. Samuel Raj, Jorge Kalil and Edecio Cunha-Neto

Volume 22, Issue 7, 2021

Published on: 24 November, 2020

Page: [835 - 841] Pages: 7

DOI: 10.2174/1389450121999201124122643

Price: $65

Abstract

Chagas disease, caused by the protozoan Trypanosoma cruzi is a neglected tropical disease with high prevalence (5.7 million in Latin America, WHO 2015), significant burden, and significant morbimortality mostly due to severe heart disorders during the chronic phase of infection. Chagas disease is endemic in Latin America, and medical care for the disease is the major expense for Brazil’s Universal Healthcare System (Sistema Único de Saúde (SUS). The efficacy of the available drugs benznidazole and nifurtimox are low for the chronic phase of Chagas disease, the phase in which most patients are diagnosed, and there are frequent side effects, and drug resistance occurs. The rapid deployment of new drug regimens that are effective for the chronic phase treatment is low-cost and less toxic than the currently available therapy, which is a global priority. Repurposing drugs already in clinical use with other combinations would be the fastest and safest strategy for treating Chagas disease patients. We hypothesize that the combined treatment using repurposing drugs with benznidazole will be more efficacious than benznidazole alone. This needs to be tested further both in vitro and in animal models to understand the efficacy of the treatment before performing human clinical trials. We further hypothesize that producing nanoparticle formulation of the drugs can reduce their toxicity and improve therapeutic use.

Keywords: Chagas disease, Trypanosoma cruzi, Heart disorders, Repurposing drugs, Nanoparticle formulation, benznidazole.

« Previous
Graphical Abstract

[1]
Nascimento MS, Stolf AMS, Andrade Junior HF, Pandey RP, Umezawa ES. Vimentin and anti vimentin antibodies in chagas’ disease. Arq Bras Cardiol 2018; 110(4): 348-53.
[http://dx.doi.org/10.5935/abc.20180038] [PMID: 29538505]
[2]
Chevillard C, Nunes JPS, Frade AF, et al. Disease tolerance and pathogen resistance genes may underlie Trypanosoma cruzi persistence and differential progression to chagas disease cardiomyopathy. Front Immunol 2018; 9: 2791.
[http://dx.doi.org/10.3389/fimmu.2018.02791] [PMID: 30559742]
[3]
Ferreira LRP, Ferreira FM, Laugier L, et al. Integration of miRNA and gene expression profiles suggest a role for miRNAs in the pathobiological processes of acute Trypanosoma cruzi infection. Sci Rep 2017; 7(1): 17990.
[http://dx.doi.org/10.1038/s41598-017-18080-9] [PMID: 29269773]
[4]
Chatelain E. Chagas disease research and development: Is there light at the end of the tunnel? Comput Struct Biotechnol J 2016; 15: 98-103.
[http://dx.doi.org/10.1016/j.csbj.2016.12.002] [PMID: 28066534]
[5]
Available from: http://www.dndi.org/diseases-projects/chagas/
[6]
Bellera CL, Sbaraglini ML, Balcazar DE, et al. High-throughput drug repositioning for the discovery of new treatments for Chagas disease. Mini Rev Med Chem 2015; 15(3): 182-93.
[http://dx.doi.org/10.2174/138955751503150312120208] [PMID: 25769967]
[7]
Kirchhoff LV, Paredes P, Lomelí-Guerrero A, et al. Transfusion-associated Chagas disease (American trypanosomiasis) in Mexico: implications for transfusion medicine in the United States. Transfusion 2006; 46(2): 298-304.
[http://dx.doi.org/10.1111/j.1537-2995.2006.00715.x] [PMID: 16441610]
[8]
Available from: http://conitec.gov.br/index.php
[9]
Cançado JR. Criteria of Chagas disease cure. Mem Inst Oswaldo Cruz 1999; 94(Suppl. 1): 331-5.
[http://dx.doi.org/10.1590/S0074-02761999000700064] [PMID: 10677750]
[10]
Morillo CA, Marin-Neto JA, Avezum A, et al. Randomized Trial of Benznidazole for Chronic Chagas’ Cardiomyopathy. N Engl J Med 2015; 373(14): 1295-306.
[http://dx.doi.org/10.1056/NEJMoa1507574] [PMID: 26323937]
[11]
Martín UO, Afchain D, de Marteleur A, Ledesma O, Caprón A. [Circulating immune complexes in different developmental stages of Chagas’ disease]. Medicina (B Aires) 1987; 47(2): 159-62. [Circulating immune complexes in different developmental stages of Chagas' disease].
[PMID: 3121979]
[12]
Barbosa AP, Cardinalli Neto A, Otaviano AP, Rocha BF, Bestetti RB. Comparison of outcome between Chagas cardiomyopathy and idiopathic dilated cardiomyopathy. Arq Bras Cardiol 2011; 97(6): 517-25.
[http://dx.doi.org/10.1590/S0066-782X2011005000112] [PMID: 22030565]
[13]
Bestetti RB, Muccillo G. Clinical course of Chagas’ heart disease: a comparison with dilated cardiomyopathy. Int J Cardiol 1997; 60(2): 187-93.
[http://dx.doi.org/10.1016/S0167-5273(97)00083-1] [PMID: 9226290]
[14]
Higuchi ML, De Morais CF, Pereira Barreto AC, et al. The role of active myocarditis in the development of heart failure in chronic Chagas’ disease: a study based on endomyocardial biopsies. Clin Cardiol 1987; 10(11): 665-70.
[http://dx.doi.org/10.1002/clc.4960101113] [PMID: 3677499]
[15]
Cunha-Neto E, Nogueira LG, Teixeira PC, et al. Immunological and non-immunological effects of cytokines and chemokines in the pathogenesis of chronic Chagas disease cardiomyopathy. Mem Inst Oswaldo Cruz 2009; 104(Suppl. 1): 252-8.
[http://dx.doi.org/10.1590/S0074-02762009000900032] [PMID: 19753481]
[16]
Milei J, Storino R, Fernandez Alonso G, Beigelman R, Vanzulli S, Ferrans VJ. Endomyocardial biopsies in chronic chagasic cardiomyopathy. Immunohistochemical and ultrastructural findings. Cardiology 1992; 80(5-6): 424-37.
[http://dx.doi.org/10.1159/000175035] [PMID: 1451131]
[17]
Higuchi MdeL, Gutierrez PS, Aiello VD, et al. Immunohistochemical characterization of infiltrating cells in human chronic chagasic myocarditis: comparison with myocardial rejection process. Virchows Arch A Pathol Anat Histopathol 1993; 423(3): 157-60.
[http://dx.doi.org/10.1007/BF01614765] [PMID: 7901937]
[18]
Reis DD, Jones EM, Tostes S Jr, et al. Characterization of inflammatory infiltrates in chronic chagasic myocardial lesions: presence of tumor necrosis factor-alpha+ cells and dominance of granzyme A+, CD8+ lymphocytes. Am J Trop Med Hyg 1993; 48(5): 637-44.
[http://dx.doi.org/10.4269/ajtmh.1993.48.637] [PMID: 8517482]
[19]
Abel LC, Rizzo LV, Ianni B, et al. Chronic Chagas’ disease cardiomyopathy patients display an increased IFN-gamma response to Trypanosoma cruzi infection. J Autoimmun 2001; 17(1): 99-107.
[http://dx.doi.org/10.1006/jaut.2001.0523] [PMID: 11488642]
[20]
Rocha Rodrigues DB, dos Reis MA, Romano A, et al. In situ expression of regulatory cytokines by heart inflammatory cells in Chagas’ disease patients with heart failure. Clin Dev Immunol 2012; 2012: 361730.
[PMID: 22811738]
[21]
Nogueira LG, Santos RH, Fiorelli AI, et al. Myocardial gene expression of T-bet, GATA-3, Ror-γt, FoxP3, and hallmark cytokines in chronic Chagas disease cardiomyopathy: an essentially unopposed TH1-type response. Mediators Inflamm 2014; 2014: 914326.
[http://dx.doi.org/10.1155/2014/914326] [PMID: 25152568]
[22]
Cunha-Neto E, Dzau VJ, Allen PD, et al. Cardiac gene expression profiling provides evidence for cytokinopathy as a molecular mechanism in Chagas’ disease cardiomyopathy. Am J Pathol 2005; 167(2): 305-13.
[http://dx.doi.org/10.1016/S0002-9440(10)62976-8] [PMID: 16049318]
[23]
Cunha-Neto E, Coelho V, Guilherme L, Fiorelli A, Stolf N, Kalil J. Autoimmunity in Chagas’ disease. Identification of cardiac myosin-B13 Trypanosoma cruzi protein crossreactive T cell clones in heart lesions of a chronic Chagas’ cardiomyopathy patient. J Clin Invest 1996; 98(8): 1709-12.
[http://dx.doi.org/10.1172/JCI118969] [PMID: 8878420]
[24]
Fonseca SG, Moins-Teisserenc H, Clave E, et al. Identification of multiple HLA-A*0201-restricted cruzipain and FL-160 CD8+ epitopes recognized by T cells from chronically Trypanosoma cruzi-infected patients. Microbes Infect 2005; 7(4): 688-97.
[http://dx.doi.org/10.1016/j.micinf.2005.01.001] [PMID: 15848276]
[25]
Docampo R, Moreno SN. Free radical metabolism of antiparasitic agents. Fed Proc 1986; 45(10): 2471-6.
[PMID: 3017765]
[26]
Docampo R. Sensitivity of parasites to free radical damage by antiparasitic drugs. Chem Biol Interact 1990; 73(1): 1-27.
[http://dx.doi.org/10.1016/0009-2797(90)90106-W] [PMID: 2406032]
[27]
Trochine A, Creek DJ, Faral-Tello P, Barrett MP, Robello C. Benznidazole biotransformation and multiple targets in Trypanosoma cruzi revealed by metabolomics. PLoS Negl Trop Dis 2014; 8(5): e2844.
[http://dx.doi.org/10.1371/journal.pntd.0002844] [PMID: 24853684]
[28]
Rajão MA, Furtado C, Alves CL, et al. Unveiling benznidazole’s mechanism of action through overexpression of DNA repair proteins in Trypanosoma cruzi. Environ Mol Mutagen 2014; 55(4): 309-21.
[http://dx.doi.org/10.1002/em.21839] [PMID: 24347026]
[29]
Rodriques Coura J, de Castro SL. A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz 2002; 97(1): 3-24.
[http://dx.doi.org/10.1590/S0074-02762002000100001] [PMID: 11992141]
[30]
Miller DA, Hernandez S, Rodriguez De Armas L, et al. Tolerance of benznidazole in a United States Chagas Disease clinic. Clin Infect Dis 2015; 60(8): 1237-40.
[http://dx.doi.org/10.1093/cid/civ005] [PMID: 25601454]
[31]
Filardi LS, Brener Z. Susceptibility and natural resistance of Trypanosoma cruzi strains to drugs used clinically in Chagas disease. Trans R Soc Trop Med Hyg 1987; 81(5): 755-9.
[http://dx.doi.org/10.1016/0035-9203(87)90020-4] [PMID: 3130683]
[32]
Murta SM, Gazzinelli RT, Brener Z, Romanha AJ. Molecular characterization of susceptible and naturally resistant strains of Trypanosoma cruzi to benznidazole and nifurtimox. Mol Biochem Parasitol 1998; 93(2): 203-14.
[http://dx.doi.org/10.1016/S0166-6851(98)00037-1] [PMID: 9662705]
[33]
Zingales B, Miles MA, Moraes CB, et al. Drug discovery for Chagas disease should consider Trypanosoma cruzi strain diversity. Mem Inst Oswaldo Cruz 2014; 109(6): 828-33.
[http://dx.doi.org/10.1590/0074-0276140156] [PMID: 25317712]
[34]
Garcia S, Ramos CO, Senra JF, et al. Treatment with benznidazole during the chronic phase of experimental Chagas’ disease decreases cardiac alterations. Antimicrob Agents Chemother 2005; 49(4): 1521-8.
[http://dx.doi.org/10.1128/AAC.49.4.1521-1528.2005] [PMID: 15793134]
[35]
Urbina JA. Parasitological cure of Chagas disease: is it possible? Is it relevant? Mem Inst Oswaldo Cruz 1999; 94(Suppl. 1): 349-55.
[http://dx.doi.org/10.1590/S0074-02761999000700068] [PMID: 10677754]
[36]
Urbina JA, Concepcion JL, Montalvetti A, Rodriguez JB, Docampo R. Mechanism of action of 4-phenoxyphenoxyethyl thiocyanate (WC-9) against Trypanosoma cruzi, the causative agent of Chagas’ disease. Antimicrob Agents Chemother 2003; 47(6): 2047-50.
[http://dx.doi.org/10.1128/AAC.47.6.2047-2050.2003] [PMID: 12760897]
[37]
Michailowsky V, Murta SM, Carvalho-Oliveira L, et al. Interleukin-12 enhances in vivo parasiticidal effect of benznidazole during acute experimental infection with a naturally drug-resistant strain of Trypanosoma cruzi. Antimicrob Agents Chemother 1998; 42(10): 2549-56.
[http://dx.doi.org/10.1128/AAC.42.10.2549] [PMID: 9756754]
[38]
Available from: http: //www.dndi.org/diseases-projects/chagas/chagas-target-product-profile
[39]
Buckner FS, Urbina JA. Recent Developments in Sterol 14-demethylase Inhibitors for Chagas Disease. Int J Parasitol Drugs Drug Resist 2012; 2: 236-42.
[http://dx.doi.org/10.1016/j.ijpddr.2011.12.002] [PMID: 23277882]
[40]
Olivieri BP, Molina JT, de Castro SL, et al. A comparative study of posaconazole and benznidazole in the prevention of heart damage and promotion of trypanocidal immune response in a murine model of Chagas disease. Int J Antimicrob Agents 2010; 36(1): 79-83.
[http://dx.doi.org/10.1016/j.ijantimicag.2010.03.006] [PMID: 20452188]
[41]
Urbina JA, de Andrade IM, Mazzeti AL, Martins TA, Caldas IS, Talvani A, Ribeiro I and Bahia MT. Benznidazole and posaconazole in experimental Chagas disease: positive interaction in concomitant and sequential treatments. PLoS Negl Trop Dis 2013; 7: e2367.
[http://dx.doi.org/10.1371/journal.pntd.0002367]
[42]
Planer JD, Hulverson MA, Arif JA, Ranade RM, Don R, Buckner FS. Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi. PLoS Negl Trop Dis 2014; 8(7): e2977.
[http://dx.doi.org/10.1371/journal.pntd.0002977] [PMID: 25033456]
[43]
Schwegmann A, Brombacher F. Host-directed drug targeting of factors hijacked by pathogens. Sci Signal 2008; 1(29): re8.
[http://dx.doi.org/10.1126/scisignal.129re8] [PMID: 18648074]
[44]
Parihar SP, Guler R, Khutlang R, et al. Statin therapy reduces the mycobacterium tuberculosis burden in human macrophages and in mice by enhancing autophagy and phagosome maturation. J Infect Dis 2014; 209(5): 754-63.
[http://dx.doi.org/10.1093/infdis/jit550] [PMID: 24133190]
[45]
Chatelain E, Konar N. Translational challenges of animal models in Chagas disease drug development: a review. Drug Des Devel Ther 2015; 9: 4807-23.
[http://dx.doi.org/10.2147/DDDT.S90208] [PMID: 26316715]
[46]
Bilate AM, Salemi VM, Ramires FJ, et al. The Syrian hamster as a model for the dilated cardiomyopathy of Chagas’ disease: a quantitative echocardiographical and histopathological analysis. Microbes Infect 2003; 5(12): 1116-24.
[http://dx.doi.org/10.1016/j.micinf.2003.07.001] [PMID: 14554253]
[47]
Ramírez LE, Lages-Silva E, Soares Júnior JM, Chapadeiro E. The hamster (Mesocricetus auratus) as experimental model in Chagas’ disease: parasitological and histopathological studies in acute and chronic phases of Trypanosoma cruzi infection. Rev Soc Bras Med Trop 1994; 27(3): 163-9.
[http://dx.doi.org/10.1590/S0037-86821994000300007] [PMID: 7972946]
[48]
Bilate AM, Salemi VM, Ramires FJ, et al. TNF blockade aggravates experimental chronic Chagas disease cardiomyopathy. Microbes Infect 2007; 9(9): 1104-13.
[http://dx.doi.org/10.1016/j.micinf.2007.05.014] [PMID: 17644389]
[49]
Bilate AM, Teixeira PC, Ribeiro SP, et al. Distinct outcomes of Trypanosoma cruzi infection in hamsters are related to myocardial parasitism, cytokine/chemokine gene expression, and protein expression profile. J Infect Dis 2008; 198(4): 614-23.
[http://dx.doi.org/10.1086/590347] [PMID: 18598198]
[50]
Ramires FJ, Lanni BM, Salemi VM, Bilate AM, Cunha-Neto E, Oliveira AM, Fernandes F and Mady C. The effect of beta-blockade on myocardial remodelling in Chagas’ cardiomyopathy. Clinics (São Paulo) 2012; 67: 1063-9.
[51]
Fernandes F, Ramires FJ, Ianni BM, et al. Effect of colchicine on myocardial injury induced by Trypanosoma cruzi in experimental Chagas disease. J Card Fail 2012; 18(8): 654-9.
[http://dx.doi.org/10.1016/j.cardfail.2012.06.419] [PMID: 22858082]
[52]
Tanaka DM. Estudo do efeito do agente vasodilatador da microcirculação coronariana sobre os distúrbios de perfusão miocárdica e disfunção ventricular esquerda em modelo de cardiomatia chagásica crônica em hamsters. Tese de Mestrado: Programa de Pós-Graduação em clínica médica da Faculdade de Medicina de Ribeirão PretoUniversidade de São Paulo, Ribeirão Preto, SP 2016.
[53]
Sánchez G, Cuellar D, Zulantay I, Gajardo M, González-Martin G. Cytotoxicity and trypanocidal activity of nifurtimox encapsulated in ethylcyanoacrylate nanoparticles. Biol Res 2002; 35(1): 39-45.
[http://dx.doi.org/10.4067/S0716-97602002000100007] [PMID: 12125203]
[54]
Scalise ML, Arrúa EC, Rial MS, Esteva MI, Salomon CJ, Fichera LE. Promising Efficacy of Benznidazole Nanoparticles in Acute Trypanosoma cruzi Murine Model: In-Vitro and In-Vivo Studies. Am J Trop Med Hyg 2016; 95(2): 388-93.
[http://dx.doi.org/10.4269/ajtmh.15-0889] [PMID: 27246447]

Rights & Permissions Print Cite
Article Metrics
93
2
World Malaria Day
© 2024 Bentham Science Publishers | Privacy Policy