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Monotherapy and combination chemotherapy for Chagas disease treatment: a systematic review of clinical efficacy and safety based on randomized controlled trials

Published online by Cambridge University Press:  12 August 2022

Silas Santana Nogueira ,
Eliziária Cardoso Santos ,
Roberta Oliveira Silva ,
Reggiani Vilela Gonçalves ,
Graziela Domingues Almeida Lima  and
Rômulo Dias Novaes Open the ORCID record for Rômulo Dias Novaes [Opens in a new window]
Silas Santana Nogueira
Affiliation:
Programa de Pós-Graduação em Biociências Aplicadas à Saúde, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, 37130-000, Minas Gerais, Brazil Instituto Federal do Sul de Minas Gerais, Pouso Alegre, Minas Gerais, Brazil
Eliziária Cardoso Santos
Affiliation:
Faculdade de Medicina, Universidade Federal dos Vales do Jequitinhonha e Mucuri, Diamantina, MG, Brazil
Roberta Oliveira Silva
Affiliation:
Programa de Pós-Graduação em Biociências Aplicadas à Saúde, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, 37130-000, Minas Gerais, Brazil
Reggiani Vilela Gonçalves
Affiliation:
Departamento de Biologia Animal, Universidade Federal de Viçosa, Viçosa, 36570-900, Minas Gerais, Brazil
Graziela Domingues Almeida Lima
Affiliation:
Programa de Pós-Graduação em Biociências Aplicadas à Saúde, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, 37130-000, Minas Gerais, Brazil
Rômulo Dias Novaes*
Affiliation:
Programa de Pós-Graduação em Biociências Aplicadas à Saúde, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, 37130-000, Minas Gerais, Brazil Departamento de Biologia Estrutural, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, 37130-000, Minas Gerais, Brazil
*
Author for correspondence: Rômulo Dias Novaes, E-mail: romuonovaes@yahoo.com.br
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Abstract

From a systematic review framework, we analysed the clinical evidence on the effectiveness and safety of monotherapy and combination chemotherapy for Chagas disease (ChD) treatment. The research protocol was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and patient, intervention, comparison and outcome strategy. Only randomized controlled trials (RCT) were retrieved from Embase, Medline, Scopus and Web of Science databases. Diagnostic tools, treatment protocols, seroconversion rates and adverse events were investigated. Fifteen RCT mainly concentrated in endemic countries were identified. ChD diagnosis was mainly based on haemagglutination, immunofluorescence, enzyme-linked immunosorbent assay and polymerase chain reaction. Benznidazole (BNZ), nifurtimox, fosravuconazole, posaconazole, allopurinol and thioctic acid were the identified drugs. The best negative seroconversion results (100, 96, 94 and 91.3%) were, respectively, based on BNZ (5 mg kg day−1, 200 mg day−1, 150 mg day−1 and 2.5 mg kg−1) administration for 60 days. Negative seroconversion was not achieved with allopurinol (300 mg day−1 for 60 days). Adverse reactions ranged from 5 to 73% in patients receiving antiparasitic chemotherapy. Treatment discontinuation (1.5–57%) was mainly associated with gastrointestinal, cutaneous and neurological manifestations. Current RCT-based evidence indicates that BNZ is the most viable option for ChD treatment. However, new protocols need to be developed to mitigate side effects and increase patient adherence to antiparasitic chemotherapy. Therefore, shorter regimens, lower concentrations and treatments combining BNZ with posaconazole, fosravuconazole or ravuconazole may be viable to ensure comparable efficacy to BZN-based monotherapy, contributing to reduce dose- and time-dependent toxicity reactions.

Keywords

Antiparasitic chemotherapyChagas diseaseparasitologyTrypanosoma cruzi
Type
Systematic Review
Information
Parasitology , Volume 149 , Issue 13 , November 2022 , pp. 1679 - 1694
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Copyright
Copyright © The Author(s), 2022. Published by Cambridge University Press

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References

Altoé, LS, Alves, RS, Sarandy, MM, Morais-Santos, M, Novaes, RD and Gonçalves, RV (2019) Does antibiotic use accelerate or retard cutaneous repair? A systematic review in animal models. PLoS One 14, e0223511.CrossRefGoogle ScholarPubMed
Álvarez, MG, Ramírez, JC, Bertocchi, G, Fernández, M, Hernández, Y, Lococo, B, Lopez-Albizu, C, Schijman, A, Cura, C, Abril, M, Laucella, S, Tarleton, RL, Natale, MA, Castro, , Eiro, M, Sosa-Estani, S and Viotti, R (2020) New scheme of intermittent benznidazole administration in patients chronically infected with Trypanosoma cruzi: clinical, parasitological, and serological assessment after three years of follow-up. Antimicrobials Agents and Chemotherapy 64, e00439–20.CrossRefGoogle ScholarPubMed
Andrade, AL, Martelli, CM, Oliveira, RM, Silva, SA, Aires, AI, Soussumi, LM, Covas, DT, Silva, LS, Andrade, JG, Travassos, LR and Almeida, IC (2004) Short report: benznidazole efficacy among Trypanosoma cruzi-infected adolescents after a six-year follow-up. American Journal of Tropical Medicine and Hygiene 71, 594–597.CrossRefGoogle ScholarPubMed
Andrade, JP, Marin Neto, JA, Paola, AA, Vilas-Boas, F, Oliveira, GM, Bacal, F, Bocchi, EA, Almeida, DR, Fragata Filho, AA, Moreira Mda, C, Xavier, SS, Oliveira Junior, WA and Dias, JC (2011) I Latin American Guidelines for the diagnosis and treatment of Chagas’ heart disease: executive summary. Arquivos Brasileiros de Cardiologia 96, 434–442.CrossRefGoogle ScholarPubMed
Avila, JL and Avila, A (1981) Trypanosoma cruzi: allopurinol in the treatment of mice with experimental acute Chagas disease. Experimental Parasitology 51, 204–208.CrossRefGoogle ScholarPubMed
Berens, RL, Marr, JJ, Steele da Cruz, FS and Nelson, DJ (1982) Effect of allopurinol on Trypanosoma cruzi: metabolism and biological activity in intracellular and bloodstream forms. Antimicrobials Agents and Chemotherapy 22, 657–661.CrossRefGoogle ScholarPubMed
Bern, C (2015) Chagas’ disease. New England Journal of Medicine 373, 456–466.CrossRefGoogle ScholarPubMed
Bern, C, Montgomery, SP, Herwaldt, BL, Rassi, A Jr, Marin-Neto, JA, Dantas, RO, Maguire, JH, Acquatella, H, Morillo, C, Kirchhoff, LV, Gilman, RH, Reyes, PA, Salvatella, R and Moore, AC (2007) Evaluation and treatment of Chagas disease in the United States: a systematic review. Journal of the American Medical Association 298, 2171–2181.CrossRefGoogle ScholarPubMed
Bivona, AE, Alberti, AS, Cerny, N, Trinitario, SN and Malchiodi, EL (2020) Chagas disease vaccine design: the search for an efficient Trypanosoma cruzi immune-mediated control. Biochimica et Biophysica Acta – Molecular Basis of Disease 1866, 165658.CrossRefGoogle ScholarPubMed
Blanco, SB, Segura, EL, Cura, EN, Chuit, R, Tulián, L, Flores, I, Garbarino, G, Villalonga, JF and Gürtler, RE (2000) Congenital transmission of Trypanosoma cruzi: an operational outline for detecting and treating infected infants in north-western Argentina. Tropical Medicine and International Health 5, 293–301.CrossRefGoogle ScholarPubMed
Bonney, KM, Luthringer, DJ, Kim, SA, Garg, NJ and Engman, DM (2019) Pathology and pathogenesis of Chagas heart disease. Annual Review of Pathology 14, 421–447.CrossRefGoogle ScholarPubMed
Bustamante, JM, Craft, JM, Crowe, BD, Ketchie, SA and Tarleton, RL (2014) New, combined, and reduced dosing treatment protocols cure Trypanosoma cruzi infection in mice. Journal of Infectious Diseases 209, 150–162.CrossRefGoogle ScholarPubMed
Caldas, IS, Santos, EG and Novaes, RD (2019) An evaluation of benznidazole as a Chagas disease therapeutic. Expert Opinion on Pharmacotherapy 20, 1797–1807.CrossRefGoogle ScholarPubMed
Calvet, CM, Silva, TA, Thomas, D, Suzuki, B, Hirata, K, Siqueira-Neto, JL and McKerrow, JH (2020) Long term follow-up of Trypanosoma cruzi infection and Chagas disease manifestations in mice treated with benznidazole or posaconazole. PLOS Neglected Tropical Diseases 14, e0008726.CrossRefGoogle ScholarPubMed
Castro, AM, Luquetti, AO, Rassi, A, Rassi, GG, Chiari, E and Galvão, LM (2002) Blood culture and polymerase chain reaction for the diagnosis of the chronic phase of human infection with Trypanosoma cruzi. Parasitology Research 88, 894–900.Google Scholar
Chatelain, E (2015) Chagas disease drug discovery: toward a new era. Journal of Biomolecular Screening 20, 22–35.CrossRefGoogle ScholarPubMed
Chippaux, JP, Clavijo, AN, Santalla, JA, Postigo, JR, Schneider, D and Brutus, L (2010) Antibody drop in newborns congenitally infected by Trypanosoma cruzi treated with benznidazole. Tropical Medicine and International Health 15, 87–93.Google ScholarPubMed
Coura, JR, Abreu, LL, Willcox, HPF and Petana, W (1997) Estudo comparativo controlado com emprego de benznidazole, nifurtimox e placebo, na forma crônica da doença de Chagas, em uma área de campo com transmissão interrompida. I. Avaliação preliminar. Revista da Sociedade Brasileira de Medicina Tropical 30, 139–144.CrossRefGoogle Scholar
De Andrade, AL, Zicker, F, Luquetti, AO, Oliveira, RM, Silva, SA, Souza, JM and Martelli, CM (1992) Surveillance of Trypanosoma cruzi transmission by serological screening of schoolchildren. Bulletin of the World Health Organization 70, 625–629.Google ScholarPubMed
De Andrade, AL, Zicker, F, de Oliveira, RM, Almeida Silva, S, Luquetti, A, Travassos, LR, Almeida, IC, de Andrade, SS, de Andrade, JG and Martelli, CM (1996) Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet 348, 1407–1413.CrossRefGoogle ScholarPubMed
Diniz Lde, F, Urbina, JA, de Andrade, IM, Mazzeti, AL, Martins, TA, Caldas, IS, Talvani, A, Ribeiro, I and Bahia, MT (2013) Benznidazole and posaconazole in experimental Chagas disease: positive interaction in concomitant and sequential treatments. PLOS Neglected Tropical Diseases 7, e2367.CrossRefGoogle ScholarPubMed
Downs, SH and Black, N (1998) The feasibility of creating a checklist for the assessment of the methodological quality both of randomized and non-randomized studies of health care interventions. Journal of Epidemiology and Community Health 52, 377–384.CrossRefGoogle Scholar
Echeverría, LE, Marcus, R, Novick, G, Sosa-Estani, S, Ralston, K, Zaidel, EJ, Forsyth, C, Ribeiro, ALP, Mendoza, I, Falconi, ML, Mitelman, J, Morillo, CA, Pereiro, AC, Pinazo, MJ, Salvatella, R, Martinez, F, Perel, P, Liprandi, ÁS, Piñeiro, DJ and Molina, GR (2020a) WHF IASC roadmap on Chagas disease. Global Heart 15, 26.CrossRefGoogle Scholar
Echeverría, LE, González, CI, Hernandez, JCM, Díaz, ML, Eduardo Nieto, J, López-Romero, LA, Rivera, JD, Suárez, EU, Ochoa, SAG, Rojas, LZ and Morillo, CA (2020b) Efficacy of the benznidazole + posaconazole combination therapy in parasitemia reduction: an experimental murine model of acute Chagas. Revista da Sociedade Brasileira de Medicina Tropical 53, e20190477.CrossRefGoogle Scholar
Felizardo, AA, Caldas, IS, Mendonça, AAS, Gonçalves, RV, Tana, FL, Almeida, LA and Novaes, RD (2018) Impact of Trypanosoma cruzi infection on nitric oxide synthase and arginase expression and activity in young and elderly mice. Free Radical Biology and Medicine 129, 227–236.CrossRefGoogle Scholar
Filardi, LS and Brener, Z (1987) Susceptibility and natural resistance of Trypanosoma cruzi strains to drugs used clinically in Chagas disease. Transactions of the Royal Society of Tropical Medicine and Hygiene 81, 755–759.CrossRefGoogle ScholarPubMed
Francisco, AF, Jayawardhana, S, Olmo, F, Lewis, MD, Wilkinson, SR, Taylor, MC and Kelly, JM (2020) Challenges in Chagas disease drug development. Molecules 25, 2799.CrossRefGoogle ScholarPubMed
Gonçalves, RV and Novaes, RD (2018) Chronic Chagas disease: therapeutic protocols and efficacy endpoints. Lancet Infectious Diseases 18, 719–720.CrossRefGoogle ScholarPubMed
Guarner, J (2019) Chagas disease as example of a reemerging parasite. Seminars in Diagnostic Pathology 36, 164–169.CrossRefGoogle ScholarPubMed
Guhl, F and Ramirez, JD (2021) Poverty, migration, and Chagas disease. Current Tropical Medicine Reports 8, 52–58.CrossRefGoogle Scholar
Huang, X, Lin, J and Demner-Fushman, D (2006) Evaluation of PICO as a knowledge representation for clinical questions. AMIA Annual Symposium Proceedings 2006, 359–363.Google Scholar
Marin-Neto, JA, Rassi, A Jr, Morillo, CA, Avezum, A, Connolly, SJ, Sosa-Estani, S, Rosas, F, Yusuf, S and BENEFIT Investigators (2008) Rationale and design of a randomized placebo-controlled trial assessing the effects of etiologic treatment in Chagas’ cardiomyopathy: the BENznidazole Evaluation For Interrupting Trypanosomiasis (BENEFIT). American Heart Journal 156, 37–43.CrossRefGoogle Scholar
Marques, DVB, Felizardo, AA, Souza, RLM, Pereira, AAC, Gonçalves, RV and Novaes, RD (2018) Could diet composition modulate pathological outcomes in Schistosomiasis mansoni? A systematic review of in vivo preclinical evidence. Parasitology 145, 1127–1136.CrossRefGoogle ScholarPubMed
Marr, JJ, Berens, RL and Nelson, DJ (1978) Antitrypanosomal effect of allopurinol: conversion in vivo to aminopyrazolopyrimidine nucleotides by Trypanosoma cruzi. Science 201, 1018–1020.CrossRefGoogle Scholar
Martinez, SJ, Romano, PS and Engman, DM (2020) Precision health for Chagas disease: integrating parasite and host factors to predict outcome of infection and response to therapy. Frontiers in Cellular and Infection Microbiology 10, 210.CrossRefGoogle ScholarPubMed
Martín-Escolano, J, Medina-Carmona, E and Martín-Escolano, R (2020) Chagas disease: current view of an ancient and global chemotherapy challenge. ACS Infectious Diseases 6, 2830–2843.CrossRefGoogle ScholarPubMed
Mazzeti, AL, Diniz, LF, Gonçalves, KR, WonDollinger, RS, Assíria, T, Ribeiro, I and Bahia, MT (2019) Synergic effect of allopurinol in combination with nitroheterocyclic compounds against Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy 63, e02264–18.CrossRefGoogle ScholarPubMed
McHugh, ML (2012) Interrater reliability: the kappa statistic. Biochemia Medica 22, 276–282.CrossRefGoogle ScholarPubMed
Mejía-Jaramillo, AM, Agudelo-Uribe, LA, Dib, JC, Ortiz, S, Solari, A and Triana-Chávez, O (2014) Genotyping of Trypanosoma cruzi in a hyper-endemic area of Colombia reveals an overlap among domestic and sylvatic cycles of Chagas disease. Parasites and Vectors 7, 108.CrossRefGoogle Scholar
Mendonça, AAS, Gonçalves-Santos, E, Souza-Silva, TG, González-Lozano, KJ, Caldas, IS, Gonçalves, RV, Diniz, LF and Novaes, RD (2020) Could phenothiazine-benznidazole combined chemotherapy be effective in controlling heart parasitism and acute infectious myocarditis? Pharmacological Research 158, 104907.CrossRefGoogle ScholarPubMed
Molina, I, Gómez i Prat, J, Salvador, F, Treviño, B, Sulleiro, E, Serre, N, Pou, D, Roure, S, Cabezos, J, Valerio, L, Blanco-Grau, A, Sánchez-Montalvá, A, Vidal, X and Pahissa, A (2014) Randomized trial of posaconazole and benznidazole for chronic Chagas’ disease. New England Journal of Medicine 370, 1899–1908.CrossRefGoogle ScholarPubMed
Molina-Morant, D, Fernández, ML, Bosch-Nicolau, P, Sulleiro, E, Bangher, M, Salvador, F, Sanchez-Montalva, A, Ribeiro, ALP, de Paula, AMB, Eloi, S, Correa-Oliveira, R, Villar, JC, Sosa-Estani, S and Molina, I (2020) Efficacy and safety assessment of different dosage of benznidazol for the treatment of Chagas disease in chronic phase in adults (MULTIBENZ study): study protocol for a multicenter randomized phase II non-inferiority clinical trial. Trials 21, 328.CrossRefGoogle ScholarPubMed
Moraes, CB, Giardini, MA, Kim, H, Franco, CH, Araujo-Junior, AM, Schenkman, S, Chatelain, E and Freitas-Junior, LH (2014) Nitroheterocyclic compounds are more efficacious than CYP51 inhibitors against Trypanosoma cruzi: implications for Chagas disease drug discovery and development. Scientific Reports 4, 4703.CrossRefGoogle ScholarPubMed
Morillo, CA, Marin-Neto, JA, Avezum, A, Sosa-Estani, S, Rassi, A Jr, Rosas, F, Villena, E, Quiroz, R, Bonilla, R, Britto, C, Guhl, F, Velazquez, E, Bonilla, L, Meeks, B, Rao-Melacini, P, Pogue, J, Mattos, A, Lazdins, J, Rassi, A, Connolly, SJ and Yusuf, S (2015) BENEFIT Investigators. Randomized trial of benznidazole for chronic Chagas’ cardiomyopathy. New England Journal of Medicine 373, 1295–1306.CrossRefGoogle ScholarPubMed
Morillo, CA, Waskin, H, Sosa-Estani, S, Del Carmen Bangher, M, Cuneo, C, Milesi, R, Mallagray, M, Apt, W, Beloscar, J, Gascon, J, Molina, I, Echeverria, LE, Colombo, H, Perez-Molina, JA, Wyss, F, Meeks, B, Bonilla, LR, Gao, P, Wei, B, McCarthy, M and Yusuf, S (2017) STOP-CHAGAS Investigators. Benznidazole and posaconazole in eliminating parasites in asymptomatic T. cruzi carriers: the STOP-CHAGAS trial. Journal of the American College of Cardiology 69, 939–947.CrossRefGoogle ScholarPubMed
Muñoz, MJ, Murcia, L and Segovia, M (2011) The urgent need to develop new drugs and tools for the treatment of Chagas disease. Expert Review of Anti-infective Therapy 9, 5–7.CrossRefGoogle ScholarPubMed
Nogueira, SS, Felizardo, AA, Caldas, IS, Gonçalves, RV and Novaes, RD (2018) Challenges of immunosuppressive and antitrypanosomal drug therapy after heart transplantation in patients with chronic Chagas disease: a systematic review of clinical recommendations. Transplantation Reviews 32, 157–167.CrossRefGoogle ScholarPubMed
Norman, FF and López-Vélez, R (2019) Chagas disease: comments on the 2018 PAHO Guidelines for diagnosis and management. Journal of Travel Medicine 26, taz060.CrossRefGoogle ScholarPubMed
Novaes, RD, Sartini, MV, Rodrigues, JP, Gonçalves, RV, Santos, EC, Souza, RL and Caldas, IS (2016) Curcumin enhances the anti-Trypanosoma cruzi activity of benznidazole-based chemotherapy in acute experimental Chagas disease. Antimicrobial Agents and Chemotherapy 60, 3355–3364.CrossRefGoogle ScholarPubMed
Olivieri, BP, Molina, JT, de Castro, SL, Pereira, MC, Calvet, CM, Urbina, JA and Araújo-Jorge, TC (2010) 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. International Journal of Antimicrobial Agents 36, 79–83.CrossRefGoogle Scholar
Page, MJ, McKenzie, JE, Bossuyt, PM, Boutron, I, Hoffmann, TC, Mulrow, CD, Shamseer, L, Tetzlaff, JM, Akl, EA, Brennan, SE, Chou, R, Glanville, J, Grimshaw, JM, Hróbjartsson, A, Lalu, MM, Li, T, Loder, EW, Mayo-Wilson, E, McDonald, S, McGuinness, LA, Stewart, LA, Thomas, J, Tricco, AC, Welch, VA, Whiting, P and Moher, D (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Systematic Reviews 10, 89.CrossRefGoogle ScholarPubMed
Pereira, RM, Greco, GMZ, Moreira, AM, Chagas, PF, Caldas, IS, Gonçalves, RV and Novaes, RD (2017) Applicability of plant-based products in the treatment of Trypanosoma cruzi and Trypanosoma brucei infections: a systematic review of preclinical in vivo evidence. Parasitology 144, 1275–1287.CrossRefGoogle ScholarPubMed
Pérez-Molina, JA and Molina, I (2018) Chagas disease. Lancet 391, 82–94.CrossRefGoogle ScholarPubMed
Rassi, A, Luquetti, AO, Rassi, A Jr, Rassi, GG, Rassi, SG, DA Silva, IG and Rassi, AG (2007) Specific treatment for Trypanosoma cruzi: lack of efficacy of allopurinol in the human chronic phase of Chagas disease. American Journal of Tropical Medicine and Hygiene 76, 58–61.CrossRefGoogle ScholarPubMed
Rassi, A Jr, Marin-Neto, JA and Rassi, A (2017) Chronic Chagas cardiomyopathy: a review of the main pathogenic mechanisms and the efficacy of aetiological treatment following the benznidazole evaluation for interrupting trypanosomiasis (BENEFIT) trial. Memórias do Instituto Oswaldo Cruz 112, 224–235.CrossRefGoogle ScholarPubMed
Reddy, AS and Zhang, S (2013) Polypharmacology: drug discovery for the future. Expert Review of Clinical Pharmacology 6, 41–47.CrossRefGoogle ScholarPubMed
Rodrigues, JPF, Caldas, IS, Gonçalves, RV, Almeida, LA, Souza, RLM and Novaes, RD (2017) S. mansoni–T. cruzi co-infection modulates arginase-1/iNOS expression, liver and heart disease in mice. Nitric Oxide 66, 43–52.CrossRefGoogle ScholarPubMed
Salvador, F, Sánchez-Montalvá, A, Martínez-Gallo, M, Sala-Cunill, A, Viñas, L, García-Prat, M, Aparicio, G, Sao Avilés, A, Artaza, MÁ, Ferrer, B and Molina, I (2015) Evaluation of cytokine profile and HLA association in benznidazole related cutaneous reactions in patients with Chagas disease. Clinical Infectious Diseases 61, 1688–1694.Google ScholarPubMed
Santos, EC, Novaes, RD, Cupertino, MC, Bastos, DS, Klein, RC, Silva, EA, Fietto, JL, Talvani, A, Bahia, MT and Oliveira, LL (2015) Concomitant benznidazole and suramin chemotherapy in mice infected with a virulent strain of Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy 59, 5999–6006.CrossRefGoogle ScholarPubMed
Santos, EF, Silva, ÂAO, Leony, LM, Freitas, NEM, Daltro, RT, Regis-Silva, CG, Del-Rei, RP, Souza, WV, Ostermayer, AL, Costa, VM, Silva, RA, Ramos, AN Jr, Sousa, AS, Gomes, YM and Santos, FLN (2020) Acute Chagas disease in Brazil from 2001 to 2018: a nationwide spatiotemporal analysis. PLOS Neglected Tropical Diseases 14, e0008445.CrossRefGoogle ScholarPubMed
Sardana, D, Zhu, C, Zhang, M, Gudivada, RC, Yang, L and Jegga, AG (2011) Drug repositioning for orphan diseases. Briefings in Bioinformatics 12, 346–356.CrossRefGoogle ScholarPubMed
Silva, RE, Baldim, JL, Chagas-Paula, DA, Soares, MG, Lago, JHG, Gonçalves, RV and Novaes, RD (2018) Predictive metabolomic signatures of end-stage renal disease: a multivariate analysis of population-based data. Biochimie 152, 14–30.CrossRefGoogle ScholarPubMed
Silveira, CA, Castillo, E and Castro, C (2000) Evaluation of a specific treatment for Trypanosoma cruzi in children, in the evolution of the indeterminate phase. Revista da Sociedade Brasileira de Medicina Tropical 33, 191–196.CrossRefGoogle ScholarPubMed
Solari, A, Ortíz, S, Soto, A, Arancibia, C, Campillay, R, Contreras, M, Salinas, P, Rojas, A and Schenone, H (2001) Treatment of Trypanosoma cruzi-infected children with nifurtimox: a 3 year follow-up by PCR. Journal of Antimicrobial Chemotherapy 48, 515–519.CrossRefGoogle ScholarPubMed
Sosa-Estani, S, Armenti, A, Araujo, G, Viotti, R, Lococo, B, Ruiz Vera, B, Vigliano, C, de Rissio, AM and Segura, EL (2004) Tratamiento de la enfermedad de Chagas con benznidazol y ácido tióctico. Medicina 64, 1–6.Google Scholar
Sosa Estani, S, Segura, EL, Ruiz, AM, Velazquez, E, Porcel, BM and Yampotis, C (1998) Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas' disease. American Journal of Tropical Medicine and Hygiene 59, 526–529.CrossRefGoogle ScholarPubMed
Souza-Silva, TG, Diniz, LF, Lia Mazzeti, A, Mendonça, AAS, Gonçalves, RV and Novaes, RD (2019) Could angiotensin-modulating drugs be relevant for the treatment of Trypanosoma cruzi infection? A systematic review of preclinical and clinical evidence. Parasitology 146, 914–927.CrossRefGoogle ScholarPubMed
Torrico, F, Gascon, J, Ortiz, L, Alonso-Veja, C, Pinazo, MJ, Schijman, A, Almeida, IC, Alves, F, Strub-Wourgaft, N and Ribeiro, I (2018) E1224 Study Group. Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial. Lancet Infectious Diseases 18, 419–430.CrossRefGoogle Scholar
Torrico, F, Gascón, J, Barreira, F, Blum, B, Almeida, IC, Alonso-Veja, C, Barboza, T, Bilbe, G, Correia, E, Garcia, W, Ortiz, L, Parrado, R, Ramirez, JC, Ribeiro, I, Strub-Wourgaft, N, Vaillant, M and Sosa-Estani, S (2021) BENDITA Study group. New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA): a phase 2, double-blind, randomised trial. Lancet Infectious Diseases 21, 1129–1140.CrossRefGoogle Scholar
Urbina, JA and Docampo, R (2003) Specific chemotherapy of Chagas disease: controversies and advances. Trends in Parasitology 19, 495–501.CrossRefGoogle ScholarPubMed
Urbina, JA, Payares, G, Contreras, LM, Liendo, A, Sanoja, C, Molina, J, Piras, M, Piras, R, Perez, N, Wincker, P and Loebenberg, D (1998) Antiproliferative effects and mechanism of action of SCH 56592 against Trypanosoma (Schizotrypanum) cruzi: in vitro and in vivo studies. Antimicrobial Agents and Chemotherapy 42, 1771–1777.CrossRefGoogle ScholarPubMed
Vallejo, A, Monge-Maillo, B, Gutiérrez, C, Norman, FF, López-Vélez, R and Pérez-Molina, JA (2016) Changes in the immune response after treatment with benznidazole versus no treatment in patients with chronic indeterminate Chagas disease. Acta Tropica 164, 117–124.CrossRefGoogle ScholarPubMed
Zingales, B (2018) Trypanosoma cruzi genetic diversity: something new for something known about Chagas’ disease manifestations, serodiagnosis and drug sensitivity. Acta Tropica 184, 38–52.CrossRefGoogle ScholarPubMed
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