Review of pharmacological options for the treatment of Chagas disease.
Chagas disease drugs
Chagas disease treatment
Trypanosoma cruzi
benznidazole
children
nifurtimox
paediatric clinical pharmacology
Journal
British journal of clinical pharmacology
ISSN: 1365-2125
Titre abrégé: Br J Clin Pharmacol
Pays: England
ID NLM: 7503323
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
revised:
09
11
2020
received:
24
09
2020
accepted:
02
12
2020
pubmed:
15
12
2020
medline:
12
4
2022
entrez:
14
12
2020
Statut:
ppublish
Résumé
Chagas disease (CD) is a worldwide problem, with over 8 million people infected in both rural and urban areas. CD was first described over a century ago, but only two drugs are currently available for CD treatment: benznidazole (BZN) and nifurtimox (NF). Treating CD-infected patients, especially children and women of reproductive age, is vital in order to prevent long-term sequelae, such as heart and gastrointestinal dysfunction, but this aim is still far from being accomplished. Currently, the strongest data to support benefit-risk considerations come from trials in children. Treatment response biomarkers need further development as serology is being questioned as the best method to assess treatment response. This article is a narrative review on the pharmacology of drugs for CD, particularly BZN and NF. Data on drug biopharmaceutical characteristics, safety and efficacy of both drugs are summarized from a clinical perspective. Current data on alternative compounds under evaluation for CD treatment, and new possible treatment response biomarkers are also discussed. Early diagnosis and treatment of CD, especially in paediatric patients, is vital for an effective and safe use of the available drugs (i.e. BZN and NF). New biomarkers for CD are urgently needed for the diagnosis and evaluation of treatment efficacy, and to guide efforts from academia and pharmaceutical companies to accelerate the process of new drug development.
Substances chimiques
Biomarkers
0
Nifurtimox
M84I3K7C2O
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
383-402Informations de copyright
© 2020 British Pharmacological Society.
Références
Filigheddu MT, Górgolas M, Ramos JM. Enfermedad de Chagas de transmisión oral. Med Clin (Barc). 2017;148(3):125-131. https://doi.org/10.1016/j.medcli.2016.10.038
World Health Organization. Chagas disease. https://www.who.int/health-topics/chagas-disease#tab=tab_1
Coura JR, Viñas PA, Junqueira ACV. Ecoepidemiology, short history and control of Chagas disease in the endemic countries and the new challenge for non-endemic countries. Mem Inst Oswaldo Cruz. 2014;109(7):856-862. https://doi.org/10.1590/0074-0276140236
Martins-Melo FR, da Silveira LM, Ramos AN, Alencar CH, Heukelbach J. Systematic review: Prevalence of Chagas disease in pregnant women and congenital transmission of Trypanosoma cruzi in Brazil: a systematic review and meta-analysis. Trop Med Int Health. 2014;19(8):943-957. https://doi.org/10.1111/tmi.12328
Basile L, Ciruela P, Requena-Méndez A, et al. Epidemiology of congenital Chagas disease 6 years after implementation of a public health surveillance system, Catalonia, 2010 to 2015. Eurosurveillance. 2019;24(26):1900011. https://doi.org/10.2807/1560-7917.ES.2019.24.26.19-00011
Coura JR, de Abreu LL, Pereira JB, Willcox HP. Morbidade da doenĉa de Chagas. IV. Estudo longitudinal de dez anos em Pains e Iguatama, Minas Gerais, Brasil. Mem Inst Oswaldo Cruz. 1985;80(1):73-80. https://doi.org/10.1590/s0074-02761985000100011
Pérez-Molina JA, Molina I. Chagas disease. Lancet. 2018;391(10115):82-94. https://doi.org/10.1016/S0140-6736(17)31612-4
Altcheh J, Moscatelli G, Mastrantonio G, et al. Population pharmacokinetic study of benznidazole in pediatric Chagas disease suggests efficacy despite lower plasma concentrations than in adults. PLoS Negl Trop Dis. 2014;8(5):e2907. https://doi.org/10.1371/journal.pntd.0002907
Moscatelli G, Moroni S, García-Bournissen F, et al. Prevention of congenital chagas through treatment of girls and women of childbearing age. Mem Inst Oswaldo Cruz. 2015;110(4):507-509. https://doi.org/10.1590/0074-02760140347
Sosa-Estani S, Colantonio L, Segura EL. Therapy of Chagas disease: implications for levels of prevention. J Trop Med. 2012;2012:292138. https://doi.org/10.1155/2012/292138
Pan American Health Organization/World Health Organization. Guidelines for the diagnosis and treatment of Chagas disease. 2019. https://www.paho.org/en/publications. Accessed May 29, 2020.
Laucella SA, Mazliah DP, Bertocchi G, et al. Changes in Trypanosoma cruzi - specific immune responses after treatment: surrogate markers of treatment efficacy. Clin Infect Dis. 2009;49(11):1675-1684. https://doi.org/10.1086/648072
Morillo CA, Marin-Neto JA, Avezum A, et al. Randomized trial of benznidazole for chronic Chagas' cardiomyopathy. N Engl J Med. 2015;373(14):1295-1306. https://doi.org/10.1056/NEJMoa1507574
Issa VS, Bocchi EA. Antitrypanosomal agents: treatment or threat? Lancet. 2010;376(9743):768. https://doi.org/10.1016/S0140-6736(10)61372-4
Bern C, Martin DL, Gilman RH. Acute and congenital Chagas disease. In: Weiss LM, Tanowitz HB, Kirchhoff LV, eds, Advances in Parasitology. Vol. 75. Chagas Disease. London: Academic Press; 2011:19-47. https://doi.org/10.1016/B978-0-12-385863-4.00002-2
Viotti R, Vigliano C, Lococo B, et al. Ann Intern Med. 2006;144(10):724-734. https://doi.org/10.7326/0003-4819-144-10-200605160-00006
Echeverría LE, Rojas LZ, Rueda-Ochoa OL, et al. Circulating Trypanosoma cruzi load and major cardiovascular outcomes in patients with chronic Chagas cardiomyopathy: a prospective cohort study. Trop Med Int Heal. 2020;25(12):1534-1541. https://doi.org/10.1111/TMI.13487
Rassi A, Marin-Neto JA, Rassi A. 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. Mem Inst Oswaldo Cruz. 2017;112(3):224-235. https://doi.org/10.1590/0074-02760160334
Müller Kratz J, Garcia Bournissen F, Forsyth CJ, Sosa-Estani S. Clinical and pharmacological profile of benznidazole for treatment of Chagas disease. Expert Rev Clin Pharmacol. 2018;11(10):943-957. https://doi.org/10.1080/17512433.2018.1509704
London Declaration on Neglected Tropical Diseases. https://www.who.int/neglected_diseases/London_Declaration_NTDs.pdf. Accessed September 11, 2020.
Bartsch SM, Avelis CM, Asti L, et al. The economic value of identifying and treating Chagas disease patients earlier and the impact on Trypanosoma cruzi transmission. PLoS Negl Trop Dis. 2018;12(11):1-24. https://doi.org/10.1371/journal.pntd.0006809
Altcheh J. La enfermedad de Chagas a 100 años de su descubrimiento. Arch Argent Pediatr. 2010;108(1):4-5.
Conteh L, Engels T, Molyneux DH. Socioeconomic aspects of neglected tropical diseases. Lancet. 2010;375(9710):239-247. https://doi.org/10.1016/S0140-6736(09)61422-7
Lee BY, Bacon KM, Bottazzi ME, Hotez PJ. Global economic burden of Chagas disease: a computational simulation model. Lancet Infect Dis. 2013;13(4):342-348. https://doi.org/10.1016/S1473-3099(13)70002-1
Chagas C. Nova tripanozomiaze humana: estudos sobre a morfolojia e o ciclo evolutivo do Schizotrypanum cruzi n. gen., n. sp., ajente etiolojico de nova entidade morbida do homem. Mem Inst Oswaldo Cruz. 1909;1(2):159-218. https://doi.org/10.1590/s0074-02761909000200008
Hall BS, Bot C, Wilkinson SR. Nifurtimox activation by trypanosomal type I nitroreductases generates cytotoxic nitrile metabolites. J Biol Chem. 2011;286(15):13088-13095. https://doi.org/10.1074/jbc.M111.230847
Hall BS, Wilkinson SR. Activation of benznidazole by trypanosomal type I nitroreductases results in glyoxal formation. Antimicrob Agents Chemother. 2012;56(1):115-123. https://doi.org/10.1128/AAC.05135-11
Vázquez K, Paulino M, Salas CO, Zarate-Ramos JJ, Vera B, Rivera G. Trypanothione reductase: a target for the development of anti-Trypanosoma cruzi drugs. Mini-Reviews Med Chem. 2017;17(11):939-946. https://doi.org/10.2174/1389557517666170315145410
García-Bournissen F, Moroni S, Marson ME, et al. Limited infant exposure to benznidazole through breast milk during maternal treatment for Chagas disease. Arch Dis Child. 2015;100(1):90-94. https://doi.org/10.1136/archdischild-2014-306358
Moroni S, Marson ME, Moscatelli G, et al. Negligible exposure to nifurtimox through breast milk during maternal treatment for Chagas disease. PLoS Negl Trop Dis. 2019;13(8):1-10. https://doi.org/10.1371/journal.pntd.0007647
Garcia-Bournissen F, Altcheh J, Panchaud A, Ito S. Is use of nifurtimox for the treatment of Chagas disease compatible with breast feeding? A population pharmacokinetics analysis. Arch Dis Child. 2010;95(3):224-228. https://doi.org/10.1136/adc.2008.157297
Gonzalez-Martin G, Thambo S, Paulos C, Vasquez I, Paredes J. The pharmacokinetics of nifurtimox in chronic renal failure. Eur J Clin Pharmacol. 1992;42(6):671-673. https://doi.org/10.1007/BF00265935
Streiger ML, del Barco ML, Fabbro DL, et al. Rev Soc Bras Med Trop. 2004;37(5):365-375. https://doi.org/10.1590/S0037-86822004000500001
Altcheh J, Moscatelli G, Moroni S, Garcia-Bournissen F, Freilij H. Adverse events after the use of benznidazole in infants and children with Chagas disease. Pediatrics. 2011;127(1):e212-e218. https://doi.org/10.1542/peds.2010-1172
Sgambatti De Andrade ALS, Zicker F, De Oliveira RM, et al. Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet. 1996;348(9039):1407-1413. https://doi.org/10.1016/S0140-6736(96)04128-1
Coura JR, De Castro SL. A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz. 2002;97(1):3-24. https://doi.org/10.1590/S0074-02762002000100001
Lauria-Pires L, Braga MS, Vexenat AC, Tinoco DL, Nitz N, Braga MS. Progressive chronic Chagas heart disease ten years after treatment with anti-Trypanosoma cruzi nitroderivatives. Am J Trop Med Hyg. 2000;63(3-4):111-118. https://doi.org/10.4269/ajtmh.2000.63.111
Fernández ML, Marson ME, Ramirez JC, et al. Pharmacokinetic and pharmacodynamic responses in adult patients with Chagas disease treated with a new formulation of benznidazole. Mem Inst Oswaldo Cruz. 2016;111(3):218-221. https://doi.org/10.1590/0074-02760150401
Moscatelli G, Moroni S, Bournissen FG, et al. Longitudinal follow up of serological response in children treated for Chagas disease. PLoS Negl Trop Dis. 2019;13(8):1-14. https://doi.org/10.1371/journal.pntd.0007668
Robello C, Maldonado DP, Hevia A, et al. The fecal, oral, and skin microbiota of children with Chagas disease treated with benznidazole. PLoS ONE. 2019;14(2):1-11. https://doi.org/10.1371/journal.pone.0212593
Albareda MC, Natale MA, De Rissio AM, et al. Distinct treatment outcomes of antiparasitic therapy in Trypanosoma cruzi-infected children is associated with early changes in cytokines, chemokines, and T-cell phenotypes. Front Immunol. 2018;9:1-15. https://doi.org/10.3389/fimmu.2018.01958
Monje Rumi M, Pérez Brandán C, Gil JF, et al. Benznidazole treatment in chronic children infected with Trypanosoma cruzi: serological and molecular follow-up of patients and identification of discrete typing units. Acta Trop. 2013;128(1):130-136. https://doi.org/10.1016/j.actatropica.2013.07.003
Chippaux J-P, Salas-Clavijo AN, Postigo JR, Schneider D, Santalla JA, Brutus L. Evaluation of compliance to congenital Chagas disease treatment: results of a randomised trial in Bolivia. Trans R Soc Trop Med Hyg. 2013;107(1):1-7. https://doi.org/10.1093/TRSTMH/TRS004
Chippaux J-P, Clavijo ANS, Santalla JA, Postigo JR, Schneider D, Brutus L. Antibody drop in newborns congenitally infected by Trypanosoma cruzi treated with benznidazole. Trop Med Int Health. 2010;15(1):87-93. https://doi.org/10.1111/j.1365-3156.2009.02431.x
Escribà JM, Ponce E, Romero A d D, et al. Treatment and seroconversion in a cohort of children suffering from recent chronic Chagas infection in Yoro, Honduras. Mem Inst Oswaldo Cruz. 2009;104(7):986-991. https://doi.org/10.1590/S0074-02762009000700008
Yun O, Lima MA, Ellman T, et al. Feasibility, drug safety, and effectiveness of etiological treatment programs for Chagas disease in Honduras, Guatemala, and Bolivia: 10-year experience of Médecins Sans Frontières. PLoS Negl Trop Dis. 2009;3(7):e488. https://doi.org/10.1371/journal.pntd.0000488
Flores-Chavez M, Bosseno MF, Bastrenta B, et al. Polymerase chain reaction detection and serologic follow-up after treatment with benznidazole in Bolivian children infected with a natural mixture of Trypanosoma cruzi I and II. Am J Trop Med Hyg. 2006;75(3):497-501. https://doi.org/10.4269/ajtmh.2006.75.497
Schijman AG, Altcheh J, Burgos JM, et al. Aetiological treatment of congenital Chagas' disease diagnosed and monitored by the polymerase chain reaction. J Antimicrob Chemother. 2003;52(3):441-449. https://doi.org/10.1093/jac/dkg338
Galvão L, Chiari E, Macedo AM, Luquetti A, Silva S, Andrade AL. PCR assay for monitoring Trypanosoma cruzi parasitemia in childhood after specific chemotherapy. J Clin Microbiol. 2003;41(11):5066-5070. https://doi.org/10.1128/JCM.41.11.5066-5070.2003
Schenone FH, Contreras LM, Solari IA, García CA, Rojas SA, Lorca HM. Nifurtimox treatment of chronic Chagasic infection in children. Rev Med Chil. 2003;131(9):1089-1090.
Solari A, Ortiz S, Soto A, et al. Treatment of Trypanosoma cruzi-infected children with nifurtimox: a 3 year follow-up by PCR. J Antimicrob Chemother. 2001;48(4):515-519. https://doi.org/10.1093/jac/48.4.515
Solari A, Contreras MC, Lorca M, et al. Yield of xenodiagnosis and PCR in the evaluation of specific chemotherapy of Chagas' disease in children. Bol Chil Parasitol. 1998;53:1-2.
Sosa Estani S, Segura EL, Ruiz AM, Velazquez E, Porcel BM, Yampotis C. Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas' disease. Am J Trop Med Hyg. 1998;59(4):526-529. https://doi.org/10.4269/ajtmh.1998.59.526
Villar JC, Herrera VM, Pérez Carreño JG, et al. Nifurtimox versus benznidazole or placebo for asymptomatic Trypanosoma cruzi infection (Equivalence of Usual Interventions for Trypanosomiasis - EQUITY): study protocol for a randomised controlled trial. Trials. 2019;20:1-10. https://doi.org/10.1186/s13063-019-3423-3
Marson ME, Altcheh J, Moscatelli G, Moroni S, García-Bournissen F, Mastrantonio GE. Identification of N-benzylacetamide as a major component of human plasmatic metabolic profiling of benznidazole. Eur J Drug Metab Pharmacokinet. 2015;40(2):209-217. https://doi.org/10.1007/s13318-014-0195-8
Vallejo A, Monge-Maillo B, Gutiérrez C, Norman FF, López-Vélez R, Pérez-Molina JA. Changes in the immune response after treatment with benznidazole versus no treatment in patients with chronic indeterminate Chagas disease. Acta Trop. 2016;164:117-124. https://doi.org/10.1016/j.actatropica.2016.09.010
Villar JC, Perez JG, Cortes OL, et al. Trypanocidal drugs for chronic asymptomatic Trypanosoma cruzi infection. Cochrane Database Syst Rev. 2014;2014(5):1-71. https://doi.org/10.1002/14651858.CD003463.pub2
Pinazo MJ, Thomas MC, Bua J, et al. Biological markers for evaluating therapeutic efficacy in Chagas disease, a systematic review. Expert Rev Anti Infect Ther. 2014;12(4):479-496. https://doi.org/10.1586/14787210.2014.899150
Olivera MJ, Fory JA, Olivera AJ. Therapeutic drug monitoring of benznidazole and nifurtimox: a systematic review and quality assessment of published clinical practice guidelines. Rev Soc Bras Med Trop. 2017;50(6):748-755. https://doi.org/10.1590/0037-8682-0399-2016
Jannin J, Villa L. An overview of Chagas disease treatment. Mem Inst Oswaldo Cruz. 2007;102:95-97. https://doi.org/10.1590/s0074-02762007005000106
Pinheiro E, Brum-Soares L, Reis R, Cubides JC. Chagas disease: review of needs, neglect, and obstacles to treatment access in Latin America. Rev Soc Bras Med Trop. 2017;50(3):296-300. https://doi.org/10.1590/0037-8682-0433-2016
Alpern JD, Lopez-Velez R, Stauffer WM. Access to benznidazole for Chagas disease in the United States-cautious optimism? PLoS Negl Trop Dis. 2017;11(9):e0005794. https://doi.org/10.1371/journal.pntd.0005794
Francisco AF, Jayawardhana S, Lewis MD, et al. Nitroheterocyclic drugs cure experimental Trypanosoma cruzi infections more effectively in the chronic stage than in the acute stage. Sci Rep. 2016;6:35351. https://doi.org/10.1038/srep35351
Chatelain E. Chagas disease drug discovery: toward a new era. J Biomol Screen. 2015;20(1):22-35. https://doi.org/10.1177/1087057114550585
Richle RW, Raaflaub J. Difference of effective antitrypanosomal dosages of benznidazole in mice and man. Chemotherapeutic and pharmacokinetic results. Acta Trop. 1980;37(3):257-261. http://www.ncbi.nlm.nih.gov/pubmed/6106364
Romanha AJ, de Castro SL, Soeiro M, et al. In vitro and in vivo experimental models for drug screening and development for Chagas disease. Mem Inst Oswaldo Cruz. 2010;105(2):233-238. https://doi.org/10.1590/S0074-02762010000200022
Chatelain E, Ioset JR. Phenotypic screening approaches for Chagas disease drug discovery. Expert Opin Drug Discovery. 2018;13(2):141-153. https://doi.org/10.1080/17460441.2018.1417380
Food and Drug Administration. The Biopharmaceutics Classification System (BCS) Guidance. https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/biopharmaceutics-classification-system-bcs-guidance. Accessed September 10, 2020.
del Moral Sanchez JM, Gonzalez-Alvarez I, Cerda-Revert A, et al. Biopharmaceutical optimization in neglected diseases for paediatric patients by applying the provisional paediatric biopharmaceutical classification system. Br J Clin Pharmacol. 2018;84(10):2231-2241. https://doi.org/10.1111/bcp.13650
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. https://doi.org/10.1371/journal.pntd.0002844
Zingales B, Araujo RGA, Moreno M, et al. A novel ABCG-like transporter of Trypanosoma cruzi is involved in natural resistance to benznidazole. Mem Inst Oswaldo Cruz. 2015;110(3):433-444. https://doi.org/10.1590/0074-02760140407
Moreno M, D'ávila DA, Silva MN, et al. Trypanosoma cruzi benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease. Mem Inst Oswaldo Cruz. 2010;105(7):918-924. https://doi.org/10.1590/S0074-02762010000700014
Canavaci AMC, Bustamante JM, Padilla AM, et al. In vitro and in vivo high-throughput assays for the testing of anti-Trypanosoma cruzi compounds. PLoS Negl Trop Dis. 2010;4(7):e740. https://doi.org/10.1371/journal.pntd.0000740
Moraes CB, Giardini MA, Kim H, et al. Nitroheterocyclic compounds are more efficacious than CYP51 inhibitors against Trypanosoma cruzi: implications for Chagas disease drug discovery and development. Sci Rep. 2014;4(1):1-11. https://doi.org/10.1038/srep04703
Polak A, Richle R. Mode of action of the 2-nitroimidazole derivative benznidazole. Ann Trop Med Parasitol. 1978;72(1):45-54. https://doi.org/10.1080/00034983.1978.11719278
Molina I, Salvador F, Sánchez-Montalvá A, et al. Pharmacokinetics of benznidazole in healthy volunteers and implications in future clinical trials. Antimicrob Agents Chemother. 2017;61(4):139-144. https://doi.org/10.1128/AAC.01912-16
Raaflaub J. Multiple-dose kinetics of the trypanosomicide benznidazole in man. Arzneimittelforschung. 1980;30(12):2192-2194.
Roberts JT, Bleehen NM. Benznidazole with CCNU: a clinical phase I toxicity study. Int J Radiat Oncol Biol Phys. 1985;11(2):331-334. https://doi.org/10.1016/0360-3016(85)90155-5
Workman P, White RA, Walton MI, Owen LN, Twentyman PR. Preclinical pharmacokinetics of benznidazole. Br J Cancer. 1984;50(3):291-303. https://doi.org/10.1038/bjc.1984.176
Bisio M, Altcheh J, Lattner J, et al. Benznidazole treatment of chagasic encephalitis in pregnant woman with AIDS. Emerg Infect Dis. 2013;19(9):1490-1492. https://doi.org/10.3201/eid1909.130667
Cordova E, Boschi A, Ambrosioni J, Cudos C, Corti M. Reactivation of Chagas disease with central nervous system involvement in HIV-infected patients in Argentina, 1992-2007. Int J Infect Dis. 2008;12(6):587-592. https://doi.org/10.1016/j.ijid.2007.12.007
Cohen V, Ceballos V, Rodríguez N, et al. Chagas' disease as a cause of cerebral mass in a patient with lymphoblastic leukemia in remission. Arch Argent Pediatr. 2010;108(6):134-137. https://doi.org/10.1590/S0325-00752010000600016
Montero M, Mir M, Sulleiro E, et al. High-dose benznidazole in a 62-year-old Bolivian kidney transplant recipient with Chagas central nervous system involvement. Int J Infect Dis. 2019;78:103-106. https://doi.org/10.1016/j.ijid.2018.10.014
Walton MI, Workman P. Nitroimidazole bioreductive metabolism. Quantitation and characterisation of mouse tissue benznidazole nitroreductases in vivo and in vitro. Biochem Pharmacol. 1987;36(6):887-896. https://doi.org/10.1016/0006-2952(87)90181-X
Rocco D, Perez Montilla C, Moroni S, Altcheh J, Garcia-Bournissen F. Benznidazole metabolites in urine from patients treated for Chagas disease. Meet Am Soc Clin Pharmacol. 2018.
Ministerio de Salud y Desarrollo Social de la Republica Argentina. Atención Del Paciente Infectado Con Trypanosoma Cruzi, Guia Para El Equipo de Salud. 3rd Argentina: Ministerio de Salud y Desarrollo Social de la Republica Argentina; 2018.
Viotti R, Alarcón De Noya B, Araujo-Jorge T, et al. Towards a paradigm shift in the treatment of chronic Chagas disease. Antimicrob Agents Chemother. 2014;58(2):635-639. https://doi.org/10.1128/AAC.01662-13
Álvarez MG, Hernández Y, Bertocchi G, et al. New scheme of intermittent benznidazole administration in patients chronically infected with Trypanosoma cruzi: a pilot short-term follow-up study with adult patients. Antimicrob Agents Chemother. 2016;60(2):833-837. https://doi.org/10.1128/AAC.00745-15
Soy D, Aldasoro E, Guerrero L, et al. Population pharmacokinetics of benznidazole in adult patients with Chagas disease. Antimicrob Agents Chemother. 2015;59(6):3342-3349. https://doi.org/10.1128/AAC.05018-14
Cafferata ML, Toscani MA, Althabe F, et al. Short-course benznidazole treatment to reduce Trypanosoma cruzi parasitic load in women of reproductive age (BETTY): a non-inferiority randomized controlled trial study protocol. Reprod Health. 2020;17:128. https://doi.org/10.1186/s12978-020-00972-1
Pinazo MJ, Guerrero L, Posada E, Rodríguez E, Soy D, Gascon J. Benznidazole-related adverse drug reactions and their relationship to serum drug concentrations in patients with chronic Chagas disease. Antimicrob Agents Chemother. 2013;57(1):390-395. https://doi.org/10.1128/AAC.01401-12
Aldasoro E, Posada E, Requena-Méndez A, et al. What to expect and when: benznidazole toxicity in chronic Chagas' disease treatment. J Antimicrob Chemother. 2018;73(4):1060-1067. https://doi.org/10.1093/jac/dkx516
Viotti R, Vigliano C, Lococo B, et al. Side effects of benznidazole as treatment in chronic Chagas disease: fears and realities. Expert Rev Anti Infect Ther. 2009;7(2):157-163. https://doi.org/10.1586/14787210.7.2.157
Sperandio da Silva GM, Mediano MFF, Hasslocher-Moreno AM, et al. Benznidazole treatment safety: the Médecins Sans Frontières experience in a large cohort of Bolivian patients with Chagas' disease. J Antimicrob Chemother. 2017;72(9):2596-2601. https://doi.org/10.1093/jac/dkx180
Bertocchi GL, Vigliano CA, Lococo BG, Petti MA, Viotti RJ. Clinical characteristics and outcome of 107 adult patients with chronic Chagas disease and parasitological cure criteria. Trans R Soc Trop Med Hyg. 2013;107(6):372-376. https://doi.org/10.1093/TRSTMH/TRT029
de Pontes V, de Souza JA, da Cruz F, et al. Adverse reactions in Chagas disease patients treated with benznidazole, in the State of Ceara. Rev Soc Bras Med Trop. 2010;43(2):182-187. S0037-86822010000200015
Sosa-Estani S, Armenti A, Araujo G, et al. Treatment of Chagas disease with benznidazole and thioctic acid. Medicina (B Aires). 2004;64(1):1-6.
Bartel LC, Montalto De Mecca M, Rodríguez De Castro C, Bietto FM, Castro JA. Metabolization of nifurtimox and benznidazole in cellular fractions of rat mammary tissue. Hum Exp Toxicol. 2010;29(10):813-822. https://doi.org/10.1177/0960327110361756
Docampo R, Moreno SNJ, Stoppani AOM. Nitrofuran enhancement of microsomal electron transport, superoxide anion production and lipid peroxidation. Arch Biochem Biophys. 1981;207(2):316-324. https://doi.org/10.1016/0003-9861(81)90039-4
Arancibia A, Gonzalez Martin G, Paulos C, Paredes J, Vasquez I, Thambo S. Pharmacokinetics of a nitrofuran compound, nifurtimox, in healthy volunteers. Int J Clin Pharmacol Ther Toxicol. 1989;27(9):454-457.
Patzschke K, Wegner LA, Duhm B, Maul WMH. Investigations on the pharmacokinetics of nifurtimox- 35 S in the rat and dog. Arzneimittelforschung. 1972;22(9):1617-1624. https://www.ncbi.nlm.nih.gov/pubmed/4630484
Kuemmerle A, Schmid C, Kande V, et al. Prescription of concomitant medications in patients treated with nifurtimox eflornithine combination therapy (NECT) for T.b. gambiense second stage sleeping sickness in the Democratic Republic of the Congo. PLoS Negl Trop Dis. 2020;14(1):e0008028. https://doi.org/10.1371/journal.pntd.0008028
Paulos C, Paredes J, Vasquez I, Kunze G, González-Martin G. High-performance liquid chromatographic determination of nifurtimox in human serum. J Chromatogr B Biomed Sci Appl. 1988;433(C):359-362. https://doi.org/10.1016/S0378-4347(00)80621-0
Saulnier Sholler GL, Bergendahl GM, Brard L, et al. A phase 1 study of nifurtimox in patients with relapsed/refractory neuroblastoma. J Pediatr Hematol Oncol. 2011;33(1):25-30. https://doi.org/10.1097/MPH.0b013e3181f47061
Raether W, Hänel H. Nitroheterocyclic drugs with broad spectrum activity. Parasitol Res. 2003;90(S1):S19-S39. https://doi.org/10.1007/s00436-002-0754-9
Strass H, Feleder E, Garcia-Bournisen F, et al. Biopharmaceutical characteristics of nifurtimox tablets for age and bodyweight adjusted dosing in patients with Chagas disease. Clin Pharmacol Drug Dev. 2020 Oct 8. Epub ahead of print. PMID: 33029953. https://doi.org/10.1002/cpdd.871
Gonzalez-Martin G, Paulos C, Guevara A, Ponce G. Disposition of nifurtimox and metabolite activity against Trypanosoma cruzi using rat isolated perfused liver. J Pharm Pharmacol. 1994;46(5):356-359. https://doi.org/10.1111/j.2042-7158.1994.tb03812.x
Pérez Montilla C, Moroni S, González N, Moscatelli G, Altcheh J, García BF. P38 Identification of nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS. Arch Dis Child. 2019;104(6):e32.3-e33. https://doi.org/10.1136/archdischild-2019-esdppp.76
Letelier ME, Izquierdo P, Godoy L, Lepe AM, Faúndez M. Liver microsomal biotransformation of nitro-aryl drugs: mechanism for potential oxidative stress induction. J Appl Toxicol. 2004;24(6):519-525. https://doi.org/10.1002/jat.999
Masana M, de Toranzo EG, Castro JA. Studies on nifurtimox nitroreductase activity in liver and other rat tissues. Arch Int Pharmacodyn Ther. 1984;270(1):4-10.
Watson CP, Dogruel M, Mihoreanu L, et al. The transport of nifurtimox, an anti-trypanosomal drug, in an in vitro model of the human blood-brain barrier: evidence for involvement of breast cancer resistance protein. Brain Res. 2012;1436:111-121. https://doi.org/10.1016/j.brainres.2011.11.053
Cancado J, Salgado A, Marra D, Alvares JMJ. [Clinical therapeutic trial in chronic Chagas' disease using nifurtimox in 3 schedules of long duration]. Ensaio terapeutico cl'inico na doenca de Chagas cronica com o nifurtimox em tres esquemas de dura coa prolongada. Rev Inst Med Trop Sao Paulo. 1975;17(2):111-127.
Jackson Y, Alirol E, Getaz L, Wolff H, Combescure C, Chappuis F. Tolerance and safety of nifurtimox in patients with chronic Chagas disease. Clin Infect Dis. 2010;51(10):e69-e75. https://doi.org/10.1086/656917
Ribeiro V, Dias N, Paiva T, et al. Current trends in the pharmacological management of Chagas disease. Int J Parasitol Drugs Drug Resist. 2020;12:7-17. https://doi.org/10.1016/j.ijpddr.2019.11.004
Forsyth CJ, Hernandez S, Olmedo W, et al. Safety profile of nifurtimox for treatment of Chagas disease in the United States. Clin Infect Dis. 2016;63(8):1056-1062. https://doi.org/10.1093/cid/ciw477
Alarcón de Noya B, Ruiz-Guevara R, Noya O, et al. Long-term comparative pharmacovigilance of orally transmitted Chagas disease: first report. Expert Rev Anti Infect Ther. 2017;15(3):319-325. https://doi.org/10.1080/14787210.2017.1286979
Freilij H, Altcheh J. Congenital Chagas' disease: diagnostic and clinical aspects. Clin Infect Dis. 1995;21(3):551-555. https://doi.org/10.1093/CLINIDS/21.3.551
Pérez-Molina JA, Sojo-Dorado J, Norman F, et al. Nifurtimox therapy for Chagas disease does not cause hypersensitivity reactions in patients with such previous adverse reactions during benznidazole treatment. Acta Trop. 2013;127(2):101-104. https://doi.org/10.1016/j.actatropica.2013.04.003
Alonso-Vega C, Billot C, Torrico F. Achievements and challenges upon the implementation of a program for national control of congenital Chagas in Bolivia: results 2004-2009. PLoS Negl Trop Dis. 2013;7(7):e2304. https://doi.org/10.1371/journal.pntd.0002304
Garcia-Bournissen F, Altcheh J, Giglio N, Mastrantonio G, Omar Della Védova C, Koren G. Pediatric clinical pharmacology studies in Chagas disase: focus on Argentina. Pediatric Drugs. 2009;11(1):33-37. https://doi.org/10.2165/0148581-200911010-00012
Cançado JR. Long term evaluation of etiological treatment of Chagas disease with benznidazole. Rev Inst Med Trop Sao Paulo. 2002;44(1):29-37. https://doi.org/10.1590/S0036-46652002000100006
Andrade ALSS, Martelli CMT, Oliveira RM, et al. Short report: benznidazole efficacy among Trypanosoma cruzi-infected adolescents after a six-year follow-up. Am J Trop Med Hyg. 2004;71(5):594-597. https://doi.org/10.4269/ajtmh.2004.71.594
Fabbro DL, Streiger ML, Arias ED, Bizai ML, Del Barco M, Amicone NA. Trypanocide treatment among adults with chronic Chagas disease living in Santa Fe City (Argentina), over a mean follow-up of 21 years: parasitological, serological and clinical evolution. Rev Soc Bras Med Trop. 2007;40(1):1-10. https://doi.org/10.1590/s0037-86822007000100001
Parrado R, Ramirez JC, de la Barra A, et al. Usefulness of serial blood sampling and PCR replicates for treatment monitoring of patients with chronic Chagas disease. Antimicrob Agents Chemother. 2019;63(2):e01191-e01118. https://doi.org/10.1128/AAC.01191-18
Alonso-Padilla J, Gallego M, Schijman AG, Gascon J. Molecular diagnostics for Chagas disease: up to date and novel methodologies. Expert Rev Mol Diagn. 2017;17(7):699-710. https://doi.org/10.1080/14737159.2017.1338566
Gonzalez NL, Moroni S, Moscatelli G, et al. Early antiparasitic treatment prevents progression of Chagas disease: results of a long-term cardiological follow-up study in a pediatric population. medRxiv. 2020:2020.06.30.20143370. https://doi.org/10.1101/2020.06.30.20143370
Viotti R, Vigliano C, Álvarez MG, et al. Impact of aetiological treatment on conventional and multiplex serology in chronic chagas disease. PLoS Negl Trop Dis. 2011;5(9):e1314. https://doi.org/10.1371/journal.pntd.0001314
Fabbro D, Velazquez E, Bizai ML, et al. Avaliação do tratamento tripanossomicida em coorte de adultos chagásicos crônicos através de técnicas sorológicas convencionais e ELISA-F29. Rev Inst Med Trop Sao Paulo. 2013;55(3):167-172. https://doi.org/10.1590/S0036-46652013000300005
Altcheh J, Corral R, Biancardi MA, Freilij H. Anti-F2/3 antibodies as cure marker in children with congenital Trypanosoma cruzi infection. Med (B Aires). 2003;63(1):37-40.
Almeida IC, Covas DT, Soussumi LMT, Travassos LR. A highly sensitive and specific chemiluminescent enzyme-linked immunosorbent assay for diagnosis of active Trypanosoma cruzi infection. Transfusion. 1997;37(8):850-857. https://doi.org/10.1046/j.1537-2995.1997.37897424410.x
Pinazo M-J, Thomas M-C, Bustamante J, Correia De Almeida I, Lopez M-C, Gascon J. Biomarkers of therapeutic responses in chronic Chagas disease: state of the art and future perspectives. Mem Inst Oswaldo Cruz. 2015;110(3):422-432. https://doi.org/10.1590/0074-02760140435
Negrette OS, Valdéz FJS, Lacunza CD, et al. Serological evaluation of specific-antibody levels in patients treated for chronic Chagas' disease. Clin Vaccine Immunol. 2008;15(2):297-302. https://doi.org/10.1128/CVI.00106-07
Fabbro DL, Olivera V, Bizai ML, et al. Humoral immune response against P2β from Trypanosoma cruzi in persons with chronic Chagas disease: its relationship with treatment against parasites and myocardial damage. Am J Trop Med Hyg. 2011;84(4):575-580. https://doi.org/10.4269/ajtmh.2011.10-0261
Fernández-Villegas A, Pinazo MJ, Marañón C, et al. Short-term follow-up of chagasic patients after benznidazole treatment using multiple serological markers. BMC Infect Dis. 2011;11:206. https://doi.org/10.1186/1471-2334-11-206
Flechas ID, Cuellar A, Cucunubá ZM, et al. Characterising the KMP-11 and HSP-70 recombinant antigens' humoral immune response profile in chagasic patients. BMC Infect Dis. 2009;9:186. https://doi.org/10.1186/1471-2334-9-186
Krautz GM, Galvão LM, Cançado JR, Guevara-Espinoza A, Ouaissi A, Krettli AU. Use of a 24-kilodalton Trypanosoma cruzi recombinant protein to monitor cure of human Chagas' disease. J Clin Microbiol. 1995;33(8):2086-2090.
Krettli AU. The utility of anti-trypomastigote lytic antibodies for determining cure of Trypanosoma cruzi infections in treated patients: an overview and perspectives. Mem Inst Oswaldo Cruz. 2009;104(SUPPL. 1):142-151. https://doi.org/10.1590/S0074-02762009000900020
Cooley G, Etheridgel RD, Boehlke C, et al. High throughput selection of effective serodiagnostics for Trypanosoma cruzi infection. PLoS Negl Trop Dis. 2008;2(10):e316. https://doi.org/10.1371/journal.pntd.0000316
Meira WSF, Galvão LMC, Gontijo ED, Machado-Coelho GLL, Norris KA, Chiari E. Use of the Trypanosoma cruzi recombinant complement regulatory protein to evaluate therapeutic efficacy following treatment of chronic chagasic patients. J Clin Microbiol. 2004;42(2):707-712. https://doi.org/10.1128/JCM.42.2.707-712.2004
Zrein M, Granjon E, Gueyffier L, et al. A novel antibody surrogate biomarker to monitor parasite persistence in Trypanosoma cruzi-infected patients. PLoS Negl Trop Dis. 2018;12(2):e0006226. https://doi.org/10.1371/journal.pntd.0006226
Ndao M, Spithill TW, Caffrey R, et al. Identification of novel diagnostic serum biomarkers for Chagas' disease in asymptomatic subjects by mass spectrometric profiling. J Clin Microbiol. 2010;48(4):1139-1149. https://doi.org/10.1128/JCM.02207-09
Santamaria C, Chatelain E, Jackson Y, et al. Serum biomarkers predictive of cure in Chagas disease patients after nifurtimox treatment. BMC Infect Dis. 2014;14(1):1-12. https://doi.org/10.1186/1471-2334-14-302
Pinazo M, Tàssies D, Muñoz J, et al. Hypercoagulability biomarkers in Trypanosoma cruzi-infected patients. Thromb Haemost. 2011;106(6):17-23.
Pinazo M-J, Posada E d J, Izquierdo L, et al. Altered hypercoagulability factors in patients with chronic Chagas disease: potential biomarkers of therapeutic response. PLoS Negl Trop Dis. 2016;10(1):e0004269. https://doi.org/10.1371/journal.pntd.0004269
Laucella S, Segura EL, Riarte A, Sosa ES. Soluble platelet selectin (sP-selectin) and soluble vascular cell adhesion molecule-1 (sVCAM-1) decrease during therapy with benznidazole in children with indeterminate form of Chagas' disease. Clin Exp Immunol. 1999;118(3):423-427. https://doi.org/10.1046/j.1365-2249.1999.01070.x
Dutra WO, Da Luz ZMP, Cançado JR, et al. Influence of parasite presence on the immunologic profile of peripheral blood mononuclear cells from chagasic patients after specific drug therapy. Parasite Immunol. 1996;18(11):579-585. https://doi.org/10.1046/j.1365-3024.1996.d01-29.x
Sathler-Avelar R, Vitelli-Avelar DM, Massara RL, et al. Benznidazole treatment during early-indeterminate Chagas' disease shifted the cytokine expression by innate and adaptive immunity cells toward a type 1-modulated immune profile. Scand J Immunol. 2006;64(5):554-563. https://doi.org/10.1111/j.1365-3083.2006.01843.x
Argüello RJ, Albareda MC, Alvarez MG, et al. Inhibitory receptors are expressed by Trypanosoma cruzi-specific effector T cells and in hearts of subjects with chronic chagas disease. PLoS ONE. 2012;7(5):e35966. https://doi.org/10.1371/journal.pone.0035966
Pinho RT, Waghabi MC, Cardillo F, Mengel J, Antas PRZ. Scrutinizing the biomarkers for the neglected Chagas disease: how remarkable! Front Immunol. 2016;7:306. https://doi.org/10.3389/fimmu.2016.00306
Requena-Méndez A, López MC, Angheben A, et al. Evaluating Chagas disease progression and cure through blood-derived biomarkers: a systematic review. Expert Rev Anti Infect Ther. 2013;11(9):957-976. https://doi.org/10.1586/14787210.2013.824718
Russomando G, De Tomassone MMC, De Guillen I, et al. Treatment of congenital Chagas disease diagnosed and followed up by the polymerase chain reaction. Am J Trop Med Hyg. 1998;59(3):487-491. https://doi.org/10.4269/ajtmh.1998.59.487
Bianchi F, Cucunubá Z, Guhl F, et al. Follow-up of an asymptomatic Chagas disease population of children after treatment with nifurtimox (Lampit) in a sylvatic endemic transmission area of Colombia. PLoS Negl Trop Dis. 2015;9(2):e0003465. https://doi.org/10.1371/journal.pntd.0003465
Sguassero Y, Cuesta CB, Roberts KN, et al. Course of chronic Trypanosoma cruzi infection after treatment based on parasitological and serological tests: a systematic review of follow-up studies. PLoS ONE. 2015;10(10):1-23. https://doi.org/10.1371/journal.pone.0139363
Freilij H, Altcheh J (Eds). Chagas Disease: A Clinical Approach. Cham, Switzerland: Springer International; 2019.
Implementation Strategy of Bio-Molecular Techniques for Early Diagnose of Congenital Syphilis and Chagas Diseases. https://clinicaltrials.gov/ct2/show/NCT04084379
Brito TK, Silva Viana RL, Gonçalves Moreno CJ, et al. Synthesis of silver nanoparticle employing corn cob xylan as a reducing agent with anti-Trypanosoma cruzi activity. Int J Nanomedicine. 2020;15:965-979. https://doi.org/10.2147/IJN.S216386
Arrúa EC, Seremeta KP, Bedogni GR, Okulik NB, Salomon CJ. Nanocarriers for effective delivery of benznidazole and nifurtimox in the treatment of Chagas disease: a review. Acta Trop. 2019;198:105080. https://doi.org/10.1016/j.actatropica.2019.105080
Scarim CB, Jornada DH, Chelucci RC, de Almeida L, dos Santos JL, Chung MC. Current advances in drug discovery for Chagas disease. Eur J Med Chem. 2018;155:824-838. https://doi.org/10.1016/j.ejmech.2018.06.040
Watson JA, Strub-Wourgraft N, Tarral A, Ribeiro I, Tarning J, White NJ. Pharmacokinetic-pharmacodynamic assessment of the hepatic and bone marrow toxicities of the new trypanoside fexinidazole. Antimicrob Agents Chemother. 2019;63(4):e02515. https://doi.org/10.1128/AAC.02515-18
Bahia MT, Nascimento AFS, Mazzeti AL, et al. Antitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease. Antimicrob Agents Chemother. 2014;58(8):4362-4370. https://doi.org/10.1128/AAC.02754-13
Simões-Silva MR, De Araújo JS, Peres RB, et al. Repurposing strategies for Chagas disease therapy: the effect of imatinib and derivatives against Trypanosoma cruzi. Parasitology. 2019;146(8):1006-1012. https://doi.org/10.1017/S0031182019000234
Alberca LN, Sbaraglini ML, Balcazar D, et al. Discovery of novel polyamine analogs with anti-protozoal activity by computer guided drug repositioning. J Comput Aided Mol Des. 2016;30(4):305-321. https://doi.org/10.1007/s10822-016-9903-6
Mazzeti AL, Diniz L d F, Gonçalves KR, et al. Synergic effect of allopurinol in combination with nitroheterocyclic compounds against Trypanosoma cruzi. Antimicrob Agents Chemother. 2019;63(6):e02264. https://doi.org/10.1128/AAC.02264-18
Perez-Mazliah DE, Alvarez MG, Cooley G, et al. Sequential combined treatment with allopurinol and benznidazole in the chronic phase of Trypanosoma cruzi infection: a pilot study. J Antimicrob Chemother. 2013;68(2):424-437. https://doi.org/10.1093/jac/dks390
Rassi A, Luquetti AO, Rassi A, et al. Specific treatment for Trypanosoma cruzi: lack of efficacy of allopurinol in the human chronic phase of Chagas disease. Am J Trop Med Hyg. 2007;76(1):58-61.
Molina I, Gómez i Prat J, Salvador F, et al. Randomized trial of posaconazole and benznidazole for chronic Chagas' disease. N Engl J Med. 2014;370(20):1899-1908. https://doi.org/10.1056/NEJMoa1313122
Torrico F, Gascon J, Ortiz L, et al. Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial. Lancet Infect Dis. 2018;18(4):419-430. https://doi.org/10.1016/S1473-3099(17)30538-8
Brener Z, Cançado JR, Galvão LM, et al. An experimental and clinical assay with ketoconazole in the treatment of Chagas disease. Mem Inst Oswaldo Cruz. 88(1):149-153. https://doi.org/10.1590/s0074-02761993000100023
Morillo CA, Waskin H, Sosa-Estani S, et al. Benznidazole and posaconazole in eliminating parasites in asymptomatic T. cruzi carriers: the STOP-CHAGAS trial. J Am Coll Cardiol. 2017;69(8):939-947. https://doi.org/10.1016/j.jacc.2016.12.023
Villalta F, Rachakonda G. Advances in preclinical approaches to Chagas disease drug discovery. Expert Opin Drug Discov. 2019;14(11):1161-1174. https://doi.org/10.1080/17460441.2019.1652593
Souza HFS, Rocha SC, Damasceno FS, et al. The effect of memantine, an antagonist of the NMDA glutamate receptor, in in vitro and in vivo infections by Trypanosoma cruzi. PLoS Negl Trop Dis. 2019;13(9):e0007226. https://doi.org/10.1371/journal.pntd.0007226
Mesu VKBK, Kalonji WM, Bardonneau C, et al. Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial. Lancet. 2018;391(10116):144-154. https://doi.org/10.1016/S0140-6736(17)32758-7
Deeks ED. Fexinidazole: first global approval. Drugs. 2019;79(2):215-220. https://doi.org/10.1007/s40265-019-1051-6
Veas R, Rojas-Pirela M, Castillo C, et al. Microalgae extracts: potential anti-Trypanosoma cruzi agents? Biomed Pharmacother. 2020;127:110178. https://doi.org/10.1016/j.biopha.2020.110178
Albuquerque KF, Torres MDT, Lima DB, et al. Wasp venom peptide as a new antichagasic agent. Toxicon. 2020;181:71-78. https://doi.org/10.1016/j.toxicon.2020.04.099
Soares FGN, Goëthel G, Kagami LP, et al. Novel coumarins active against Trypanosoma cruzi and toxicity assessment using the animal model Caenorhabditis elegans. BMC Pharmacol Toxicol. 2019;20(1):76. https://doi.org/10.1186/s40360-019-0357-z
Sosa A, Salamanca Capusiri E, Amaya S, et al. Trypanocidal activity of South American Vernonieae (Asteraceae) extracts and its sesquiterpene lactones. Nat Prod Res. 2020. https://doi.org/10.1080/14786419.2020.1739682
Hernández M, Wicz S, Santamaría MH, Corral RS. Curcumin exerts anti-inflammatory and vasoprotective effects through amelioration of NFAT-dependent endothelin-1 production in mice with acute Chagas cardiomyopathy. Mem Inst Oswaldo Cruz. 2018;113(9):e180171. https://doi.org/10.1590/0074-02760180171
Vilar-Pereira G, Carneiro VC, Mata-Santos H, et al. Resveratrol reverses functional Chagas heart disease in mice. PLoS Pathog. 2016;12(10):e1005947. https://doi.org/10.1371/journal.ppat.1005947
Levy AM, Boainain E, Kloetzel JK. In situ indirect fluorescent antibody: a new specific test to detect ongoing chagasic infections. J Clin Lab Anal. 1996;10(2):98-103. https://doi.org/10.1002/(sici)1098-2825(1996)10:2<98::aid-jcla7>3.0.co;2-h