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Combination therapy using nitro compounds improves the efficacy of experimental Chagas disease treatment

Published online by Cambridge University Press:  18 June 2021

Ana Lia Mazzeti Open the ORCID record for Ana Lia Mazzeti [Opens in a new window] ,
Karolina R. Gonçalves ,
Suianne L. A. Mota ,
Dário Elias Pereira ,
Lívia de F. Diniz  and
Maria Terezinha Bahia
Ana Lia Mazzeti*
Affiliation:
Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, MG35400-000, Brazil Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ21040-360, Brazil
Karolina R. Gonçalves
Affiliation:
Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, MG35400-000, Brazil
Suianne L. A. Mota
Affiliation:
Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, MG35400-000, Brazil
Dário Elias Pereira
Affiliation:
Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, MG35400-000, Brazil
Lívia de F. Diniz
Affiliation:
Laboratório de Parasitologia Básica, Departamento de Patologia e Parasitologia, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, MG37130-001, Brazil
Maria Terezinha Bahia
Affiliation:
Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, MG35400-000, Brazil
*
Author for correspondence: Ana Lia Mazzeti, E-mail: ana.mazzeti@ioc.fiocruz.br; anamazzeti@yahoo.com.br
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Abstract

Drug combinations have been evaluated for Chagas disease in an attempt to improve efficacy and safety. In this line, the objective of this work is to assess the effects of treatment with nitro drugs combinations using benznidazole (BZ) or nifurtimox (NFX) plus the sulfone metabolite of fexinidazole (fex-SFN) in vitro and in vivo on Trypanosoma cruzi infection. The in vitro interaction of fex-SFN and BZ or NFX against infected H9c2 cells by the Y strain was classified as an additive (0.5⩾ΣFIC<4), suggesting the possibility of a dose reduction in the in vivo T. cruzi infection. Next, the effect of combining suboptimal doses was assessed in an acute model of murine T. cruzi infection. Drug combinations led to a faster suppression of parasitemia than monotherapies. Also, the associations led to higher cure levels than those in the reference treatment BZ 100 mg day−1 (57.1%) (i.e. 83.3% with BZ/fex-SFN and 75% with NFX/fex-SFN). Importantly, toxic effects resulting from the associations were not observed, according to weight gain and hepatic enzyme levels in the serum of experimental animals. Taken together, this study is a starting point to explore the potential effects of nitro drugs combinations in preclinical models of kinetoplastid-related infections.

Keywords

BenznidazoleChagas diseasechemotherapycombinationnifurtimoxnitro compoundssulfone metabolite of fexinidazoleTrypanosoma cruzi
Type
Research Article
Information
Parasitology , Volume 148 , Issue 11 , September 2021 , pp. 1320 - 1327
Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press

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References

Amacher, DE (1998) Serum transaminase elevations as indicators of hepatic injury following the administration of drugs. Regulatory Toxicology and Pharmacology 27, 119–130.CrossRefGoogle ScholarPubMed
Araujo, MSS, Martins-Filho, OA, Pereira, MES and Brener, Z (2000) A combination of benznidazole and ketoconazole enhances efficacy of chemotherapy of experimental Chagas’ disease. Journal of Antimicrobial Chemotherapy 45, 819–824.CrossRefGoogle ScholarPubMed
Assíria Fontes Martins, T, de Figueiredo Diniz, L, Mazzeti, AL, da Silva do Nascimento, ÁF, Caldas, S, Caldas, IS, de Andrade, IM, Ribeiro, I and Bahia, MT (2015) Benznidazole/itraconazole combination treatment enhances anti-Trypanosoma cruzi activity in experimental Chagas disease. PLoS ONE 10, e0128707.CrossRefGoogle ScholarPubMed
Bahia, MT, de Andrade, IM, Martins, TAF, da Silva do Nascimento, ÁF, de Diniz, LF, Caldas, IS, Talvani, A, Trunz, BB, Torreele, E and Ribeiro, I (2012) Fexinidazole: a potential new drug candidate for Chagas disease. PLoS Neglected Tropical Diseases 6, e1870.CrossRefGoogle ScholarPubMed
Bahia, MT, Nascimento, AFS, Mazzeti, AL, Marques, LF, Gonçalves, KR, Mota, LWR, de Diniz, LF, Caldas, IS, Talvani, A, Shackleford, DM, Koltun, M, Saunders, J, White, KL, Scandale, I, Charman, SA and Chatelain, E (2014) Antitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease. Antimicrobial Agents and Chemotherapy 58, 4362–4370.CrossRefGoogle ScholarPubMed
Benaim, G, Sanders, JM, Garcia-Marchán, Y, Colina, C, Lira, R, Caldera, AR, Payares, G, Sanoja, C, Burgos, JM, Leon-Rossell, A, Concepcion, JL, Schijman, AG, Levin, M, Oldfield, E and Urbina, JA (2006) Amiodarone has intrinsic anti-Trypanosoma c ruzi activity and acts synergistically with posaconazole†. Journal of Medicinal Chemistry 49, 892–899.CrossRefGoogle Scholar
Berndt, ER, Cockburn, IM and Grépin, KA (2006) The impact of incremental innovation in biopharmaceuticals: drug utilisation in original and supplemental indications. PharmacoEconomics 24, 69–86.CrossRefGoogle ScholarPubMed
Brener, Z (1962) Therapeutic activity and criterion of cure on mice experimentally infected with Trypanosoma cruzi. Revista Do Instituto De Medicina Tropical De Sao Paulo 4, 389–396.Google ScholarPubMed
Caldas, S, Santos, FM, Lana, M, de Diniz, LF, Machado-Coelho, GLL, Veloso, VM and Bahia, MT (2008) Trypanosoma cruzi: acute and long-term infection in the vertebrate host can modify the response to benznidazole. Experimental Parasitology 118, 315–323.CrossRefGoogle ScholarPubMed
Cencig, S, Coltel, N, Truyens, C and Carlier, Y (2012) Evaluation of benznidazole treatment combined with nifurtimox, posaconazole or AmBisome® in mice infected with Trypanosoma cruzi strains. International Journal of Antimicrobial Agents 40, 527–532.CrossRefGoogle ScholarPubMed
Chagas, C (1909) 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. Memórias do Instituto Oswaldo Cruz 1, 159–218.CrossRefGoogle Scholar
Cummings, KL and Tarleton, RL (2003) Rapid quantitation of Trypanosoma cruzi in host tissue by real-time PCR. Molecular and Biochemical Parasitology 129, 53–59.CrossRefGoogle ScholarPubMed
Deeks, ED (2019) Fexinidazole: first global approval. Drugs 79, 215–220.CrossRefGoogle ScholarPubMed
Diniz, LF, Urbina, JA, Andrade, IM, Mazzeti, AL, Martins, TAF, 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 Scholar
Diniz, LF, Mazzeti, AL, Caldas, IS, Ribeiro, I and Bahia, MT (2018) Outcome of E1224-benznidazole combination treatment for infection with a multidrug-resistant Trypanosoma cruzi strain in mice. Antimicrobial Agents and Chemotherapy 62, e00401–18.CrossRefGoogle ScholarPubMed
DNDi (2020) Fexinidazole for Chagas | Research and development | Portifolio | Drugs for Neglected Diseases initiative.Google Scholar
Eperon, G, Balasegaram, M, Potet, J, Mowbray, C, Valverde, O and Chappuis, F (2014) Treatment options for second-stage gambiense human African trypanosomiasis. Expert Review of Anti-Infective Therapy 12, 1407–1417.CrossRefGoogle ScholarPubMed
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
Grosso, NL, Alarcon, ML, Bua, J, Laucella, SA, Riarte, A and Fichera, LE (2013) Combined treatment with benznidazole and allopurinol in mice infected with a virulent Trypanosoma cruzi isolate from Nicaragua. Parasitology 140, 1225–1233.CrossRefGoogle ScholarPubMed
Guedes-da-Silva, FH, da Batista, DGJ, Da Silva, CF, Pavão, BP, Batista, MM, Moreira, OC, Souza, LRQ, Britto, C, Rachakonda, G, Villalta, F, Lepesheva, GI and de Soeiro, MNC (2019) Successful aspects of the coadministration of sterol 14α-demethylase inhibitor VFV and benznidazole in experimental mouse models of Chagas disease caused by the drug-resistant strain of Trypanosoma cruzi. ACS Infectious Diseases 5, 365–371.CrossRefGoogle ScholarPubMed
ISO (2009) Part 5: tests for in vitro cytotoxicity – ISO 10993-5. In biological evaluation of medical devices – ISO 10993, p. International Organization for Standardization, Switzerland.Google Scholar
Janssens, PG and De Muynck, A (1977) Clinical trials with ‘nifurtimox’ in African trypanosomiasis. Annales De La Societe Belge De Medecine Tropicale 57, 475–480.Google ScholarPubMed
Jennings, FW and Urquhart, GM (1983) The use of the 2 substituted 5-nitroimidazole, fexinidazole (Hoe 239) in the treatment of chronic T. brucei infections in mice. Zeitschrift Fur Parasitenkunde 69, 577–581.CrossRefGoogle Scholar
Jia, J, Zhu, F, Ma, X, Cao, ZW, Li, YX and Chen, YZ (2009) Mechanisms of drug combinations: interaction and network perspectives. Nature Reviews Drug Discovery 8, 111–128.CrossRefGoogle ScholarPubMed
Kaiser, M, Bray, MA, Cal, M, Bourdin Trunz, B, Torreele, E and Brun, R (2011) Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness. Antimicrobial Agents and Chemotherapy 55, 5602–5608.CrossRefGoogle ScholarPubMed
Koniordou, M, Patterson, S, Wyllie, S and Seifert, K (2017) Snapshot profiling of the antileishmanial potency of lead compounds and drug candidates against intracellular Leishmania donovani amastigotes, with a focus on human-derived host cells. Antimicrobial Agents and Chemotherapy 61, e01228–16. e01228-16.CrossRefGoogle ScholarPubMed
Kratz, JM, Garcia Bournissen, F, Forsyth, CJ and Sosa-Estani, S (2018) Clinical and pharmacological profile of benznidazole for treatment of Chagas disease. Expert Review of Clinical Pharmacology 11, 943–957.CrossRefGoogle ScholarPubMed
Leonardi, D, Bombardiere, ME and Salomon, CJ (2013) Effects of benznidazole:cyclodextrin complexes on the drug bioavailability upon oral administration to rats. International Journal of Biological Macromolecules 62, 543–548.CrossRefGoogle ScholarPubMed
Lidani, KCF, Andrade, FA, Bavia, L, Damasceno, FS, Beltrame, MH, Messias-Reason, IJ and Sandri, TL (2019) Chagas disease: from discovery to a worldwide health problem. Frontiers in Public Health 7, 166.CrossRefGoogle ScholarPubMed
Machado, YA, Bahia, MT, Caldas, IS, Mazzeti, AL, Novaes, RD, Vilas Boas, BR, de Santos, LJS, Martins-Filho, OA, Marques, MJ and de Diniz, LF (2020) Amlodipine increases the therapeutic potential of ravuconazole upon Trypanosoma cruzi infection. Antimicrobial Agents and Chemotherapy 64, e02497–19.CrossRefGoogle ScholarPubMed
Martínez-Peinado, N, Cortes-Serra, N, Losada-Galvan, I, Alonso-Vega, C, Urbina, JA, Rodríguez, A, VandeBerg, JL, Pinazo, M-J, Gascon, J and Alonso-Padilla, J (2020) Emerging agents for the treatment of Chagas disease: what is in the preclinical and clinical development pipeline? Expert Opinion on Investigational Drugs 29, 947–959.CrossRefGoogle ScholarPubMed
Mazzeti, AL, de Diniz, LF, Gonçalves, KR, Nascimento, AFS, Spósito, PAF, Mosqueira, VCF, Machado-Coelho, GLL, Ribeiro, I and Bahia, MT (2018) Time and dose-dependence evaluation of nitroheterocyclic drugs for improving efficacy following Trypanosoma cruzi infection: a pre-clinical study. Biochemical Pharmacology 148, 213–221.CrossRefGoogle ScholarPubMed
Mazzeti, AL, de 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
Mazzeti, AL, Oliveira, LT, Gonçalves, KR, Schaun, GC, Mosqueira, VCF and Bahia, MT (2020) Benznidazole self-emulsifying delivery system: a novel alternative dosage form for Chagas disease treatment. European Journal of Pharmaceutical Sciences 145, 105234.CrossRefGoogle ScholarPubMed
Mesu, VKBK, Kalonji, WM, Bardonneau, C, Mordt, OV, Blesson, S, Simon, F, Delhomme, S, Bernhard, S, Kuziena, W, Lubaki, J-PF, Vuvu, SL, Ngima, PN, Mbembo, HM, Ilunga, M, Bonama, AK, Heradi, JA, Solomo, JLL, Mandula, G, Badibabi, LK, Dama, FR, Lukula, PK, Tete, DN, Lumbala, C, Scherrer, B, Strub-Wourgaft, N and Tarral, A (2018) Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial. Lancet 391, 144–154.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
Moraes, CB, Giardini, MA, Kim, H, Franco, CH, Araujo-Junior, AM, Schenkman, S, Chatelain, E and Freitas-Junior, LH (2015) Nitroheterocyclic compounds are more efficacious than CYP51 inhibitors against Trypanosoma cruzi: implications for Chagas disease drug discovery and development. Scientific Reports 4, 4703.CrossRefGoogle Scholar
Morillo, CA, Marin-Neto, JA, Avezum, A, Sosa-Estani, S, Rassi, A, 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) Randomized trial of benznidazole for chronic Chagas’ cardiomyopathy. New England Journal of Medicine 373, 1295–1306.CrossRefGoogle ScholarPubMed
Novaes, RD, Santos, EC, Cupertino, MC, Bastos, DSS, Oliveira, JM, Carvalho, TV, Neves, MM, Oliveira, LL and Talvani, A (2015) Trypanosoma cruzi infection and benznidazole therapy independently stimulate oxidative status and structural pathological remodeling of the liver tissue in mice. Parasitology Research 114, 2873–2881.CrossRefGoogle ScholarPubMed
Odds, FC (2003) Synergy, antagonism, and what the chequerboard puts between them. Journal of Antimicrobial Chemotherapy 52, 1–1.CrossRefGoogle ScholarPubMed
Patterson, S and Fairlamb, AH (2019) Current and future prospects of nitro-compounds as drugs for trypanosomiasis and leishmaniasis. Current Medicinal Chemistry 26, 4454–4475.CrossRefGoogle ScholarPubMed
Patterson, S and Wyllie, S (2014) Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects. Trends in Parasitology 30, 289–298.CrossRefGoogle ScholarPubMed
Pérez-Molina, JA and Molina, I (2018) Chagas disease. The Lancet 391, 82–94.CrossRefGoogle ScholarPubMed
Perin, L, da Fonseca, KS, de Carvalho, TV, Carvalho, LM, Madeira, JV, da Medeiros, LF, Molina, I, Correa-Oliveira, R, Carneiro, CM and de Vieira, PMA (2020) Low-dose of benznidazole promotes therapeutic cure in experimental chronic Chagas’ disease with absence of parasitism in blood, heart and colon. Experimental Parasitology 210, 107834.CrossRefGoogle ScholarPubMed
Providello, MV, Carneiro, ZA, Portapilla, GB, do Vale, GT, Camargo, RS, Tirapelli, CR and de Albuquerque, S (2018) Benefits of ascorbic acid in association with low-dose benznidazole in treatment of Chagas disease. Antimicrobial Agents and Chemotherapy 62, e00514–18.CrossRefGoogle ScholarPubMed
Raether, W and Seidenath, H (1983) The activity of fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica. Annals of Tropical Medicine & Parasitology 77, 13–26.CrossRefGoogle ScholarPubMed
Rial, MS, Scalise, ML, Arrúa, EC, Esteva, MI, Salomon, CJ and Fichera, LE (2017) Elucidating the impact of low doses of nano-formulated benznidazole in acute experimental Chagas disease. PLoS Neglected Tropical Diseases 11, e0006119.CrossRefGoogle ScholarPubMed
Rial, MS, Arrúa, EC, Natale, MA, Bua, J, Esteva, MI, Prado, NG, Laucella, SA, Salomon, CJ and Fichera, LE (2020) Efficacy of continuous versus intermittent administration of nanoformulated benznidazole during the chronic phase of Trypanosoma cruzi Nicaragua infection in mice. Journal of Antimicrobial Chemotherapy 75, 1906–1916.CrossRefGoogle ScholarPubMed
Ribeiro, V, Dias, N, Paiva, T, Hagström-Bex, L, Nitz, N, Pratesi, R and Hecht, M (2020) Current trends in the pharmacological management of Chagas disease. International Journal for Parasitology: Drugs and Drug Resistance 12, 7–17.Google ScholarPubMed
Rocha Simões-Silva, M, Brandão Peres, R, Britto, C, Machado Cascabulho, C, de Melo Oliveira, G, Nefertiti da Gama, A, França da Silva, C, Lima da Costa, K, Finamore Araújo, P, Diego de Souza Campos, J, Meuser Batista, M, Cristina Demarque, K, da Cruz Moreira, O and de Nazaré Correia Soeiro, M (2019) Impact of levamisole in co-administration with benznidazole on experimental Chagas disease. Parasitology 146, 1055–1062.CrossRefGoogle ScholarPubMed
Seremeta, KP, Arrúa, EC, Okulik, NB and Salomon, CJ (2019) Development and characterization of benznidazole nano- and microparticles: a new tool for pediatric treatment of Chagas disease? Colloids and Surfaces B: Biointerfaces 177, 169–177.CrossRefGoogle ScholarPubMed
Spósito, PÁF, Mazzeti Silva, AL, de Oliveira Faria, C, Urbina, JA, Pound-Lana, G, Bahia, MT and Mosqueira, VCF (2017) Ravuconazole self-emulsifying delivery system: in vitro activity against Trypanosoma cruzi amastigotes and in vivo toxicity. International Journal of Nanomedicine Volume 12, 3785–3799.CrossRefGoogle ScholarPubMed
Strauss, M, Lo Presti, MS, Bazán, PC, Baez, A, Fauro, R, Esteves, B, Sanchez Negrete, O, Cremonezzi, D, Paglini-Oliva, PA and Rivarola, HW (2013) Clomipramine and benznidazole association for the treatment of acute experimental Trypanosoma cruzi infection. Parasitology International 62, 293–299.CrossRefGoogle ScholarPubMed
Tarral, A, Blesson, S, Mordt, OV, Torreele, E, Sassella, D, Bray, MA, Hovsepian, L, Evène, E, Gualano, V, Felices, M and Strub-Wourgaft, N (2014) Determination of an optimal dosing regimen for fexinidazole, a novel oral drug for the treatment of human African trypanosomiasis: first-in-human studies. Clinical Pharmacokinetics 53, 565–580.CrossRefGoogle ScholarPubMed
Torreele, E, Bourdin Trunz, B, Tweats, D, Kaiser, M, Brun, R, Mazué, G, Bray, MA and Pécoul, B (2010) Fexinidazole – a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLoS Neglected Tropical Diseases 4, e923.CrossRefGoogle ScholarPubMed
Torrico, F, Gascon, J, Ortiz, L, Alonso-Vega, C, Pinazo, M-J, Schijman, A, Almeida, IC, Alves, F, Strub-Wourgaft, N, Ribeiro, I, Santina, G, Blum, B, Correia, E, Garcia-Bournisen, F, Vaillant, M, Morales, JR, Pinto Rocha, JJ, Rojas Delgadillo, G, Magne Anzoleaga, HR, Mendoza, N, Quechover, RC, Caballero, MYE, Lozano Beltran, DF, Zalabar, AM, Rojas Panozo, L, Palacios Lopez, A, Torrico Terceros, D, Fernandez Galvez, VA, Cardozo, L, Cuellar, G, Vasco Arenas, RN, Gonzales, I, Hoyos Delfin, CF, Garcia, L, Parrado, R, de la Barra, A, Montano, N, Villarroel, S, Duffy, T, Bisio, M, Ramirez, JC, Duncanson, F, Everson, M, Daniels, A, Asada, M, Cox, E, Wesche, D, Diderichsen, PM, Marques, AF, Izquierdo, L, Sender, SS, Reverter, JC, Morales, M and Jimenez, W (2018) Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial. The Lancet Infectious Diseases 18, 419–430.CrossRefGoogle ScholarPubMed
Villalta, F and Rachakonda, G (2019) Advances in preclinical approaches to Chagas disease drug discovery. Expert Opinion on Drug Discovery 14, 1161–1174.CrossRefGoogle ScholarPubMed
Wertheimer, AI and Morrison, A (2002) Combination drugs: innovation in pharmacology. Pharmacology & Therapeutics 27, 44–49.Google Scholar
WHO (2020). Chagas disease (American trypanosomiasis). WHO Technical Report Series. Geneva, Switzerland. World Health Organization.Google Scholar
Winkelmann, E and Raether, W (1978) Chemotherapeutically acitve nitro compounds. 4. 5–nitroimidazoles (part III). Arzneimittel-Forschung 28, 739–749.Google Scholar
Wyllie, S, Patterson, S, Stojanovski, L, Simeons, FRC, Norval, S, Kime, R, Read, KD and Fairlamb, AH (2012) The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis. Science Translational Medicine 4, 119re1.CrossRefGoogle ScholarPubMed
Zingales, B, Andrade, S, Briones, M, Campbell, D, Chiari, E, Fernandes, O, Guhl, F, Lages-Silva, E, Macedo, A, Machado, C, Miles, M, Romanha, A, Sturm, N, Tibayrenc, M and Schijman, A (2009) A new consensus for Trypanosoma cruzi intraspecific nomenclature: second revision meeting recommends TcI to TcVI. Memórias do Instituto Oswaldo Cruz 104, 1051–1054.CrossRefGoogle ScholarPubMed