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Impact of levamisole in co-administration with benznidazole on experimental Chagas disease

Published online by Cambridge University Press:  03 May 2019

Marianne Rocha Simões-Silva ,
Raiza Brandão Peres ,
Constança Britto ,
Cynthia Machado Cascabulho ,
Gabriel de Melo Oliveira ,
Aline Nefertiti da Gama ,
Cristiane França da Silva ,
Karine Lima da Costa ,
Paula Finamore Araújo  and
Jerônimo Diego de Souza Campos
...Show all authors
Marianne Rocha Simões-Silva
Affiliation:
Laboratório de Biologia Celular, Pavilhão Cardoso Fontes, Instituto Oswaldo Cruz (IOC/Fiocruz), Avenida Brasil, 4365, Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
Raiza Brandão Peres
Affiliation:
Laboratório de Biologia Celular, Pavilhão Cardoso Fontes, Instituto Oswaldo Cruz (IOC/Fiocruz), Avenida Brasil, 4365, Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
Constança Britto
Affiliation:
Laboratório de Biologia Molecular e Doenças Endêmicas, Pavilhão Leônidas Deane, Instituto Oswaldo Cruz (IOC/Fiocruz), Avenida Brasil, 4365, Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
Cynthia Machado Cascabulho
Affiliation:
Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Pavilhão Cardoso Fontes, Instituto Oswaldo Cruz (IOC/Fiocruz), Avenida Brasil, 4365, Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
Gabriel de Melo Oliveira
Affiliation:
Laboratório de Biologia Celular, Pavilhão Cardoso Fontes, Instituto Oswaldo Cruz (IOC/Fiocruz), Avenida Brasil, 4365, Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
Aline Nefertiti da Gama
Affiliation:
Laboratório de Biologia Celular, Pavilhão Cardoso Fontes, Instituto Oswaldo Cruz (IOC/Fiocruz), Avenida Brasil, 4365, Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
Cristiane França da Silva
Affiliation:
Laboratório de Biologia Celular, Pavilhão Cardoso Fontes, Instituto Oswaldo Cruz (IOC/Fiocruz), Avenida Brasil, 4365, Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
Karine Lima da Costa
Affiliation:
Laboratório de Biologia Celular, Pavilhão Cardoso Fontes, Instituto Oswaldo Cruz (IOC/Fiocruz), Avenida Brasil, 4365, Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
Paula Finamore Araújo
Affiliation:
Laboratório de Biologia Molecular e Doenças Endêmicas, Pavilhão Leônidas Deane, Instituto Oswaldo Cruz (IOC/Fiocruz), Avenida Brasil, 4365, Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
Jerônimo Diego de Souza Campos
Affiliation:
Laboratório de Biologia Celular, Pavilhão Cardoso Fontes, Instituto Oswaldo Cruz (IOC/Fiocruz), Avenida Brasil, 4365, Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
Marcos Meuser Batista
Affiliation:
Laboratório de Biologia Celular, Pavilhão Cardoso Fontes, Instituto Oswaldo Cruz (IOC/Fiocruz), Avenida Brasil, 4365, Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
Kelly Cristina Demarque
Affiliation:
Laboratório de Biologia Celular, Pavilhão Cardoso Fontes, Instituto Oswaldo Cruz (IOC/Fiocruz), Avenida Brasil, 4365, Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
Otacílio da Cruz Moreira
Affiliation:
Laboratório de Biologia Molecular e Doenças Endêmicas, Pavilhão Leônidas Deane, Instituto Oswaldo Cruz (IOC/Fiocruz), Avenida Brasil, 4365, Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
Maria de Nazaré Correia Soeiro*
Affiliation:
Laboratório de Biologia Celular, Pavilhão Cardoso Fontes, Instituto Oswaldo Cruz (IOC/Fiocruz), Avenida Brasil, 4365, Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
*
Author for correspondence: Maria de Nazaré Correia Soeiro, E-mail: soeiro@ioc.fioruz.br
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Abstract

Levamisole (Lms) is an anthelminthic drug with immunomodulatory activity. Chagas disease (CD) is caused by Trypanosoma cruzi and there is very low access to the drugs available, benznidazole (Bz) and nifurtimox, both far from ideal. In a drug-repurposing strategy to test potential activity as antiparasitic and immunomodulatory agent for CD, Lms was assayed on acute T. cruzi murine infection, alone and in co-administration with Bz. During protocol standardization, 100 and 10 mpk of Bz given for five consecutive days resulted in parasitaemia suppression and 100% animal survival only with the highest dose. Flow cytometry showed that both optimal (100 mpk) and suboptimal (10 mpk) doses of Bz equally decreased the plasma levels of cytokines commonly elevated in this acute infection model. Lms alone (10–0.5 mpk) did not decrease parasitaemia nor mortality rates. Co-administration was investigated using the suboptimal dose of Bz and different doses of Lms. While Bz 10 mpk did not alter parasitaemia, the combo partially reduced it but only slightly promoted animal survival. This effect could be related to Th1-response modulation since interleukin-6 and interferon-γ were higher after treatment with the combo.

Keywords

Chagas diseasedrug co-administrationimmunomodulationlevamisole
Type
Research Article
Information
Parasitology , Volume 146 , Issue 8 , July 2019 , pp. 1055 - 1062
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Copyright
Copyright © Cambridge University Press 2019 

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References

Abath, FG, Coutinho, EM, Montenegro, SM, Gomes, YM and Carvalho, AB (1988) The use of non-specific immunopotentiators in experimental Trypanosoma cruzi infection. Transactions of the Royal Society of Tropical Medicine and Hygiene 82, 73–76.Google Scholar
Amery, WK and Bruynseels, JP (1992) Levamisole, the story and the lessons. International Journal of Immunopharmacology 14, 481–486.Google Scholar
Brener, Z (1962) Therapeutic activity and criterion of cure on mice experimentally infected with Trypanosoma cruzi. Revista do Instituto de Medicina Tropical de São Paulo 4, 386–396.Google Scholar
Brunner, CJ and Muscoplat, CC (1980) Immunomodulatory effects of levamisole. Journal of the American Veterinary Medical Association 176(10 Spec No), 1159–1162.Google Scholar
Butler, PG (1982) Levamisole and immune response phenomena in cutaneous leishmaniasis. Journal of the American Academy of Dermatology 6, 1070–1077.Google Scholar
Chandrasekar, B, Melby, PC, Troyer, DA and Freeman, GL (1996) Induction of proinflammatory cytokine expression in experimental acute Chagasic cardiomyopathy. Biochemical and Biophysical Research Communications 223, 365–371.Google Scholar
Coura, JR (2009) Present situation and new strategies for Chagas disease chemotherapy: a proposal. Memórias do Instituto Oswaldo Cruz 104, 549–554.Google Scholar
Duffy, T, Cura, CI, Ramirez, JC, Abate, T, Cayo, NM, Parrado, R, Bello, ZD, Velazquez, E, Muñoz-Calderon, A, Juiz, NA, Basile, J, Garcia, L, Riarte, A, Nasser, JR, Ocampo, SB, Yadon, ZE, Torrico, F, de Noya, BA, Ribeiro, I and Schijman, AG (2013) Analytical performance of a multiplex real-time PCR assay using TaqMan probes for quantification of Trypanosoma cruzi satellite DNA in blood samples. PLoS Neglected Tropical Diseases 7, e2000.Google Scholar
Ferraz, ML, Gazzinelli, RT, Alves, RO, Urbina, JA and Romanha, AJ (2007) The anti-Trypanosoma cruzi activity of posaconazole in a murine model of acute Chagas' disease is less dependent on gamma interferon than that of benznidazole. Antimicrobial Agents and Chemotherapy 51, 1359–1364.Google 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.Google Scholar
Fredericks, C, Yon, JR, Alex, G, Morton, M, Messer, T, Bokhari, F and Poulakidas, S (2017) Levamisole-induced necrosis syndrome: presentation and management. Wounds 29, 71–76.Google Scholar
Gao, W and Pereira, MA (2002) Interleukin-6 is required for parasite specific response and host resistance to Trypanosoma cruzi. International Journal of Parasitology 32, 167–170.Google Scholar
Köksal, ZŞ, Yanik, K, Bilgin, K, Yılmaz, EM and Hokelek, M (2016) In vivo efficacy of drugs against Toxoplasma gondii combined with immunomodulators. Japanese Journal of Infectious Diseases 69, 113–117.Google Scholar
Libeau, G and Pinder, M (1981) Deleterious effect of levamisole on experimental trypanosomiasis in mice. Revue d’Élevage et de Médecine Vétérinaire des Pays Tropicaux 34, 399–404, Article in French.Google Scholar
Lionel, ND, Mirando, EH, Nanayakkara, JC and Soysa, PE (1969) Levamisole in the treatment of ascariasis in children. British Medical Journal 4, 340–341.Google Scholar
Maude, RJ, Silamut, K, Plewes, K, Charunwatthana, P, Ho, M, Abul Faiz, M, Rahman, R, Hossain, MA, Hassan, MU, Bin Yunus, E, Hoque, G, Islam, F, Ghose, A, Hanson, J, Schlatter, J, Lacey, R, Eastaugh, A, Tarning, J, Lee, SJ, White, NJ, Chotivanich, K, Day, NP and Dondorp, AM (2014) Randomized controlled trial of levamisole hydrochloride as adjunctive therapy in severe falciparum malaria with high parasitemia. Journal of Infectious Diseases 209, 120–129.Google Scholar
Morato, MJ, Colley, DG and Powell, MR (1998) Cytokine profiles during experimental Chagas’ disease. Brazilian Journal of Medical and Biological Research 31, 123–125.Google Scholar
Moreira, OC, Ramírez, JD, Velázquez, E, Melo, MF, Lima-Ferreira, C, Guhl, F, Sosa-Estani, S, Marin-Neto, JA, Morillo, CA and Britto, C (2013) Towards the establishment of a consensus real-time qPCR to monitor Trypanosoma cruzi parasitemia in patients with chronic Chagas disease cardiomyopathy: a substudy from the BENEFIT trial. Acta Tropica 125, 23–31.Google Scholar
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, Yusuf, S and STOP-CHAGAS Investigators. (2017) 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.Google Scholar
Mutch, RS and Hutson, PR (1991) Levamisole in the adjuvant treatment of colon cancer. Clinical Pharmacology 10, 95–109.Google Scholar
Nabors, GS and Tarleton, RL (1991) Differential control of IFN-gamma and IL-2 production during Trypanosoma cruzi infection. Journal of Immunology 146, 3591–3598.Google Scholar
Prata, A (2001) Clinical and epidemiological aspects of Chagas disease. The Lancet Infectious Diseases 1, 92–100.Google Scholar
Rassi, AJ, Rassi, A and Marin-Neto, A (2010) Chagas disease. The Lancet 375, 1388–1402.Google Scholar
Rezai, HR, Behbehani, AB, Gettner, S and Ardehali, S (1988) Effect of levamisole on the course of experimental leishmaniasis in Guinea-pigs and mice: haematological and immunological findings. Annals of Tropical Medicine & Parasitology 82, 243–249.Google Scholar
Renoux, G (1980) The general immunopharmacology of levamisole. Drugs 20, 89–99.Google Scholar
Rifaat, LK, Mohammad, MA and Jawdat, SZ (1989) Ivermectin, levamisole and thymic extract for chemotherapy and immunostimulation of visceral leishmaniasis in hamsters and mice. Japanese Journal of Medical Science and Biology 42, 51–61.Google Scholar
Risvanli, A and Aydin, M (2003) The effects of levamisole on the pregnancy rate, average litter size, sexuality, living rate and lactation period in rats. Firat University Journal of Health Sciences (Turkey) 17, 45–47.Google Scholar
Scarim, CB, Jornada, DH, Chelucci, RC, de Almeida, L, Dos Santos, JL and Chung, MC (2018) Current advances in drug discovery for Chagas disease. European Journal of Medicinal Chemistry 155, 824–838.Google Scholar
Scherb, J (1969) Therapeutic efficiency of levamisole in human ascariasis. Hospital (Rio J) 76, 1067–1070, Article in Portuguese.Google Scholar
Simões-Silva, MR, De Araújo, JS, Oliveira, GM, Demarque, KC, Peres, RB, D'Almeida-Melo, I, Batista, DGJ, Da Silva, CF, Cardoso-Santos, C, Da Silva, PB, Batista, MM, Bahia, MT and Soeiro, MNC (2017) Drug repurposing strategy against Trypanosoma cruzi infection: in vitro and in vivo assessment of the activity of metronidazole in mono- and combined therapy. Biochemical Pharmacology 145, 46–53.Google Scholar
Torrico, F, Gascon, J, Ortiz, L, Alonso-Vega, C, Pinazo, MJ, Schijman, A, Almeida, IC, Alves, F, Strub-Wourgaft, N, Ribeiro, I and E1224 Study Group (2018) 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.Google Scholar
Truyens, C, Angelo-Barrios, A, Torrico, F, Van Damme, J, Heremans, H and Carlier, Y (1994) Interleukin-6 (IL-6) production in mice infected with Trypanosoma cruzi: effect of its paradoxical increase by anti-IL-6 monoclonal antibody treatment on infection and acute-phase and humoral immune responses. Infectious Immunology 62, 692–696.Google Scholar