Hostname: page-component-6d856f89d9-mhpxw Total loading time: 0 Render date: 2024-07-16T04:04:20.212Z Has data issue: false hasContentIssue false
  • English
  • Français

Combined treatment with benznidazole and allopurinol in mice infected with a virulent Trypanosoma cruzi isolate from Nicaragua

Published online by Cambridge University Press:  18 March 2013

NOELIA L. GROSSO ,
MICAELA LOPEZ ALARCON ,
JAQUELINE BUA ,
SUSANA A. LAUCELLA ,
ADELINA RIARTE  and
LAURA E. FICHERA
NOELIA L. GROSSO
Affiliation:
Instituto Nacional de Parasitología Dr M. Fatala Chaben, ANLIS Malbran, Ministerio de Salud. Av. Paseo Colón 568 Ciudad de Buenos Aires, Argentina
MICAELA LOPEZ ALARCON
Affiliation:
Instituto Nacional de Parasitología Dr M. Fatala Chaben, ANLIS Malbran, Ministerio de Salud. Av. Paseo Colón 568 Ciudad de Buenos Aires, Argentina Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana. Montes de Oca 745 Ciudad de Buenos Aires, Argentina
JAQUELINE BUA
Affiliation:
Instituto Nacional de Parasitología Dr M. Fatala Chaben, ANLIS Malbran, Ministerio de Salud. Av. Paseo Colón 568 Ciudad de Buenos Aires, Argentina
SUSANA A. LAUCELLA
Affiliation:
Instituto Nacional de Parasitología Dr M. Fatala Chaben, ANLIS Malbran, Ministerio de Salud. Av. Paseo Colón 568 Ciudad de Buenos Aires, Argentina
ADELINA RIARTE
Affiliation:
Instituto Nacional de Parasitología Dr M. Fatala Chaben, ANLIS Malbran, Ministerio de Salud. Av. Paseo Colón 568 Ciudad de Buenos Aires, Argentina
LAURA E. FICHERA*
Affiliation:
Instituto Nacional de Parasitología Dr M. Fatala Chaben, ANLIS Malbran, Ministerio de Salud. Av. Paseo Colón 568 Ciudad de Buenos Aires, Argentina
*
*Corresponding author. Avenida Paseo Colón 568 Ciudad de Buenos Aires, CP 1063Argentina. Tel: 54 11 43317732. Fax: 54 11 43317142. E-mail: lfichera@yahoo.com
Get access Rights & Permissions [Opens in a new window]

Summary

We evaluated the effect of chemotherapy with a sequential combined treatment of a low dose of benznidazole and allopurinol, in different schedules of administration, in experimental models of acute and chronic Trypanosoma cruzi infection. Mice were infected with Nicaragua T. cruzi isolate, a virulent parasite from an endemic area of Nicaragua, genotyped as TcI (Grosso et al. 2010). We assessed survival rate, IgG levels, histopathological studies and quantified parasitaemia. A 15% survival rate was recorded in untreated mice during the acute phase of T. cruzi infection. Allopurinol administered immediately after benznidazole treatment was able to reduce parasitaemia and attenuate tissue damage by reducing inflammation. Trypanosoma cruzi-specific antibodies also decreased in 40–50% of the treated mice. The addition of allopurinol during the chronic phase showed the highest beneficial effect, not only by reducing parasitaemia but also by lowering the degree of inflammation and fibrosis.

Keywords

Trypanosoma cruzibenznidazoleallopurinolChagas cardiomyopathymice
Type
Research Article
Information
Parasitology , Volume 140 , Issue 10 , September 2013 , pp. 1225 - 1233
Copyright
Copyright © Cambridge University Press 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Apt, W., Arribada, A., Zulantay, I., Sanchez, G., Vargas, S. L. and Rodriguez, J. (2003). Itraconazole or allopurinol in the treatment of chronic American trypanosomiasis: the regression and prevention of electrocardiographic abnormalities during 9 years of follow-up. Annals of Tropical Medicine and Parasitology 97, 23–29. doi: 10.1179/000349803125002751.CrossRefGoogle ScholarPubMed
Apt, W., Arribada, A., Zulantay, I., Solari, A., Sánchez, G., Mundaca, K., Coronado, X., Rodríguez, J., Gil, L. C. and Osuna, A. (2005). Itraconazole or allopurinol in the treatment of chronic American trypanosomiasis: the results of clinical and parasitological examinations 11 years post-treatment. Annals of Tropical Medicine and Parasitology 99, 733–741. doi: 10.1179/136485905X75403.CrossRefGoogle ScholarPubMed
Bern, C. (2011). Antitrypanosomal therapy for chronic Chagas disease. New England Journal of Medicine 364, 2527–2534. doi: 10.1056/NEJMct1014204.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 São Paulo 4, 389–396.Google ScholarPubMed
Bustamante, J. M., Presti, M. S., Rivarola, H. W., Fernández, A. R., Enders, J. E., Fretesm, R. E. and Paglini-Oliva, P. (2007). Treatment with benznidazole or thioridazine in the chronic phase of experimental Chagas disease improves cardiopathy. International Journal of Antimicrobial Agents 29, 733–737. doi: 10.1016/j.ijantimicag.2007.01.014.CrossRefGoogle ScholarPubMed
Bustamante, J. M., Bixby, L. M. and Tarleton, R. L. (2008). Drug-induced cure drives conversion to a stable and protective CD8+ T central memory response in chronic Chagas disease. Nature Medicine 14, 542–550. doi: 10.1038/nm1744.CrossRefGoogle ScholarPubMed
Caldas, I. S., Talvani, A., Caldas, S., Carneiro, C. M., de Lana, M., da Matta Guedes, P. M. and Bahia, M. T. (2008). Benznidazole therapy during acute phase of Chagas disease reduces parasite load but does not prevent chronic cardiac lesions. Parasitology Research 103, 413–421. doi: 10.1007/s00436-008-0992-6.CrossRefGoogle Scholar
Cançado, J. R. (1985). Tratamiento específico. In Cardiopatía Chagásica (ed. Cancado, J. R. and Chuster, M.), pp. 327–355. Fundacao Carlos Chagas, Belo Horizonte, Brazil.Google Scholar
Cooley, G., Etheridge, R. D., Boehlke, C., Bundy, B., Weatherly, D. B., Minning, T., Haney, M., Postan, M., Laucella, S. and Tarleton, R. L. (2008). High throughput selection of effective serodiagnostics for Trypanosoma cruzi infection. PLoS Neglected Tropical Diseases 2, e316. doi: 10.1371/journal.pntd.0000316.CrossRefGoogle ScholarPubMed
da Silva, C., Batista Dda, G., Oliveira, G. M., de Souza, E. M., Hammer, E. R., da Silva, P. B., Daliry, A., Araujo, J. S., Britto, C., Rodrigues, A. C., Liu, Z., Farahat, A. A., Kumar, A., Boykin, D. W. and Soeiro Mde, N. (2012). In vitro and in vivo investigation of the efficacy of arylimidamide DB1831 and its mesylated salt form – DB1965 – against Trypanosoma cruzi infection. PLoS One 7, e30356. doi: 10.1371/journal.pone.0030356.CrossRefGoogle ScholarPubMed
Duffy, T., Bisio, M., Altcheh, J., Burgos, J. M., Diez, M., Levin, M. J., Favaloro, R. R., Freilij, H. and Schijman, A. G. (2009). Accurate real-time PCR strategy for monitoring bloodstream parasitic loads in Chagas disease patients. PLoS Neglected Tropical Diseases 3, e419. doi: 10.1371/journal.pntd.0000419.CrossRefGoogle ScholarPubMed
Fabbro, D., Arias, E., Streiger, M., Bizai, M. L., del Barco, M. and Amicone, N. A. (2006). 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. Revista da Sociedade Brasileira de Medicina Tropical 40, 1–10.CrossRefGoogle Scholar
Gallerano, R. H., Marr, J. J. and Sosa, R. R. (1990). Therapeutic efficacy of allopurinol in patients with chronic Chagas’ disease. American Journal of Tropical Medicine and Hygiene 43, 159–166.CrossRefGoogle ScholarPubMed
Garcia, S., Ramos, C. O., Senra, J. F., Vilas-Boas, F., Rodrigues, M. M., Campos de Carvalho, A. C., Ribeiro-Dos-Santos, R. and Soares, M. B. (2005). Treatment with benznidazole during the chronic phase of experimental Chagas’ disease decreases cardiac alterations. Antimicrobial Agents and Chemotherapy 49, 1521–1528. doi: 10.1128/AAC.49.4.1521-1528.2005.CrossRefGoogle ScholarPubMed
Grosso, N., Búa, J., Perrone, A., Gonzalez, M., Bustos, P., Postan, M. and Fichera, L. (2010). Biological characterization of a Trypanosoma cruzi isolate from an endemic area and its susceptibility to conventional drugs. Experimental Parasitology 126, 239–244. doi: 10.1016/j.exppara.2010.05.010.CrossRefGoogle ScholarPubMed
Gobbi, P., Lo Presti, M. S., Fernandez, A. R., Enders, J. E., Fretes, R., Gea, S., Paglini-Oliva, P. and Rivarola, H. W. (2007). Allopurinol is effective to modify the evolution of Trypanosoma cruzi infection in mice. Parasitology Research 101, 1459–1462. doi: 10.1007/s00436-010-2002-z.CrossRefGoogle ScholarPubMed
Gobbi, P., Baez, A., Lo Presti, M. S., Fernández, A. R., Enders, J. E., Fretes, R., Gea, S., Paglini-Oliva, P. A. and Rivarola, H. W. (2010). Association of clomipramine and allopurinol for the treatment of the experimental infection with Trypanosome cruzi. Parasitology 107, 1279–1283. doi: 10.1007/s00436-010-2002-z.CrossRefGoogle Scholar
Gupta, S. and Garg, N. J. (2010). Prophylactic efficacy of TcVac2 against Trypanosoma cruzi in mice. PloS Neglected Tropical Diseases 4, e797. doi: 10.1371/journal.pntd.0000797.CrossRefGoogle ScholarPubMed
Laucella, S. A., Mazliah, D. P., Bertocchi, G., Alvarez, M. G., Cooley, G., Viotti, R., Albareda, M. C., Lococo, B., Postan, M., Armenti, A. and Tarleton, R. L. (2009). Changes in Trypanosoma cruzi-specific immune responses after treatment: surrogate markers of treatment efficacy. Clinical Infectious Diseases 49, 1675–1684. doi: 10.1086/648072.CrossRefGoogle ScholarPubMed
Marr, J. J. (1991). Purine analogs as chemotherapeutic agents in leishmaniasis and American trypanosomiasis. Journal of Laboratory and Clinical Medicine 118, 111–119.Google ScholarPubMed
Miyamoto, C. T., Gomes, M. L., Marangon, A. V., de Araújo, S. M., Bahia, M. T., Martins-Filho, O. A., de Lana, M. and de Ornelas Toledo, M. J. (2008). Usefulness of the polymerase chain reaction for monitoring cure of mice infected with different Trypanosoma cruzi clonal genotypes following treatment with benznidazole. Experimental Parasitology 120, 45–49. doi: 10.1016/j.exppara.2008.04.018.CrossRefGoogle ScholarPubMed
Namazi, M. R. (2004). Cetirizine and allopurinol as novel weapons against cellular autoimmune disorders. International Immunopharmacology 4, 349–353. doi: 10.1016/2004.01.022.CrossRefGoogle ScholarPubMed
Osarogiagbon, U. R., Choong, S., Belcher, J. D., Vercellotti, G. M., Paller, M. S. and Hebbel, R. P. (2000). Reperfusion injury pathophysiology in sickle transgenic mice. Blood 96, 314–320.CrossRefGoogle ScholarPubMed
Pacher, P., Nivorozhkin, A. and Szabó, C. (2006). Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacological Reviews 58, 87–114. doi: 10.1124/pr.58.1.6.CrossRefGoogle ScholarPubMed
Perez-Mazliah, D., Albareda, M. C., Alvarez, M. G., Lococo, B., Bertocchi, G. L., Petti, M., Viotti, R. J. and Laucella, S. A. (2012). Allopurinol reduces antigen-specific and polyclonal activation of human T cells. www.frontiersin.org. 3, 295.1–12. doi: 10.3389/fimmu.2012.00295.CrossRefGoogle Scholar
Perez-Mazliah, D. E., Alvarez, M. G., Cooley, G., Lococo, B. E., Bertocchi, G., Petti, M., Albareda, M. C., Armenti, A. H., Tarleton, R. L., Laucella, S. A. and Viotti, R. (2013). Sequential combined treatment with allopurinol and benznidazole in the chronic phase of Trypanosoma cruzi infection: a pilot study. Journal of Antimicrobial Chemotherapy 68, 424–437. doi:10.1093/jac/dks390.CrossRefGoogle ScholarPubMed
Pissetti, C. W., Correia, D., de Oliveira, R. F., Llaguno, M. M., Balarin, M. A., Silva-Grecco, R. L. and Rodrigues, V. Jr. (2011). Genetic and functional role of TNF-alpha in the development Trypanosoma cruzi infection. PloS Neglected Tropical Diseases 5, e976. doi: 10.1371/journal.pntd.0000976.CrossRefGoogle ScholarPubMed
Rassi, A., Luquetti, A. O., Rassi, A. Jr., Rassi, G. G., Rassi, G. S., García da Silva, I. and Rassi, A. G. (2007). Specific treatment of Trypanosoma cruzi: lack of efficacy of allopurinol in the human chronic phase of Chagas disease. American Journal of Tropical Medicine and Hygiene 73, 58–61.CrossRefGoogle Scholar
Rodrigues Coura, J. and Borges-Pereira, J. (2011). Chronic phase of Chagas disease: why should it be treated? A comprehensive review. Memórias do Instituto Oswaldo Cruz, Rio de Janeiro 106, 641–645.CrossRefGoogle Scholar
Sosa Estani, S., Segura, E. L., Ruiz, A. M., Velazquez, E., Porcel, B. M. 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
Sosa Estani, S., Viotti, R. and Segura, E. (2009). Therapy, diagnosis and prognosis of chronic Chagas disease: insight gained in Argentina. Memórias do Instituto Oswaldo Cruz, Rio de Janeiro 104(Suppl. 1), 167–180.CrossRefGoogle ScholarPubMed
Viotti, R., Vigliano, C., Armenti, H. and Segura, E. (1994). Treatment of chronic Chagas disease with benznidazole: clinical and serologic evolution of patients with long-term follow-up. American Heart Journal 127, 151–162.CrossRefGoogle ScholarPubMed
Viotti, R., Vigliano, C., Lococo, B., Alvarez, M. G., Petti, M., Bertocchi, G. and Armenti, A. (2009). Side effects of benznidazole as treatment in chronic Chagas disease: fears and realities. Expert Review of Anti-Infective Therapy 7, 157–163. doi: 10.1586/14787210.7.2.157.CrossRefGoogle ScholarPubMed