Background Chagas disease is one of the most important public health problems and a leading cause of cardiac failure in Latin America. The currently available drugs to treat T. cruzi infection (benznidazole and nifurtimox) are effective in humans when administered during months. AmBisome (liposomal amphotericin B), already shown efficient after administration for some days in human and experimental infection with Leishmania, has been scarcely studied in T. cruzi infection. Aims This work investigates the effect of AmBisome treatment, administered in 6 intraperitoneal injections at various times during acute and/or chronic phases of mouse T. cruzi infection, comparing survival rates and parasitic loads in several tissues. Methodology Quantitative PCR was used to determine parasitic DNA amounts in tissues. Immunosuppressive treatment with cyclophosphamide was used to investigate residual infection in tissues. Findings Administration of AmBisome during the acute phase of infection prevented mice from fatal issue. Parasitaemias (microscopic examination) were reduced in acute phase and undetectable in chronic infection. Quantitative PCR analyses showed significant parasite load reductions in heart, liver, spleen, skeletal muscle and adipose tissues in acute as well as in chronic infection. An earlier administration of AmBisome (one day after parasite inoculation) had a better effect in reducing parasite loads in spleen and liver, whereas repetition of treatment in chronic phase enhanced the parasite load reduction in heart and liver. However, whatever the treatment schedule, cyclophosphamide injections boosted infection to parasite amounts comparable to those observed in acutely infected and untreated mice. Conclusions Though AmBisome treatment fails to completely cure mice from T. cruzi infection, it impedes mortality and reduces significantly the parasitic loads in most tissues. Such a beneficial effect, obtained by administrating it over a short time, should stimulate studies on using AmBisome in association with other drugs in order to shorten recovery from T. cruzi infection.
References
[1]
Carlier Y, Pinto Dias JC, Ostermayer Luquetti A, Hontebeyrie M, Truyens C (2002) Trypanosomiase américaine ou maladie de Chagas. Encyclopédie Médico-Chirurgicale 1–21.
[2]
Carlier Y, Truyens C (2010) Maternal-Fetal Transmission of Trypanosoma cruzi. In: Telleria J, Tibayrenc M, editors. American Trypanosomiasis, Chagas Disease: One Hundred Years of Research. ELSEVIER. pp. 539–581.
[3]
Rassi A Jr, Rassi A, Marin-Neto JA (2010) Chagas disease. Lancet 375: 1388–1402. doi: 10.1016/S0140-6736(10)60061-X
[4]
Coura JR, Vi?as PA (2010) Chagas disease : a new worldwide challenge. Nature 465: S6–S7. doi: 10.1038/nature09221
[5]
Bern C, Montgomery SP (2009) An estimate of the burden of Chagas disease in the United States. Clin Infect Dis 49: e52–e54. doi: 10.1086/605091
[6]
Buekens P, Almendares O, Carlier Y, Dumonteil E, Eberhard M, et al. (2008) Mother-to-child transmission of Chagas' disease in North America: why don't we do more? Matern Child Health J 12: 283–286. doi: 10.1007/s10995-007-0246-8
[7]
Gascon J, Bern C, Pinazo MJ (2009) Chagas disease in Spain, the United States and other non-endemic countries. Acta Trop. doi: 10.1016/j.actatropica.2009.07.019
[8]
Lescure FX, Canestri A, Melliez H, Jaureguiberry S, Develoux M, et al. (2008) Chagas disease, France. Emerg Infect Dis 14: 644–646. doi: 10.3201/eid1404.070489
[9]
Croft SL, Barrett MP, Urbina JA (2005) Chemotherapy of trypanosomiases and leishmaniasis. Trends Parasitol 21: 508–512. doi: 10.1016/j.pt.2005.08.026
[10]
Sosa-Estani S, Segura EL (2006) Etiological treatment in patients infected by Trypanosoma cruzi: experiences in Argentina. Curr Opin Infect Dis 19: 583–587. doi: 10.1097/01.qco.0000247592.21295.a5
[11]
Viotti R, Vigliano C, Lococo B, Bertocchi G, Petti M, et al. (2006) Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial. Ann Intern Med 144: 724–734. doi: 10.7326/0003-4819-144-10-200605160-00006
[12]
Viotti R, Vigliano C, Lococo B, Alvarez MG, Petti M, et al. (2009) Side effects of benznidazole as treatment in chronic Chagas disease: fears and realities. Expert Rev Anti Infect Ther 7: 157–163. doi: 10.1586/14787210.7.2.157
[13]
Ribeiro I, Sevcsik AM, Alves F, Diap G, Don R, et al. (2009) New, improved treatments for Chagas disease: from the R&D pipeline to the patients. PLoS Negl Trop Dis 3: e484. doi: 10.1371/journal.pntd.0000484
[14]
Urbina JA (2010) Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches. Acta Trop 115: 55–68. doi: 10.1016/j.actatropica.2009.10.023
[15]
Janknegt R, de Marie S, Bakker-Woudenberg IA, Crommelin DJ (1992) Liposomal and lipid formulations of amphotericin B. Clinical pharmacokinetics. Clin Pharmacokinet 23: 279–291. doi: 10.2165/00003088-199223040-00004
[16]
Chen SC, Sorrell TC (2007) Antifungal agents. Med J Aust 187: 404–409.
[17]
Moen MD, Lyseng-Williamson KA, Scott LJ (2009) Liposomal amphotericin B: a review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections. Drugs 69: 361–392. doi: 10.2165/00003495-200969030-00010
[18]
Takemoto K, Yamamoto Y, Ueda Y (2006) Evaluation of antifungal pharmacodynamic characteristics of AmBisome against Candida albicans. Microbiol Immunol 50: 579–586.
[19]
Roberts CW, McLeod R, Rice DW, Ginger M, Chance ML, et al. (2003) Fatty acid and sterol metabolism: potential antimicrobial targets in apicomplexan and trypanosomatid parasitic protozoa. Mol Biochem Parasitol 126: 129–142. doi: 10.1016/S0166-6851(02)00280-3
[20]
Bern C, Adler-Moore J, Berenguer J, Boelaert M, den Boer M, et al. (2006) Liposomal amphotericin B for the treatment of visceral leishmaniasis. Clin Infect Dis 43: 917–924. doi: 10.1086/507530
[21]
Chappuis F, Sundar S, Hailu A, Ghalib H, Rijal S, et al. (2007) Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? Nat Rev Microbiol 5: 873–882. doi: 10.1038/nrmicro1748
[22]
Cruz I, Chicharro C, Nieto J, Bailo B, Canavate C, et al. (2006) Comparison of new diagnostic tools for management of pediatric Mediterranean visceral leishmaniasis. J Clin Microbiol 44: 2343–2347. doi: 10.1128/JCM.02297-05
[23]
Minodier P, Robert S, Noel G, Blanc P, Retornaz K, et al. (2005) [First-line liposomal amphotericin B for pediatric visceral leishmaniasis in southern France]. Arch Pediatr 12: 1102–1108. doi: 10.1016/j.arcped.2005.01.009
[24]
Mondal S, Bhattacharya P, Ali N (2010) Current diagnosis and treatment of visceral leishmaniasis. Expert Rev Anti Infect Ther 8: 919–944. doi: 10.1586/eri.10.78
[25]
Hunt RC, Ellar DJ (1974) Isolation of the plasma membrane of a trypanosomatid flagellate: general characterisation and lipid composition. Biochim Biophys Acta 339: 173–189. doi: 10.1016/0005-2736(74)90316-2
[26]
Urbina JA (2009) Ergosterol biosynthesis and drug development for Chagas disease. Mem Inst Oswaldo Cruz 104: Suppl 1311–318. doi: 10.1590/S0074-02762009000900041
[27]
Abitbol H, Pattini RE, Salvador J (1960) [The “in vitro” action of amphotericin B on Trypanosoma cruzi.]. Rev Soc Argent Biol 36: 41–44.
[28]
Croft SL, Walker JJ, Gutteridge WE (1988) Screening of drugs for rapid activity against Trypanosoma cruzi trypomastigotes in vitro. Trop Med Parasitol 39: 145–148.
[29]
de Castro SL, Soeiro MN, Higashi KO, Meirelles MN (1993) Differential effect of amphotericin B on the three evolutive stages of Trypanosoma cruzi and on the host cell-parasite interaction. Braz J Med Biol Res 26: 1219–1229.
[30]
Haido RM, Barreto-Bergter E (1989) Amphotericin B-induced damage of Trypanosoma cruzi epimastigotes. Chem Biol Interact 71: 91–103. doi: 10.1016/0009-2797(89)90092-6
[31]
Haido RM, Esteves MJ, Barreto-Bergter E (1992) Amphotericin B-induced carbohydrate changes on the Trypanosoma cruzi surface membrane. J Protozool 39: 609–612. doi: 10.1111/j.1550-7408.1992.tb04859.x
[32]
Horvath AE, Zierdt CH (1974) The effect of amphotericin B on Trypanosoma cruzi in vitro and in vivo. J Trop Med Hyg 77: 144–149.
[33]
Rolon M, Seco EM, Vega C, Nogal JJ, Escario JA, et al. (2006) Selective activity of polyene macrolides produced by genetically modified Streptomyces on Trypanosoma cruzi. Int J Antimicrob Agents 28: 104–109. doi: 10.1016/j.ijantimicag.2006.02.025
[34]
Yardley V, Croft SL (1999) In vitro and in vivo activity of amphotericin B-lipid formulations against experimental Trypanosoma cruzi infections. Am J Trop Med Hyg 61: 193–197.
[35]
Zingales B, Andrade SG, Briones MR, Campbell DA, Chiari E, et al. (2009) A new consensus for Trypanosoma cruzi intraspecific nomenclature: second revision meeting recommends TcI to TcVI. Mem Inst Oswaldo Cruz 104: 1051–1054. doi: 10.1590/S0074-02762009000700021
[36]
Talliaferro WH, Pizzi T (1955) Connective tissue reactions in normal and immunized mice to a reticulotropic strain of T. cruzi. J Infect Dis 96: 199–226. doi: 10.1093/infdis/96.3.199
[37]
Bustamante JM, Bixby LM, Tarleton RL (2008) Drug-induced cure drives conversion to a stable and protective CD8+ T central memory response in chronic Chagas disease. Nat Med 14: 542–550. doi: 10.1038/nm1744
[38]
Ye X, Ding J, Zhou X, Chen G, Liu SF (2008) Divergent roles of endothelial NF-kappaB in multiple organ injury and bacterial clearance in mouse models of sepsis. J Exp Med 205: 1303–1315. doi: 10.1084/jem.20071393
[39]
Cummings KL, Tarleton RL (2003) Rapid quantitation of Trypanosoma cruzi in host tissue by real-time PCR. Mol Biochem Parasitol 129: 53–59. doi: 10.1016/S0166-6851(03)00093-8
[40]
Virreira M, Martinez S, Alonso-Vega C, Torrico F, Solano M, et al. (2006) Amniotic fluid is not useful for diagnosis of congenital Trypanosoma cruzi infection. Am J Trop Med Hyg 75: 1082–1084.
[41]
Virreira M, Truyens C, Alonso-Vega C, Brutus L, Jijena J, et al. (2007) Comparison of Trypanosoma cruzi lineages and levels of parasitic DNA in infected mothers and their newborns. Am J Trop Med Hyg 77: 102–106.
[42]
Carlier Y, Rivera MT, Truyens C, Puissant F, Milaire J (1987) Interactions between chronic murine Trypanosoma cruzi infection and pregnancy: fetal growth retardation. Am J Trop Med Hyg 37: 534–540.
[43]
Carlier Y, Rivera MT, Truyens C, Goldman M, Lambert P, et al. (1987) Pregnancy and humoral immune response in mice chronically infected by Trypanosoma cruzi. Infect Immun 55: 2496–2501.
[44]
Combs TP, Nagajyothi , Mukherjee S, de Almeida CJ, Jelicks LA, et al. (2005) The adipocyte as an important target cell for Trypanosoma cruzi infection. J Biol Chem 280: 24085–24094. doi: 10.1074/jbc.M412802200
[45]
Andrade SG, Magalhaes JB, Pontes AL (1985) Evaluation of chemotherapy with benznidazole and nifurtimox in mice infected with Trypanosoma cruzi strains of different types. Bull World Health Organ 63: 721–726.
[46]
Sardinha LR, Mosca T, Elias RM, do Nascimento RS, Goncalves LA, et al. (2010) The liver plays a major role in clearance and destruction of blood trypomastigotes in Trypanosoma cruzi chronically infected mice. PLoS Negl Trop Dis 4: e578. doi: 10.1371/journal.pntd.0000578
[47]
Scharfstein J, Barcinski MA, Leon LL (1982) Induction of the acute-phase protein serum amyloid P in experimental Chagas' disease. Infect Immun 35: 46–51.
[48]
Bickerstaff MC, Botto M, Hutchinson WL, Herbert J, Tennent GA, et al. (1999) Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nat Med 5: 694–697. doi: 10.1038/9544
[49]
Hutchinson WL, Noble GE, Hawkins PN, Pepys MB (1994) The pentraxins, C-reactive protein and serum amyloid P component, are cleared and catabolized by hepatocytes in vivo. J Clin Invest 94: 1390–1396. doi: 10.1172/JCI117474
[50]
Ramos H, Valdivieso E, Gamargo M, Dagger F, Cohen BE (1996) Amphotericin B kills unicellular leishmanias by forming aqueous pores permeable to small cations and anions. J Membr Biol 152: 65–75. doi: 10.1007/s002329900086