In vitro susceptibility of Trypanosoma cruzi strains from Santander, Colombia, to hexadecylphosphocholine (miltefosine), nifurtimox and benznidazole
Keywords:
Trypanosoma cruzi, Chagas disease, miltefosine benznidazole, nifurtimox, drug therapy, Colombia
Abstract
Introduction. The current chemotherapy for Chagas disease is unsatisfactory with only two drugs available for treatment. Research to discover new drugs for Chagas disease is urgent. Hexadecyl-phosphocholine (HPC, miltefosine) has been demonstrated to have in vitro activity against Trypanosoma cruzi parasites, but its activity on different Colombian T. cruzi strains is not known.Objective. To evaluate the in vitro susceptibility of T. cruzi strains isolated from humans and vectors in Santander, Colombia. to miltefosine, nifurtimox and benznidazole.
Materials and methods. Eight T. cruzi Colombian strains and three reference strains (Esmeraldo, SilvioX10 and Y) were studied. Drug activities against extracellular epimastigotes and intracellular amastigotes were determined by microscopic counting. The results were expressed as the concentrations that inhibited 50% and 90% growth (IC50 and IC90).
Results. For miltefosine a similar range of drug activity was observed against all the Colombian strains, all parasites being more susceptible to miltefosine than to the reference drugs. The intracellular amastigotes were more susceptible to miltefosine (IC50 0.08 to 0.63 μM and IC90 0.21 to 2.21 μM) than extracellular forms (IC50 <0.92 to 2.29 μM and IC90 1.38 to 4.76 μM). For reference drugs, parasites were more susceptible to nifurtimox than to benznidazole and some differences in activity of benznidazole between T. cruzi strains was observed.
Conclusions. The results showed the significant in vitro activity of miltefosine against T. cruzi stages, and the expected results for the reference drugs. Further in vivo studies with miltefosine are planned.
Downloads
Download data is not yet available.
References
1. World Health Organization. Tropical disease research, progress 2003-2004: 17th Programme Report of the UNICEF/UNDP/World Bank/WHO. Special Programme for Research and Training in Tropical Diseases. Report No. 17. Geneva: WHO; 2005.
2. Brisse S, Barnabe C, Tibayrenc M. Identification of six Trypanosoma cruzi phylogenetic lineages by random amplified polymorphic DNA and multilocus enzyme electrophoresis. Int J Parasitol. 2000;30:35-44.
3. Saravia NG, Holguin AF, Cibulskis RE, D’Alessandro A. Divergent isoenzyme profiles of sylvatic and domiciliary Trypanosoma cruzi in the eastern plains, piedmont, and highlands of Colombia. Am J Trop Med Hyg. 1987;36:59-69.
4. Ruiz-García M, Montilla M, Nicholls SO, Angarita L, Álvarez D. Genetic relationships and spatial genetic structure among clonal stocks of Trypanosoma cruzi in Colombia. Heredity. 2000;85:318-27.
5. Cuervo P, Cupolillo E, Segura I, Saravia N, Fernandes O. Genetic diversity of Colombian sylvatic Trypanosoma cruzi isolates revealed by the ribosomal DNA. Mem Inst Oswaldo Cruz. 2002;97:877-80.
6. Montilla MM, Guhl F, Jaramillo C, Nicholls S, Barnabe C, Bosseno MF, et al. Isoenzyme clustering of Trypanosomatidae Colombian populations. Am J Trop Med Hyg. 2002;66:394-400.
7. Salazar A, Schijman AG, Triana-Chávez O. High variability of Colombian Trypanosoma cruzi lineage I stocks as revealed by low-stringency single primer-PCR minicircle signatures. Acta Trop. 2006;100:110-8.
8. Moncayo A. Chagas disease: current epidemiological trends after the interruption of vectorial and transfusional transmission in the Southern Cone countries. Mem Inst Oswaldo Cruz. 2003;98:577-91.
9. Gutiérrez R, Angulo VM, Tarazona Z, Britto C, Fernandes O. Comparison of four serological tests for the diagnosis of Chagas disease in a Colombian endemic area. Parasitology. 2004;129:439-44.
10. Sosa S, Segura E. Tratamiento de la infección por Trypanosoma cruzi en fase indeterminada. Experiencia y normatización actual en la Argentina. Medicina. 1999;59(Suppl.2):166-70.
11. Lauria-Pires L, Braga MS, Vexenat AC, Nitz N, Simoes-Barbosa A, Tinoco DL, et al. Progressive chronic Chagas heart disease ten years after treatment with anti-Trypanosoma cruzi nitroderivatives. Am J Trop Med Hyg. 2000;63:111-8.
12. Urbina JA, Docampo R. Specific chemotherapy of Chagas disease: controversies and advances. Trends Parasitol. 2003;19:495-501.
13. Jannin J, Villa L. An overview of Chagas disease treat-ment. Mem Inst Oswaldo Cruz. 2007;102(Suppl.1):95-7.
14. Bhattacharya SK, Sinha PK, Sundar S, Thakur CP, Jha TK, Pandey K, et al. Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis. J Infect Dis. 2007;196:591-8.
15. Soto J, Soto P. Miltefosina oral para el tratamiento de la leishmaniasis. Biomédica. 2006;26(Suppl.1):207-17.
16. Croft SL, Seifert K, Duchene M. Antiprotozoal activities of phospholipid analogues. Mol Biochem Parasitol. 2003;126:165-72.
17. Saraiva VB, Gibaldi D, Previato JO, Mendonca-Previato L, Bozza MT, Freire-De-Lima CG, et al. Proinflammatory and cytotoxic effects of hexadecylphosphocholine (miltefosine) against drug-resistant strains of Trypanosoma cruzi. Antimicrob Agents Chemother. 2002;46:3472-7.
18. Lira R, Contreras LM, Rita RM, Urbina JA. Mechanism of action of anti-proliferative lysophospholipid analogues against the protozoan parasite Trypanosoma cruzi: potentiation of in vitro activity by the sterol biosynthesis inhibitor ketoconazole. J Antimicrob Chemother. 2001;47:537-46.
19. Santa-Rita RM, Santos H, Meirelles MN, de Castro SL. Effect of the alkyl-lysophospholipids on the proliferation and differentiation of Trypanosoma cruzi. Acta Trop. 2000;75:219-28.
20. Santa-Rita RM, Lira R, Barbosa HS, Urbina JA, de Castro SL. Anti-proliferative synergy of lysophospholipid analogues and ketoconazole against Trypanosoma cruzi (Kinetoplastida: Trypanosomatidae): cellular and ultrastructural analysis. J Antimicrob Chemother. 2005;55:780-4.
21. Andrade SG, Andrade V, Brodskyn C, Magalhaes JB, Netto MB. Immunological response of Swiss mice to infection with three different strains of Trypanosoma cruzi. Ann Trop Med Parasitol. 1985;79:397-407.
22. Filardi LS, Brener Z. Susceptibility and natural resistance of Trypanosoma cruzi strains to drugs used clinically in Chagas disease. Trans R Soc Trop Med Hyg. 1987;81:755-9.
23. Revollo S, Oury B, Laurent JP, Barnabe C, Quesney V, Carriere V, et al. Trypanosoma cruzi: impact of clonal evolution of the parasite on its biological and medical properties. Exp Parasitol. 1998;89:30-9.
24. Croft SL, Snowdon D, Yardley V. The activities of four anticancer alkyllysophospholipids against Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei. J Antimicrob Chemother. 1996;38:1041-7.
25. Klenner T, Beckers T, Nooter K, Holtmann H. Influence of hexadecylphosphocholine (miltefosine) on cytokine synthesis and biological responses. Adv Exp Med Biol. 1996;416:181-7.
26. Escobar P, Matu S, Marques C, Croft SL. Sensitivities of Leishmania species to hexadecylphosphocholine (miltefosine), ET-18-OCH(3) (edelfosine) and ampho-tericin B. Acta Trop. 2002;81:151-7.
27. Soto J, Arana BA, Toledo J, Rizzo N, Vega JC, Díaz A, et al. Miltefosine for new world cutaneous leishmaniasis. Clin Infect Dis. 2004;38:1266-72.
28. Escobar P, Yardley V, Croft SL. Activities of hexadecylphosphocholine (miltefosine), AmBisome, and sodium stibogluconate (Pentostam) against Leishmania donovani in immunodeficient scid mice. Antimicrob Agents Chemother. 2001;45:1872-5.
29. Murray HW, Delph-Etienne S. Visceral leishmanicidal activity of hexadecylphosphocholine (miltefosine) in mice deficient in T cells and activated macrophage microbicidal mechanisms. J Infect Dis. 2000;181:795-9.
30. Maya JD, Repetto Y, Agosin M, Ojeda JM, Téllez R, Gaule C, et al. Effects of nifurtimox and benznidazole upon glutathione and trypanothione content in epimastigote, trypomastigote and amastigote forms of Trypanosoma cruzi. Mol Biochem Parasitol. 1997;86:101-6.
31. de Castro SL. The challenge of Chagas’ disease chemotherapy: an update of drugs assayed against Trypanosoma cruzi. Acta Trop. 1993;53:83-98.
32. Andrade SG, Rassi A, Magalhaes JB, Ferriolli Filho F, Luquetti AO. Specific chemotherapy of Chagas disease: a comparison between the response in patients and experimental animals inoculated with the same strains. Trans R Soc Trop Med Hyg. 1992;86:624-6.
33. Toledo MJ, Guilherme AL, da Silva JC, de Gasperi MV, Mendes AP, Gomes ML, et al. Trypanosoma cruzi: chemotherapy with benznidazole in mice inoculated with strains from Parana state and from different endemic areas of Brazil. Rev Inst Med Trop Sao Paulo. 1997;39:283-90.
34. Murta SM, Gazzinelli RT, Brener Z, Romanha AJ. Molecular characterization of susceptible and naturally resistant strains of Trypanosoma cruzi to benznidazole and nifurtimox. Mol Biochem Parasitol. 1998;93:203-14.
35. Laurent JP, Barnabe C, Quesney V, Noel S, Tibayrenc M. Impact of clonal evolution on the biological diversity of Trypanosoma cruzi. Parasitology. 1997;114:213-8.
36. de Lana M, da Silveira A, Barnabe C, Quesney V, Noel S, Tibayrenc M. Trypanosoma cruzi: compared vectorial transmissibility of three major clonal genotypes by Triatoma infestans. Exp Parasitol. 1998;90:20-5.
37. Toledo MJ, de Lana M, Carneiro CM, Bahia MT, Machado-Coelho GL, Veloso VM, et al. Impact of Trypanosoma cruzi clonal evolution on its biological properties in mice. Exp Parasitol. 2002;100:161-72.
38. Toledo MJ, Bahia MT, Carneiro CM, Martins-Filho OA, Tibayrenc M, Barnabe C, et al. Chemotherapy with benznidazole and itraconazole for mice infected with different Trypanosoma cruzi clonal genotypes. Antimicrob Agents Chemother. 2003;47:223-30.
39. Villarreal D, Barnabe C, Sereno D, Tibayrenc M. Lack of correlation between in vitro susceptibility to benznidazole and phylogenetic diversity of Trypanosoma cruzi, the agent of Chagas disease. Exp Parasitol. 2004;108:24-31.
2. Brisse S, Barnabe C, Tibayrenc M. Identification of six Trypanosoma cruzi phylogenetic lineages by random amplified polymorphic DNA and multilocus enzyme electrophoresis. Int J Parasitol. 2000;30:35-44.
3. Saravia NG, Holguin AF, Cibulskis RE, D’Alessandro A. Divergent isoenzyme profiles of sylvatic and domiciliary Trypanosoma cruzi in the eastern plains, piedmont, and highlands of Colombia. Am J Trop Med Hyg. 1987;36:59-69.
4. Ruiz-García M, Montilla M, Nicholls SO, Angarita L, Álvarez D. Genetic relationships and spatial genetic structure among clonal stocks of Trypanosoma cruzi in Colombia. Heredity. 2000;85:318-27.
5. Cuervo P, Cupolillo E, Segura I, Saravia N, Fernandes O. Genetic diversity of Colombian sylvatic Trypanosoma cruzi isolates revealed by the ribosomal DNA. Mem Inst Oswaldo Cruz. 2002;97:877-80.
6. Montilla MM, Guhl F, Jaramillo C, Nicholls S, Barnabe C, Bosseno MF, et al. Isoenzyme clustering of Trypanosomatidae Colombian populations. Am J Trop Med Hyg. 2002;66:394-400.
7. Salazar A, Schijman AG, Triana-Chávez O. High variability of Colombian Trypanosoma cruzi lineage I stocks as revealed by low-stringency single primer-PCR minicircle signatures. Acta Trop. 2006;100:110-8.
8. Moncayo A. Chagas disease: current epidemiological trends after the interruption of vectorial and transfusional transmission in the Southern Cone countries. Mem Inst Oswaldo Cruz. 2003;98:577-91.
9. Gutiérrez R, Angulo VM, Tarazona Z, Britto C, Fernandes O. Comparison of four serological tests for the diagnosis of Chagas disease in a Colombian endemic area. Parasitology. 2004;129:439-44.
10. Sosa S, Segura E. Tratamiento de la infección por Trypanosoma cruzi en fase indeterminada. Experiencia y normatización actual en la Argentina. Medicina. 1999;59(Suppl.2):166-70.
11. Lauria-Pires L, Braga MS, Vexenat AC, Nitz N, Simoes-Barbosa A, Tinoco DL, et al. Progressive chronic Chagas heart disease ten years after treatment with anti-Trypanosoma cruzi nitroderivatives. Am J Trop Med Hyg. 2000;63:111-8.
12. Urbina JA, Docampo R. Specific chemotherapy of Chagas disease: controversies and advances. Trends Parasitol. 2003;19:495-501.
13. Jannin J, Villa L. An overview of Chagas disease treat-ment. Mem Inst Oswaldo Cruz. 2007;102(Suppl.1):95-7.
14. Bhattacharya SK, Sinha PK, Sundar S, Thakur CP, Jha TK, Pandey K, et al. Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis. J Infect Dis. 2007;196:591-8.
15. Soto J, Soto P. Miltefosina oral para el tratamiento de la leishmaniasis. Biomédica. 2006;26(Suppl.1):207-17.
16. Croft SL, Seifert K, Duchene M. Antiprotozoal activities of phospholipid analogues. Mol Biochem Parasitol. 2003;126:165-72.
17. Saraiva VB, Gibaldi D, Previato JO, Mendonca-Previato L, Bozza MT, Freire-De-Lima CG, et al. Proinflammatory and cytotoxic effects of hexadecylphosphocholine (miltefosine) against drug-resistant strains of Trypanosoma cruzi. Antimicrob Agents Chemother. 2002;46:3472-7.
18. Lira R, Contreras LM, Rita RM, Urbina JA. Mechanism of action of anti-proliferative lysophospholipid analogues against the protozoan parasite Trypanosoma cruzi: potentiation of in vitro activity by the sterol biosynthesis inhibitor ketoconazole. J Antimicrob Chemother. 2001;47:537-46.
19. Santa-Rita RM, Santos H, Meirelles MN, de Castro SL. Effect of the alkyl-lysophospholipids on the proliferation and differentiation of Trypanosoma cruzi. Acta Trop. 2000;75:219-28.
20. Santa-Rita RM, Lira R, Barbosa HS, Urbina JA, de Castro SL. Anti-proliferative synergy of lysophospholipid analogues and ketoconazole against Trypanosoma cruzi (Kinetoplastida: Trypanosomatidae): cellular and ultrastructural analysis. J Antimicrob Chemother. 2005;55:780-4.
21. Andrade SG, Andrade V, Brodskyn C, Magalhaes JB, Netto MB. Immunological response of Swiss mice to infection with three different strains of Trypanosoma cruzi. Ann Trop Med Parasitol. 1985;79:397-407.
22. Filardi LS, Brener Z. Susceptibility and natural resistance of Trypanosoma cruzi strains to drugs used clinically in Chagas disease. Trans R Soc Trop Med Hyg. 1987;81:755-9.
23. Revollo S, Oury B, Laurent JP, Barnabe C, Quesney V, Carriere V, et al. Trypanosoma cruzi: impact of clonal evolution of the parasite on its biological and medical properties. Exp Parasitol. 1998;89:30-9.
24. Croft SL, Snowdon D, Yardley V. The activities of four anticancer alkyllysophospholipids against Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei. J Antimicrob Chemother. 1996;38:1041-7.
25. Klenner T, Beckers T, Nooter K, Holtmann H. Influence of hexadecylphosphocholine (miltefosine) on cytokine synthesis and biological responses. Adv Exp Med Biol. 1996;416:181-7.
26. Escobar P, Matu S, Marques C, Croft SL. Sensitivities of Leishmania species to hexadecylphosphocholine (miltefosine), ET-18-OCH(3) (edelfosine) and ampho-tericin B. Acta Trop. 2002;81:151-7.
27. Soto J, Arana BA, Toledo J, Rizzo N, Vega JC, Díaz A, et al. Miltefosine for new world cutaneous leishmaniasis. Clin Infect Dis. 2004;38:1266-72.
28. Escobar P, Yardley V, Croft SL. Activities of hexadecylphosphocholine (miltefosine), AmBisome, and sodium stibogluconate (Pentostam) against Leishmania donovani in immunodeficient scid mice. Antimicrob Agents Chemother. 2001;45:1872-5.
29. Murray HW, Delph-Etienne S. Visceral leishmanicidal activity of hexadecylphosphocholine (miltefosine) in mice deficient in T cells and activated macrophage microbicidal mechanisms. J Infect Dis. 2000;181:795-9.
30. Maya JD, Repetto Y, Agosin M, Ojeda JM, Téllez R, Gaule C, et al. Effects of nifurtimox and benznidazole upon glutathione and trypanothione content in epimastigote, trypomastigote and amastigote forms of Trypanosoma cruzi. Mol Biochem Parasitol. 1997;86:101-6.
31. de Castro SL. The challenge of Chagas’ disease chemotherapy: an update of drugs assayed against Trypanosoma cruzi. Acta Trop. 1993;53:83-98.
32. Andrade SG, Rassi A, Magalhaes JB, Ferriolli Filho F, Luquetti AO. Specific chemotherapy of Chagas disease: a comparison between the response in patients and experimental animals inoculated with the same strains. Trans R Soc Trop Med Hyg. 1992;86:624-6.
33. Toledo MJ, Guilherme AL, da Silva JC, de Gasperi MV, Mendes AP, Gomes ML, et al. Trypanosoma cruzi: chemotherapy with benznidazole in mice inoculated with strains from Parana state and from different endemic areas of Brazil. Rev Inst Med Trop Sao Paulo. 1997;39:283-90.
34. Murta SM, Gazzinelli RT, Brener Z, Romanha AJ. Molecular characterization of susceptible and naturally resistant strains of Trypanosoma cruzi to benznidazole and nifurtimox. Mol Biochem Parasitol. 1998;93:203-14.
35. Laurent JP, Barnabe C, Quesney V, Noel S, Tibayrenc M. Impact of clonal evolution on the biological diversity of Trypanosoma cruzi. Parasitology. 1997;114:213-8.
36. de Lana M, da Silveira A, Barnabe C, Quesney V, Noel S, Tibayrenc M. Trypanosoma cruzi: compared vectorial transmissibility of three major clonal genotypes by Triatoma infestans. Exp Parasitol. 1998;90:20-5.
37. Toledo MJ, de Lana M, Carneiro CM, Bahia MT, Machado-Coelho GL, Veloso VM, et al. Impact of Trypanosoma cruzi clonal evolution on its biological properties in mice. Exp Parasitol. 2002;100:161-72.
38. Toledo MJ, Bahia MT, Carneiro CM, Martins-Filho OA, Tibayrenc M, Barnabe C, et al. Chemotherapy with benznidazole and itraconazole for mice infected with different Trypanosoma cruzi clonal genotypes. Antimicrob Agents Chemother. 2003;47:223-30.
39. Villarreal D, Barnabe C, Sereno D, Tibayrenc M. Lack of correlation between in vitro susceptibility to benznidazole and phylogenetic diversity of Trypanosoma cruzi, the agent of Chagas disease. Exp Parasitol. 2004;108:24-31.
How to Cite
1.
Escobar P, Luna KP, Hernández IP, Rueda CM, Zorro MM, Croft SL. In vitro susceptibility of Trypanosoma cruzi strains from Santander, Colombia, to hexadecylphosphocholine (miltefosine), nifurtimox and benznidazole. Biomed. [Internet]. 2009 Sep. 1 [cited 2026 Jan. 12];29(3):448-55. Available from: https://revistabiomedicaorg.biteca.online/index.php/biomedica/article/view/15
Some similar items:
- Luis C. Orozco, Diana Camargo, Myriam C. López, Sofía Duque, Luis E. Gualdrón, Elvia Cáceres, Margarita Ronderos, Maritza Rey, Augusto Corredor, Immunodiagnosis of Trypanosoma cruzi infection in humans using ELISA on blood collected on filter paper , Biomedica: Vol. 19 No. 2 (1999)
- Constanza Pardo, Ricardo Cendales, Survival analysis of cervical cancer patients , Biomedica: Vol. 29 No. 3 (2009)
- Iveth J. González, Metacaspases and their role in the life cycle of human protozoan parasites , Biomedica: Vol. 29 No. 3 (2009)
- Raúl Murillo, Ricardo Cendales, Carolina Wiesner, Marion Piñeros, Sandra Tovar, Effectiveness of cytology-based cervical cancer screening in the Colombian health system , Biomedica: Vol. 29 No. 3 (2009)
- Sandra Lorena Girón, Julio César Mateus, Fabián Méndez, Impact of an open waste disposal site on the occurrence of respiratory symptoms and on health care costs of children , Biomedica: Vol. 29 No. 3 (2009)
- José Joaquín Carvajal, Ligia Inés Moncada, Mauricio Humberto Rodríguez, Ligia del Pilar Pérez, Víctor Alberto Olano, Characterization of Aedes albopictus (Skuse, 1894) (Diptera:Culicidae) larval habitats near the Amazon River in Colombia , Biomedica: Vol. 29 No. 3 (2009)
- Andrés Páez, Gloria Rey, Carlos Agudelo, Alvaro Dulce, Edgar Parra, Hernando Díaz-Granados, Damaris Heredia, Luis Polo, Outbreak of urban rabies transmitted by dogs in Santa Marta, northern Colombia , Biomedica: Vol. 29 No. 3 (2009)
- Gustavo Pradilla, Julio César Mantilla, Reynaldo Badillo, Human rabies encephalitis by a vampire bat bite in an urban area of Colombia , Biomedica: Vol. 29 No. 2 (2009)
- Mauricio Beltrán, María Cristina Navas, María Patricia Arbeláez, Jorge Donado, Sergio Jaramillo, Fernando De la Hoz, Cecilia Estrada, Lucía del Pilar Cortés, Amalia de Maldonado, Gloria Rey, Seroprevalence of hepatitis B virus and human immunodeficiency virus infection in a population of multiply-transfused patients in Colombia , Biomedica: Vol. 29 No. 2 (2009)
- Rosa Magdalena Uscátegui, Adriana M. Correa, Jaime Carmona-Fonseca, Changes in retinol, hemoglobin and ferritin concentrations in Colombian children with malaria , Biomedica: Vol. 29 No. 2 (2009)
Issue
Section
Original articles
| Article metrics | |
|---|---|
| Abstract views | |
| Galley vies | |
| PDF Views | |
| HTML views | |
| Other views | |
Escanea para compartir
