In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approach

Autores
Strauss, Mariana; Rodrigues, Jean Henrique S.; Lo Presti, Maria Silvina; Bazán, Paola Carolina; Báez, Alejandra Lidia; Paglini Oliva, Patricia; Nakamura, Celso Vataru; Bustamante, Juan Manuel; Rivarola, Hector Walter
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Combination therapies based on the available drugs have been proposed as promising therapeutic alternatives for many diseases. Clomipramine (CLO) has been found to modify the evolution of the experimental infection. The objective of this study was to evaluate the combined effect of benznidazole (BZ) and clomipramine (CLO) against different life-stages of Trypanosoma cruzi in vitro and their efficacy in a murine model. Life-stages of T. cruzi, BZ-partially-resistant (Y) strain, were incubated with BZ and CLO and isobolograms and combination index (CI) were obtained. Swiss mice were infected with trypomastigotes and different treatment schedules were performed, each of which consisted of 30 consecutive daily doses. Treatment efficacy was evaluated by comparing parasitemia, qPCR, survival and histological analysis. These results were analyzed using multivariate analysis to determine the combined effect of the drugs in vivo. CLO + BZ showed synergistic activity in vitro against the clinically relevant life-stages of T. cruzi. The most susceptible forms were the intracellular amastigotes (CI: 0.20), followed by trypomastigotes (CI: 0.60), with no toxicity upon mammalian cells. The combination of both drugs CLO (1.25 mg/kg) and BZ (6.25 mg/kg), in vivo, significantly diminished the parasitic load in blood and the mortality rate. CLO + BZ presented a similar inflammatory response in cardiac and skeletal muscle (amount of inflammatory cells) to BZ (6.25 mg/kg). Finally, the results from the principal component analysis reaffirmed that both drugs administered in combination presented higher activity compared with the individual administration in the acute experimental model.
Fil: Strauss, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina
Fil: Rodrigues, Jean Henrique S.. Universidade Estadual de Maringá; Brasil
Fil: Lo Presti, Maria Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina
Fil: Bazán, Paola Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina
Fil: Báez, Alejandra Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina
Fil: Paglini Oliva, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina
Fil: Nakamura, Celso Vataru. Universidade Estadual de Maringá; Brasil
Fil: Bustamante, Juan Manuel. University of Georgia; Estados Unidos
Fil: Rivarola, Hector Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina
Materia
BENZNIDAZOLE
CLOMIPRAMINE
SYNERGISM
TRYPANOSOMA CRUZI
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/87068
Acceder
id CONICETDig_9cb10d155b31482cac660655d9b0cb33
oai_identifier_str oai:ri.conicet.gov.ar:11336/87068
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approachStrauss, MarianaRodrigues, Jean Henrique S.Lo Presti, Maria SilvinaBazán, Paola CarolinaBáez, Alejandra LidiaPaglini Oliva, PatriciaNakamura, Celso VataruBustamante, Juan ManuelRivarola, Hector WalterBENZNIDAZOLECLOMIPRAMINESYNERGISMTRYPANOSOMA CRUZIhttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Combination therapies based on the available drugs have been proposed as promising therapeutic alternatives for many diseases. Clomipramine (CLO) has been found to modify the evolution of the experimental infection. The objective of this study was to evaluate the combined effect of benznidazole (BZ) and clomipramine (CLO) against different life-stages of Trypanosoma cruzi in vitro and their efficacy in a murine model. Life-stages of T. cruzi, BZ-partially-resistant (Y) strain, were incubated with BZ and CLO and isobolograms and combination index (CI) were obtained. Swiss mice were infected with trypomastigotes and different treatment schedules were performed, each of which consisted of 30 consecutive daily doses. Treatment efficacy was evaluated by comparing parasitemia, qPCR, survival and histological analysis. These results were analyzed using multivariate analysis to determine the combined effect of the drugs in vivo. CLO + BZ showed synergistic activity in vitro against the clinically relevant life-stages of T. cruzi. The most susceptible forms were the intracellular amastigotes (CI: 0.20), followed by trypomastigotes (CI: 0.60), with no toxicity upon mammalian cells. The combination of both drugs CLO (1.25 mg/kg) and BZ (6.25 mg/kg), in vivo, significantly diminished the parasitic load in blood and the mortality rate. CLO + BZ presented a similar inflammatory response in cardiac and skeletal muscle (amount of inflammatory cells) to BZ (6.25 mg/kg). Finally, the results from the principal component analysis reaffirmed that both drugs administered in combination presented higher activity compared with the individual administration in the acute experimental model.Fil: Strauss, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Rodrigues, Jean Henrique S.. Universidade Estadual de Maringá; BrasilFil: Lo Presti, Maria Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Bazán, Paola Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Báez, Alejandra Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Paglini Oliva, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Nakamura, Celso Vataru. Universidade Estadual de Maringá; BrasilFil: Bustamante, Juan Manuel. University of Georgia; Estados UnidosFil: Rivarola, Hector Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaAcademic Press Inc Elsevier Science2018-06-16info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/87068Strauss, Mariana; Rodrigues, Jean Henrique S.; Lo Presti, Maria Silvina; Bazán, Paola Carolina; Báez, Alejandra Lidia; et al.; In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approach; Academic Press Inc Elsevier Science; Experimental Parasitology; 189; 16-6-2018; 19-270014-4894CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://linkinghub.elsevier.com/retrieve/pii/S0014489417306537info:eu-repo/semantics/altIdentifier/doi/10.1016/j.exppara.2018.04.016info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:48:12Zoai:ri.conicet.gov.ar:11336/87068instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:48:13.103CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approach
title In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approach
spellingShingle In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approach
Strauss, Mariana
BENZNIDAZOLE
CLOMIPRAMINE
SYNERGISM
TRYPANOSOMA CRUZI
title_short In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approach
title_full In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approach
title_fullStr In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approach
title_full_unstemmed In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approach
title_sort In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approach
dc.creator.none.fl_str_mv Strauss, Mariana
Rodrigues, Jean Henrique S.
Lo Presti, Maria Silvina
Bazán, Paola Carolina
Báez, Alejandra Lidia
Paglini Oliva, Patricia
Nakamura, Celso Vataru
Bustamante, Juan Manuel
Rivarola, Hector Walter
author Strauss, Mariana
author_facet Strauss, Mariana
Rodrigues, Jean Henrique S.
Lo Presti, Maria Silvina
Bazán, Paola Carolina
Báez, Alejandra Lidia
Paglini Oliva, Patricia
Nakamura, Celso Vataru
Bustamante, Juan Manuel
Rivarola, Hector Walter
author_role author
author2 Rodrigues, Jean Henrique S.
Lo Presti, Maria Silvina
Bazán, Paola Carolina
Báez, Alejandra Lidia
Paglini Oliva, Patricia
Nakamura, Celso Vataru
Bustamante, Juan Manuel
Rivarola, Hector Walter
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv BENZNIDAZOLE
CLOMIPRAMINE
SYNERGISM
TRYPANOSOMA CRUZI
topic BENZNIDAZOLE
CLOMIPRAMINE
SYNERGISM
TRYPANOSOMA CRUZI
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Combination therapies based on the available drugs have been proposed as promising therapeutic alternatives for many diseases. Clomipramine (CLO) has been found to modify the evolution of the experimental infection. The objective of this study was to evaluate the combined effect of benznidazole (BZ) and clomipramine (CLO) against different life-stages of Trypanosoma cruzi in vitro and their efficacy in a murine model. Life-stages of T. cruzi, BZ-partially-resistant (Y) strain, were incubated with BZ and CLO and isobolograms and combination index (CI) were obtained. Swiss mice were infected with trypomastigotes and different treatment schedules were performed, each of which consisted of 30 consecutive daily doses. Treatment efficacy was evaluated by comparing parasitemia, qPCR, survival and histological analysis. These results were analyzed using multivariate analysis to determine the combined effect of the drugs in vivo. CLO + BZ showed synergistic activity in vitro against the clinically relevant life-stages of T. cruzi. The most susceptible forms were the intracellular amastigotes (CI: 0.20), followed by trypomastigotes (CI: 0.60), with no toxicity upon mammalian cells. The combination of both drugs CLO (1.25 mg/kg) and BZ (6.25 mg/kg), in vivo, significantly diminished the parasitic load in blood and the mortality rate. CLO + BZ presented a similar inflammatory response in cardiac and skeletal muscle (amount of inflammatory cells) to BZ (6.25 mg/kg). Finally, the results from the principal component analysis reaffirmed that both drugs administered in combination presented higher activity compared with the individual administration in the acute experimental model.
Fil: Strauss, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina
Fil: Rodrigues, Jean Henrique S.. Universidade Estadual de Maringá; Brasil
Fil: Lo Presti, Maria Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina
Fil: Bazán, Paola Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina
Fil: Báez, Alejandra Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina
Fil: Paglini Oliva, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina
Fil: Nakamura, Celso Vataru. Universidade Estadual de Maringá; Brasil
Fil: Bustamante, Juan Manuel. University of Georgia; Estados Unidos
Fil: Rivarola, Hector Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina
description Combination therapies based on the available drugs have been proposed as promising therapeutic alternatives for many diseases. Clomipramine (CLO) has been found to modify the evolution of the experimental infection. The objective of this study was to evaluate the combined effect of benznidazole (BZ) and clomipramine (CLO) against different life-stages of Trypanosoma cruzi in vitro and their efficacy in a murine model. Life-stages of T. cruzi, BZ-partially-resistant (Y) strain, were incubated with BZ and CLO and isobolograms and combination index (CI) were obtained. Swiss mice were infected with trypomastigotes and different treatment schedules were performed, each of which consisted of 30 consecutive daily doses. Treatment efficacy was evaluated by comparing parasitemia, qPCR, survival and histological analysis. These results were analyzed using multivariate analysis to determine the combined effect of the drugs in vivo. CLO + BZ showed synergistic activity in vitro against the clinically relevant life-stages of T. cruzi. The most susceptible forms were the intracellular amastigotes (CI: 0.20), followed by trypomastigotes (CI: 0.60), with no toxicity upon mammalian cells. The combination of both drugs CLO (1.25 mg/kg) and BZ (6.25 mg/kg), in vivo, significantly diminished the parasitic load in blood and the mortality rate. CLO + BZ presented a similar inflammatory response in cardiac and skeletal muscle (amount of inflammatory cells) to BZ (6.25 mg/kg). Finally, the results from the principal component analysis reaffirmed that both drugs administered in combination presented higher activity compared with the individual administration in the acute experimental model.
publishDate 2018
dc.date.none.fl_str_mv 2018-06-16
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/87068
Strauss, Mariana; Rodrigues, Jean Henrique S.; Lo Presti, Maria Silvina; Bazán, Paola Carolina; Báez, Alejandra Lidia; et al.; In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approach; Academic Press Inc Elsevier Science; Experimental Parasitology; 189; 16-6-2018; 19-27
0014-4894
CONICET Digital
CONICET
url http://hdl.handle.net/11336/87068
identifier_str_mv Strauss, Mariana; Rodrigues, Jean Henrique S.; Lo Presti, Maria Silvina; Bazán, Paola Carolina; Báez, Alejandra Lidia; et al.; In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approach; Academic Press Inc Elsevier Science; Experimental Parasitology; 189; 16-6-2018; 19-27
0014-4894
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://linkinghub.elsevier.com/retrieve/pii/S0014489417306537
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.exppara.2018.04.016
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Academic Press Inc Elsevier Science
publisher.none.fl_str_mv Academic Press Inc Elsevier Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842268910410268672
score 13.13397

Publicaciones similares