Old drugs for new uses: pharmacokinetic assessment to support Oxfendazole repurposing as a flukicidal compound

Autores
Ceballos, Laura; Cantón, Candela; Gayo, Valeria; Moreno Torrejon, Laura; Dominguez, Maria Paula; Lanusse, Carlos Edmundo; Alvarez, Luis Ignacio
Año de publicación
2018
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Introduction: Fascioliasis caused by Fasciola hepatica can cause considerable financial losses in livestock production. The main strategy for liver fluke control is based on the use of chemical-based treatments. However, the frequent use of effective flukicidal compounds had led to the development of drug resistance, largely to triclabendazole, the most extensively used drug.   Oxfendazole (OFZ) is a broad spectrum anthelmintic used as nematodicidal, without flukicidal activity at therapeutic doses (5 mg/kg). However, activity against F. hepatica has been reported after a single OFZ dose of 30 mg/kg in both sheep and pigs. The goals of the current work were 1) to compare the plasma pharmacokinetic (PK) profile of different OFZ doses in non-infected sheep, and 2) to evaluate the dose-related pattern of in vivo accumulation of OFZ/metabolites into adult F. hepatica. Materials and methods: 1) PK trial: sheep were allocated into two groups (n=6 each) and orally treated with OFZ at either 5 (OFZ5) or 30 (OFZ30) mg/kg. Blood samples were collected during 96 h post-treatment, and plasma analyzed for OFZ/metabolites by HPLC. 2) Drug accumulation trial: Animals (8) were each orally infected with seventy five (75) metacercariae of F. hepatica. Sixteen weeks after infection, animals were randomly allocated into two experimental groups (n=4) and orally treated with OFZ at either 5 or 30mg/kg. Animals were killed at different times post-treatment and samples of blood, bile, liver and adult liver flukes were obtained. Samples were analyzed by HPLC. Results and conclusions: OFZ parent drug was the main analyte detected in plasma from OFZ treated sheep. The Cmax and AUC0-t values were approx. 4-fold higher in the OFZ30 group (2.5±0.6 µg/mL and 83.7 ± 20.5 µg.h/mL, respectively), compared to that observed after the 5 mg/kg dose (0.6±0.1 µg/mL and 18.0±3.7 µg.h/mL, respectively). These differences were also reflected in the pattern of OFZ accumulation into F. hepatica, which results 332 % higher after the 30 mg/kg dose (4.28 µg/g) compared to the lower dose (0.99 µg/g). The data shown here demonstrates that the OFZ dose increment is associated with a higher plasma drug exposure and accumulation into the target parasite, which help to explain OFZ efficacy against adult liver flukes at 30 mg/kg dose. The reported pharmacological data may contribute to assess OFZ repurposing for a new use as flukicidal.
Fil: Ceballos, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Cantón, Candela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Gayo, Valeria. No especifíca;
Fil: Moreno Torrejon, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Dominguez, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Alvarez, Luis Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
14th International Congress of the European Association for Veterinary Pharmacology and Toxicology
Wroclaw
Polonia
European Association for Veterinary Pharmacology and Toxicology
Materia
OXFENDAZOLE
FASCIOLA HEPÁTICA
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:11336/173731
Acceder
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spelling Old drugs for new uses: pharmacokinetic assessment to support Oxfendazole repurposing as a flukicidal compoundCeballos, LauraCantón, CandelaGayo, ValeriaMoreno Torrejon, LauraDominguez, Maria PaulaLanusse, Carlos EdmundoAlvarez, Luis IgnacioOXFENDAZOLEFASCIOLA HEPÁTICAhttps://purl.org/becyt/ford/4.3https://purl.org/becyt/ford/4Introduction: Fascioliasis caused by Fasciola hepatica can cause considerable financial losses in livestock production. The main strategy for liver fluke control is based on the use of chemical-based treatments. However, the frequent use of effective flukicidal compounds had led to the development of drug resistance, largely to triclabendazole, the most extensively used drug.   Oxfendazole (OFZ) is a broad spectrum anthelmintic used as nematodicidal, without flukicidal activity at therapeutic doses (5 mg/kg). However, activity against F. hepatica has been reported after a single OFZ dose of 30 mg/kg in both sheep and pigs. The goals of the current work were 1) to compare the plasma pharmacokinetic (PK) profile of different OFZ doses in non-infected sheep, and 2) to evaluate the dose-related pattern of in vivo accumulation of OFZ/metabolites into adult F. hepatica. Materials and methods: 1) PK trial: sheep were allocated into two groups (n=6 each) and orally treated with OFZ at either 5 (OFZ5) or 30 (OFZ30) mg/kg. Blood samples were collected during 96 h post-treatment, and plasma analyzed for OFZ/metabolites by HPLC. 2) Drug accumulation trial: Animals (8) were each orally infected with seventy five (75) metacercariae of F. hepatica. Sixteen weeks after infection, animals were randomly allocated into two experimental groups (n=4) and orally treated with OFZ at either 5 or 30mg/kg. Animals were killed at different times post-treatment and samples of blood, bile, liver and adult liver flukes were obtained. Samples were analyzed by HPLC. Results and conclusions: OFZ parent drug was the main analyte detected in plasma from OFZ treated sheep. The Cmax and AUC0-t values were approx. 4-fold higher in the OFZ30 group (2.5±0.6 µg/mL and 83.7 ± 20.5 µg.h/mL, respectively), compared to that observed after the 5 mg/kg dose (0.6±0.1 µg/mL and 18.0±3.7 µg.h/mL, respectively). These differences were also reflected in the pattern of OFZ accumulation into F. hepatica, which results 332 % higher after the 30 mg/kg dose (4.28 µg/g) compared to the lower dose (0.99 µg/g). The data shown here demonstrates that the OFZ dose increment is associated with a higher plasma drug exposure and accumulation into the target parasite, which help to explain OFZ efficacy against adult liver flukes at 30 mg/kg dose. The reported pharmacological data may contribute to assess OFZ repurposing for a new use as flukicidal.Fil: Ceballos, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Cantón, Candela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Gayo, Valeria. No especifíca;Fil: Moreno Torrejon, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Dominguez, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Alvarez, Luis Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina14th International Congress of the European Association for Veterinary Pharmacology and ToxicologyWroclawPoloniaEuropean Association for Veterinary Pharmacology and ToxicologyWiley2018info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/173731Old drugs for new uses: pharmacokinetic assessment to support Oxfendazole repurposing as a flukicidal compound; 14th International Congress of the European Association for Veterinary Pharmacology and Toxicology; Wroclaw; Polonia; 2018; 74-740140-77831365-2885CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/toc/13652885/2018/41/S1Internacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:00:50Zoai:ri.conicet.gov.ar:11336/173731instacron: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 10:00:50.526CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Old drugs for new uses: pharmacokinetic assessment to support Oxfendazole repurposing as a flukicidal compound
title Old drugs for new uses: pharmacokinetic assessment to support Oxfendazole repurposing as a flukicidal compound
spellingShingle Old drugs for new uses: pharmacokinetic assessment to support Oxfendazole repurposing as a flukicidal compound
Ceballos, Laura
OXFENDAZOLE
FASCIOLA HEPÁTICA
title_short Old drugs for new uses: pharmacokinetic assessment to support Oxfendazole repurposing as a flukicidal compound
title_full Old drugs for new uses: pharmacokinetic assessment to support Oxfendazole repurposing as a flukicidal compound
title_fullStr Old drugs for new uses: pharmacokinetic assessment to support Oxfendazole repurposing as a flukicidal compound
title_full_unstemmed Old drugs for new uses: pharmacokinetic assessment to support Oxfendazole repurposing as a flukicidal compound
title_sort Old drugs for new uses: pharmacokinetic assessment to support Oxfendazole repurposing as a flukicidal compound
dc.creator.none.fl_str_mv Ceballos, Laura
Cantón, Candela
Gayo, Valeria
Moreno Torrejon, Laura
Dominguez, Maria Paula
Lanusse, Carlos Edmundo
Alvarez, Luis Ignacio
author Ceballos, Laura
author_facet Ceballos, Laura
Cantón, Candela
Gayo, Valeria
Moreno Torrejon, Laura
Dominguez, Maria Paula
Lanusse, Carlos Edmundo
Alvarez, Luis Ignacio
author_role author
author2 Cantón, Candela
Gayo, Valeria
Moreno Torrejon, Laura
Dominguez, Maria Paula
Lanusse, Carlos Edmundo
Alvarez, Luis Ignacio
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv OXFENDAZOLE
FASCIOLA HEPÁTICA
topic OXFENDAZOLE
FASCIOLA HEPÁTICA
purl_subject.fl_str_mv https://purl.org/becyt/ford/4.3
https://purl.org/becyt/ford/4
dc.description.none.fl_txt_mv Introduction: Fascioliasis caused by Fasciola hepatica can cause considerable financial losses in livestock production. The main strategy for liver fluke control is based on the use of chemical-based treatments. However, the frequent use of effective flukicidal compounds had led to the development of drug resistance, largely to triclabendazole, the most extensively used drug.   Oxfendazole (OFZ) is a broad spectrum anthelmintic used as nematodicidal, without flukicidal activity at therapeutic doses (5 mg/kg). However, activity against F. hepatica has been reported after a single OFZ dose of 30 mg/kg in both sheep and pigs. The goals of the current work were 1) to compare the plasma pharmacokinetic (PK) profile of different OFZ doses in non-infected sheep, and 2) to evaluate the dose-related pattern of in vivo accumulation of OFZ/metabolites into adult F. hepatica. Materials and methods: 1) PK trial: sheep were allocated into two groups (n=6 each) and orally treated with OFZ at either 5 (OFZ5) or 30 (OFZ30) mg/kg. Blood samples were collected during 96 h post-treatment, and plasma analyzed for OFZ/metabolites by HPLC. 2) Drug accumulation trial: Animals (8) were each orally infected with seventy five (75) metacercariae of F. hepatica. Sixteen weeks after infection, animals were randomly allocated into two experimental groups (n=4) and orally treated with OFZ at either 5 or 30mg/kg. Animals were killed at different times post-treatment and samples of blood, bile, liver and adult liver flukes were obtained. Samples were analyzed by HPLC. Results and conclusions: OFZ parent drug was the main analyte detected in plasma from OFZ treated sheep. The Cmax and AUC0-t values were approx. 4-fold higher in the OFZ30 group (2.5±0.6 µg/mL and 83.7 ± 20.5 µg.h/mL, respectively), compared to that observed after the 5 mg/kg dose (0.6±0.1 µg/mL and 18.0±3.7 µg.h/mL, respectively). These differences were also reflected in the pattern of OFZ accumulation into F. hepatica, which results 332 % higher after the 30 mg/kg dose (4.28 µg/g) compared to the lower dose (0.99 µg/g). The data shown here demonstrates that the OFZ dose increment is associated with a higher plasma drug exposure and accumulation into the target parasite, which help to explain OFZ efficacy against adult liver flukes at 30 mg/kg dose. The reported pharmacological data may contribute to assess OFZ repurposing for a new use as flukicidal.
Fil: Ceballos, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Cantón, Candela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Gayo, Valeria. No especifíca;
Fil: Moreno Torrejon, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Dominguez, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Alvarez, Luis Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
14th International Congress of the European Association for Veterinary Pharmacology and Toxicology
Wroclaw
Polonia
European Association for Veterinary Pharmacology and Toxicology
description Introduction: Fascioliasis caused by Fasciola hepatica can cause considerable financial losses in livestock production. The main strategy for liver fluke control is based on the use of chemical-based treatments. However, the frequent use of effective flukicidal compounds had led to the development of drug resistance, largely to triclabendazole, the most extensively used drug.   Oxfendazole (OFZ) is a broad spectrum anthelmintic used as nematodicidal, without flukicidal activity at therapeutic doses (5 mg/kg). However, activity against F. hepatica has been reported after a single OFZ dose of 30 mg/kg in both sheep and pigs. The goals of the current work were 1) to compare the plasma pharmacokinetic (PK) profile of different OFZ doses in non-infected sheep, and 2) to evaluate the dose-related pattern of in vivo accumulation of OFZ/metabolites into adult F. hepatica. Materials and methods: 1) PK trial: sheep were allocated into two groups (n=6 each) and orally treated with OFZ at either 5 (OFZ5) or 30 (OFZ30) mg/kg. Blood samples were collected during 96 h post-treatment, and plasma analyzed for OFZ/metabolites by HPLC. 2) Drug accumulation trial: Animals (8) were each orally infected with seventy five (75) metacercariae of F. hepatica. Sixteen weeks after infection, animals were randomly allocated into two experimental groups (n=4) and orally treated with OFZ at either 5 or 30mg/kg. Animals were killed at different times post-treatment and samples of blood, bile, liver and adult liver flukes were obtained. Samples were analyzed by HPLC. Results and conclusions: OFZ parent drug was the main analyte detected in plasma from OFZ treated sheep. The Cmax and AUC0-t values were approx. 4-fold higher in the OFZ30 group (2.5±0.6 µg/mL and 83.7 ± 20.5 µg.h/mL, respectively), compared to that observed after the 5 mg/kg dose (0.6±0.1 µg/mL and 18.0±3.7 µg.h/mL, respectively). These differences were also reflected in the pattern of OFZ accumulation into F. hepatica, which results 332 % higher after the 30 mg/kg dose (4.28 µg/g) compared to the lower dose (0.99 µg/g). The data shown here demonstrates that the OFZ dose increment is associated with a higher plasma drug exposure and accumulation into the target parasite, which help to explain OFZ efficacy against adult liver flukes at 30 mg/kg dose. The reported pharmacological data may contribute to assess OFZ repurposing for a new use as flukicidal.
publishDate 2018
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Old drugs for new uses: pharmacokinetic assessment to support Oxfendazole repurposing as a flukicidal compound; 14th International Congress of the European Association for Veterinary Pharmacology and Toxicology; Wroclaw; Polonia; 2018; 74-74
0140-7783
1365-2885
CONICET Digital
CONICET
url http://hdl.handle.net/11336/173731
identifier_str_mv Old drugs for new uses: pharmacokinetic assessment to support Oxfendazole repurposing as a flukicidal compound; 14th International Congress of the European Association for Veterinary Pharmacology and Toxicology; Wroclaw; Polonia; 2018; 74-74
0140-7783
1365-2885
CONICET Digital
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