Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels

The main goals of the current work were: (a) to assess the ivermectin (IVM) systemic exposure and plasma disposition kinetics after its administration at the recommended dose, x5 and x10 doses to lambs, (b) to compare the clinical efficacy of the same IVM dosages in lambs infected with an IVM-resist...

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Autores: Alvarez, Luis Ignacio, Suárez, Gonzalo Pablo, Ceballos, Laura, Moreno, Laura Susana, Cantón, Candela, Lifschitz, Adrian Luis, Maté, María Laura, Ballent, Mariana, Virkel, Guillermo Leon, Lanusse, Carlos Edmundo
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:Argentina
Institución:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:CONICET Digital (CONICET)
Idioma:inglés
OAI Identifier:oai:ri.conicet.gov.ar:11336/50626
Acceso en línea:http://hdl.handle.net/11336/50626
Access Level:acceso abierto
Palabra clave:Anthelmintic Resistance
Dose Proportionality
Haemonchus Contortus
Ivermectin
P-Glycoprotein
https://purl.org/becyt/ford/4.3
https://purl.org/becyt/ford/4
id AR_b8d48a7bc68f252c192958c52b61e938
oai_identifier_str oai:ri.conicet.gov.ar:11336/50626
network_acronym_str AR
network_name_str Argentina
repository_id_str
dc.title.none.fl_str_mv Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels
title Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels
spellingShingle Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels
Alvarez, Luis Ignacio
Anthelmintic Resistance
Dose Proportionality
Haemonchus Contortus
Ivermectin
P-Glycoprotein
https://purl.org/becyt/ford/4.3
https://purl.org/becyt/ford/4
title_short Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels
title_full Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels
title_fullStr Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels
title_full_unstemmed Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels
title_sort Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels
dc.creator.none.fl_str_mv Alvarez, Luis Ignacio
Suárez, Gonzalo Pablo
Ceballos, Laura
Moreno, Laura Susana
Cantón, Candela
Lifschitz, Adrian Luis
Maté, María Laura
Ballent, Mariana
Virkel, Guillermo Leon
Lanusse, Carlos Edmundo
author Alvarez, Luis Ignacio
author_facet Alvarez, Luis Ignacio
Suárez, Gonzalo Pablo
Ceballos, Laura
Moreno, Laura Susana
Cantón, Candela
Lifschitz, Adrian Luis
Maté, María Laura
Ballent, Mariana
Virkel, Guillermo Leon
Lanusse, Carlos Edmundo
author_role author
author2 Suárez, Gonzalo Pablo
Ceballos, Laura
Moreno, Laura Susana
Cantón, Candela
Lifschitz, Adrian Luis
Maté, María Laura
Ballent, Mariana
Virkel, Guillermo Leon
Lanusse, Carlos Edmundo
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Anthelmintic Resistance
Dose Proportionality
Haemonchus Contortus
Ivermectin
P-Glycoprotein
https://purl.org/becyt/ford/4.3
https://purl.org/becyt/ford/4
topic Anthelmintic Resistance
Dose Proportionality
Haemonchus Contortus
Ivermectin
P-Glycoprotein
https://purl.org/becyt/ford/4.3
https://purl.org/becyt/ford/4
description The main goals of the current work were: (a) to assess the ivermectin (IVM) systemic exposure and plasma disposition kinetics after its administration at the recommended dose, x5 and x10 doses to lambs, (b) to compare the clinical efficacy of the same IVM dosages in lambs infected with an IVM-resistant isolate of Haemonchus contortus, and (c) to assess the expression of the transporter protein P-glycoprotein (P-gp) in H. contortus recovered at 14 days after administration of the IVM dose regimens. There were two separated trials where IVM was administered either subcutaneously (SC, Experiment I) or intraruminally (IR, Experiment II). Each experiment involved twenty-four (24) lambs artificially infected with a highly resistant H. contortus isolate. Animals were allocated into 4 groups (n=6) and treated with IVM at either 0.2 (IVMx1), 1 (IVMx5) or 2mg/kg (IVMx10). Plasma samples were collected up to 12 days post-treatment and analysed by HPLC. An untreated-control Group was included to assess the comparative anthelmintic efficacy of the different treatments. The level of expression of Pgp in H. contortus specimens obtained from lambs both untreated and IR treated with the different IVM doses was quantified by real time PCR. Parametric and non-parametric tests were used to compare the statistical significance of the results (P<0.05). After the SC treatment, the IVM plasma area under the concentration-time curve (AUC0-LOQ) increased from 41.9 (IVMSCx1) up to 221 (IVMSCx5) and 287 (IVMSCx10)ng.day/mL and after the IR treatment from 20.8 (IVMIRx1) up to 121 (IVMIRx5) and 323 (IVMIRx10)ng.day/mL. Dose-adjusted AUC0-LOQ and Cmax were similar among doses, demonstrating dose proportionality for IVM after both SC and IR administration at the three different doses. The efficacies against resistant H. contortus after the SC treatment were 42% (IVMSC1), 75% (IVMSCx5) and 75% (IVMSCx10). However, the IR IVM treatment reached clinical efficacies ranging from 48% (IVMIRx1) up to 96% (IVMIRx5) and 98% (IVMIRx10). None of the IR IVM treatments increased the expression of P-gp in adult H. contortus at 14 days post-treatment compared to samples collected from the untreated control group. An enhanced parasite exposure of the drug at the abomasum may explain the improved efficacy against this recalcitrant H. contortus isolate observed only after the IR administration at 5- and 10-fold the IVM therapeutic dosage.
publishDate 2015
dc.date.none.fl_str_mv 2015-05
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/11336/50626
Alvarez, Luis Ignacio; Suárez, Gonzalo Pablo; Ceballos, Laura; Moreno, Laura Susana; Cantón, Candela; et al.; Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels; Elsevier Science; Veterinary Parasitology; 210; 1-2; 5-2015; 53-63
0304-4017
CONICET Digital
CONICET
url http://hdl.handle.net/11336/50626
identifier_str_mv Alvarez, Luis Ignacio; Suárez, Gonzalo Pablo; Ceballos, Laura; Moreno, Laura Susana; Cantón, Candela; et al.; Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels; Elsevier Science; Veterinary Parasitology; 210; 1-2; 5-2015; 53-63
0304-4017
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.vetpar.2015.03.001
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0304401715001119
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier Science
publisher.none.fl_str_mv Elsevier Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
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_ 1799194994016256000
spelling Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levelsAlvarez, Luis IgnacioSuárez, Gonzalo PabloCeballos, LauraMoreno, Laura SusanaCantón, CandelaLifschitz, Adrian LuisMaté, María LauraBallent, MarianaVirkel, Guillermo LeonLanusse, Carlos EdmundoAnthelmintic ResistanceDose ProportionalityHaemonchus ContortusIvermectinP-Glycoproteinhttps://purl.org/becyt/ford/4.3https://purl.org/becyt/ford/4The main goals of the current work were: (a) to assess the ivermectin (IVM) systemic exposure and plasma disposition kinetics after its administration at the recommended dose, x5 and x10 doses to lambs, (b) to compare the clinical efficacy of the same IVM dosages in lambs infected with an IVM-resistant isolate of Haemonchus contortus, and (c) to assess the expression of the transporter protein P-glycoprotein (P-gp) in H. contortus recovered at 14 days after administration of the IVM dose regimens. There were two separated trials where IVM was administered either subcutaneously (SC, Experiment I) or intraruminally (IR, Experiment II). Each experiment involved twenty-four (24) lambs artificially infected with a highly resistant H. contortus isolate. Animals were allocated into 4 groups (n=6) and treated with IVM at either 0.2 (IVMx1), 1 (IVMx5) or 2mg/kg (IVMx10). Plasma samples were collected up to 12 days post-treatment and analysed by HPLC. An untreated-control Group was included to assess the comparative anthelmintic efficacy of the different treatments. The level of expression of Pgp in H. contortus specimens obtained from lambs both untreated and IR treated with the different IVM doses was quantified by real time PCR. Parametric and non-parametric tests were used to compare the statistical significance of the results (P<0.05). After the SC treatment, the IVM plasma area under the concentration-time curve (AUC0-LOQ) increased from 41.9 (IVMSCx1) up to 221 (IVMSCx5) and 287 (IVMSCx10)ng.day/mL and after the IR treatment from 20.8 (IVMIRx1) up to 121 (IVMIRx5) and 323 (IVMIRx10)ng.day/mL. Dose-adjusted AUC0-LOQ and Cmax were similar among doses, demonstrating dose proportionality for IVM after both SC and IR administration at the three different doses. The efficacies against resistant H. contortus after the SC treatment were 42% (IVMSC1), 75% (IVMSCx5) and 75% (IVMSCx10). However, the IR IVM treatment reached clinical efficacies ranging from 48% (IVMIRx1) up to 96% (IVMIRx5) and 98% (IVMIRx10). None of the IR IVM treatments increased the expression of P-gp in adult H. contortus at 14 days post-treatment compared to samples collected from the untreated control group. An enhanced parasite exposure of the drug at the abomasum may explain the improved efficacy against this recalcitrant H. contortus isolate observed only after the IR administration at 5- and 10-fold the IVM therapeutic dosage.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; ArgentinaFil: Suárez, Gonzalo Pablo. Universidad de la República; UruguayFil: 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: Moreno, Laura Susana. 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: Lifschitz, Adrian Luis. 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: Maté, María 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: Ballent, Mariana. 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: Virkel, Guillermo Leon. 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; ArgentinaElsevier Science2015-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/50626Alvarez, Luis Ignacio; Suárez, Gonzalo Pablo; Ceballos, Laura; Moreno, Laura Susana; Cantón, Candela; et al.; Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels; Elsevier Science; Veterinary Parasitology; 210; 1-2; 5-2015; 53-630304-4017CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.vetpar.2015.03.001info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0304401715001119info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2024-05-08T13:40:47Zoai:ri.conicet.gov.ar:11336/50626instacron: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:34982024-05-08 13:40:47.538CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
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