PROCEDIMIENTO DE PURIFICACION DEL FACTOR VIII
LA PRESENTE INVENCION SE REFIERE A UN PROCEDIMIENTO PARA PURIFICAR EL FACTOR VIII RECOMBINANTE DE COAGULACION MEDIANTE LA CARGA DE UNA SOLUCION ACUOSA QUE CONTIENE FACTOR VIII EN UN GEL DE CROMATOGRAFIA DE INTERACCION HIDROFOBA (HIC), EN DONDE AL MENOS HAY PRESENTE UN SURFACTANTE EN LA SOLUCION ACUO...
Gespeichert in:
1. Verfasser: | |
---|---|
Format: | Patent |
Sprache: | spa |
Schlagworte: | |
Online-Zugang: | Volltext bestellen |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | |
---|---|
container_issue | |
container_start_page | |
container_title | |
container_volume | |
creator | SMEDS, ANNA-LISA |
description | LA PRESENTE INVENCION SE REFIERE A UN PROCEDIMIENTO PARA PURIFICAR EL FACTOR VIII RECOMBINANTE DE COAGULACION MEDIANTE LA CARGA DE UNA SOLUCION ACUOSA QUE CONTIENE FACTOR VIII EN UN GEL DE CROMATOGRAFIA DE INTERACCION HIDROFOBA (HIC), EN DONDE AL MENOS HAY PRESENTE UN SURFACTANTE EN LA SOLUCION ACUOSA Y/O UNA SOLUCION DE TAMPON ES UTILIZADA PARA EQUILIBRAR EL GEL ANTES DE CARGAR LA SOLUCION ACUOSA EN EL GEL. LA PRESENCIA DE UN SURFACTANTE AL CARGAR LA SOLUCION QUE CONTIENE FACTOR VIII EN EL GEL HIC, HACE POSIBLE SEPARAR EFICAZMENTE LAS MOLECULAS DE FACTOR VIII INTACTAS Y ACTIVAS DE MOLECULAS CON DESVIOS ESTRUCTURALES. CON LA PRESENTE INVENCION ES ADEMAS POSIBLE REDUCIR EL CONTENIDO DE ADN Y/O CONTAMINANTES DE CELULA CHO DE FORMA CONSIDERABLE Y AUMENTAR LA ACTIVIDAD DEL PRODUCTO DE FACTOR VIII A UNA EXTENSION HASTA AHORA DESCONOCIDA. LA INVENCION SE REFIERE ADEMAS A UNA SOLUCION ACUOSA QUE CONTIENE FACTOR VIII RECOMBINANTE QUE HA SIDO PURIFICADO DE ACUERDO CON EL PRESENTE PROCEDIMIENTO Y ALUSO DE DICHA SOLUCION ACUOSA, PARA LA FABRICACION DE UN MEDICAMENTO PARA ADMINISTRACION A UN PACIENTE QUE TENGA LOS SINTOMAS DE HEMOFILIA. ADEMAS, LA INVENCION SE REFIERE A UN METODO DE TRATAMIENTO DE HEMOFILIA MEDIANTE LA ADMINISTRACION DE UNA CANTIDAD TERAPEUTICAMENTE EFICAZ DE FACTOR VIII RECOMBINANTE QUE HA SIDO PURIFICADO DE ACUERDO CON EL PRESENTE PROCEDIMIENTO.
PCT No. PCT/SE95/01350 Sec. 371 Date Mar. 27, 1997 Sec. 102(e) Date Mar. 27, 1997 PCT Filed Nov. 14, 1995 PCT Pub. No. WO96/15140 PCT Pub. Date May 23, 1996The present invention relates to a process for purifying recombinant coagulation factor VIII by loading an aqueous solution containing factor VIII onto a hydrophobic interaction chromatography (HIC) gel, wherein at least one surfactant is present in the aqueous solution and/or a buffer solution used to equilibrate the gel prior to loading the aqueous solution onto the gel. The presence of a surfactant when loading the solution containing factor VIII onto the HIC gel, makes it possible to efficiently separate the intact and active factor VIII molecules from molecules with structural deviations. With the present invention it is further possible to reduce the content of DNA and/or CHO cell contaminants considerably and increase the activity of the factor VIII product to a hitherto unknown extent. The invention further relates to an aqueous solution containing recombinant factor VIII which has been purified according to the present process and use of such an |
format | Patent |
fullrecord | <record><control><sourceid>epo_EVB</sourceid><recordid>TN_cdi_epo_espacenet_ES2182915TT3</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>ES2182915TT3</sourcerecordid><originalsourceid>FETCH-epo_espacenet_ES2182915TT33</originalsourceid><addsrcrecordid>eNrjZNANCPJ3dnXx9PV09QvxV3BxVQgIDfJ083R2dPb09wPyfRTcHJ1D_IMUwjw9PXkYWNMSc4pTeaE0N4Oim2uIs4duakF-fGpxQWJyal5qSbxrsJGhhZGloWlIiLExMWoAvO0lyg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>patent</recordtype></control><display><type>patent</type><title>PROCEDIMIENTO DE PURIFICACION DEL FACTOR VIII</title><source>esp@cenet</source><creator>SMEDS, ANNA-LISA</creator><creatorcontrib>SMEDS, ANNA-LISA</creatorcontrib><description>LA PRESENTE INVENCION SE REFIERE A UN PROCEDIMIENTO PARA PURIFICAR EL FACTOR VIII RECOMBINANTE DE COAGULACION MEDIANTE LA CARGA DE UNA SOLUCION ACUOSA QUE CONTIENE FACTOR VIII EN UN GEL DE CROMATOGRAFIA DE INTERACCION HIDROFOBA (HIC), EN DONDE AL MENOS HAY PRESENTE UN SURFACTANTE EN LA SOLUCION ACUOSA Y/O UNA SOLUCION DE TAMPON ES UTILIZADA PARA EQUILIBRAR EL GEL ANTES DE CARGAR LA SOLUCION ACUOSA EN EL GEL. LA PRESENCIA DE UN SURFACTANTE AL CARGAR LA SOLUCION QUE CONTIENE FACTOR VIII EN EL GEL HIC, HACE POSIBLE SEPARAR EFICAZMENTE LAS MOLECULAS DE FACTOR VIII INTACTAS Y ACTIVAS DE MOLECULAS CON DESVIOS ESTRUCTURALES. CON LA PRESENTE INVENCION ES ADEMAS POSIBLE REDUCIR EL CONTENIDO DE ADN Y/O CONTAMINANTES DE CELULA CHO DE FORMA CONSIDERABLE Y AUMENTAR LA ACTIVIDAD DEL PRODUCTO DE FACTOR VIII A UNA EXTENSION HASTA AHORA DESCONOCIDA. LA INVENCION SE REFIERE ADEMAS A UNA SOLUCION ACUOSA QUE CONTIENE FACTOR VIII RECOMBINANTE QUE HA SIDO PURIFICADO DE ACUERDO CON EL PRESENTE PROCEDIMIENTO Y ALUSO DE DICHA SOLUCION ACUOSA, PARA LA FABRICACION DE UN MEDICAMENTO PARA ADMINISTRACION A UN PACIENTE QUE TENGA LOS SINTOMAS DE HEMOFILIA. ADEMAS, LA INVENCION SE REFIERE A UN METODO DE TRATAMIENTO DE HEMOFILIA MEDIANTE LA ADMINISTRACION DE UNA CANTIDAD TERAPEUTICAMENTE EFICAZ DE FACTOR VIII RECOMBINANTE QUE HA SIDO PURIFICADO DE ACUERDO CON EL PRESENTE PROCEDIMIENTO.
PCT No. PCT/SE95/01350 Sec. 371 Date Mar. 27, 1997 Sec. 102(e) Date Mar. 27, 1997 PCT Filed Nov. 14, 1995 PCT Pub. No. WO96/15140 PCT Pub. Date May 23, 1996The present invention relates to a process for purifying recombinant coagulation factor VIII by loading an aqueous solution containing factor VIII onto a hydrophobic interaction chromatography (HIC) gel, wherein at least one surfactant is present in the aqueous solution and/or a buffer solution used to equilibrate the gel prior to loading the aqueous solution onto the gel. The presence of a surfactant when loading the solution containing factor VIII onto the HIC gel, makes it possible to efficiently separate the intact and active factor VIII molecules from molecules with structural deviations. With the present invention it is further possible to reduce the content of DNA and/or CHO cell contaminants considerably and increase the activity of the factor VIII product to a hitherto unknown extent. The invention further relates to an aqueous solution containing recombinant factor VIII which has been purified according to the present process and use of such an aqueous solution, for the manufacture of a medicament for administration to a patient having the symptoms of hemophilia. Also, the invention relates to a method for treatment of hemophilia by administration of a therapeutically effective amount of recombinant factor VIII which has been purified according to the present process.</description><edition>4</edition><language>spa</language><subject>BEER ; BIOCHEMISTRY ; CHEMISTRY ; COMPOSITIONS THEREOF ; CULTURE MEDIA ; ENZYMOLOGY ; FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIREDCHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERSFROM A RACEMIC MIXTURE ; HUMAN NECESSITIES ; HYGIENE ; MEDICAL OR VETERINARY SCIENCE ; METALLURGY ; MICROBIOLOGY ; MICROORGANISMS OR ENZYMES ; MUTATION OR GENETIC ENGINEERING ; ORGANIC CHEMISTRY ; PEPTIDES ; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES ; PROCESSES USING MICROORGANISMS ; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS ; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS ; SPIRITS ; VINEGAR ; WINE</subject><creationdate>2003</creationdate><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://worldwide.espacenet.com/publicationDetails/biblio?FT=D&date=20030316&DB=EPODOC&CC=ES&NR=2182915T3$$EHTML$$P50$$Gepo$$Hfree_for_read</linktohtml><link.rule.ids>230,308,776,881,25543,76294</link.rule.ids><linktorsrc>$$Uhttps://worldwide.espacenet.com/publicationDetails/biblio?FT=D&date=20030316&DB=EPODOC&CC=ES&NR=2182915T3$$EView_record_in_European_Patent_Office$$FView_record_in_$$GEuropean_Patent_Office$$Hfree_for_read</linktorsrc></links><search><creatorcontrib>SMEDS, ANNA-LISA</creatorcontrib><title>PROCEDIMIENTO DE PURIFICACION DEL FACTOR VIII</title><description>LA PRESENTE INVENCION SE REFIERE A UN PROCEDIMIENTO PARA PURIFICAR EL FACTOR VIII RECOMBINANTE DE COAGULACION MEDIANTE LA CARGA DE UNA SOLUCION ACUOSA QUE CONTIENE FACTOR VIII EN UN GEL DE CROMATOGRAFIA DE INTERACCION HIDROFOBA (HIC), EN DONDE AL MENOS HAY PRESENTE UN SURFACTANTE EN LA SOLUCION ACUOSA Y/O UNA SOLUCION DE TAMPON ES UTILIZADA PARA EQUILIBRAR EL GEL ANTES DE CARGAR LA SOLUCION ACUOSA EN EL GEL. LA PRESENCIA DE UN SURFACTANTE AL CARGAR LA SOLUCION QUE CONTIENE FACTOR VIII EN EL GEL HIC, HACE POSIBLE SEPARAR EFICAZMENTE LAS MOLECULAS DE FACTOR VIII INTACTAS Y ACTIVAS DE MOLECULAS CON DESVIOS ESTRUCTURALES. CON LA PRESENTE INVENCION ES ADEMAS POSIBLE REDUCIR EL CONTENIDO DE ADN Y/O CONTAMINANTES DE CELULA CHO DE FORMA CONSIDERABLE Y AUMENTAR LA ACTIVIDAD DEL PRODUCTO DE FACTOR VIII A UNA EXTENSION HASTA AHORA DESCONOCIDA. LA INVENCION SE REFIERE ADEMAS A UNA SOLUCION ACUOSA QUE CONTIENE FACTOR VIII RECOMBINANTE QUE HA SIDO PURIFICADO DE ACUERDO CON EL PRESENTE PROCEDIMIENTO Y ALUSO DE DICHA SOLUCION ACUOSA, PARA LA FABRICACION DE UN MEDICAMENTO PARA ADMINISTRACION A UN PACIENTE QUE TENGA LOS SINTOMAS DE HEMOFILIA. ADEMAS, LA INVENCION SE REFIERE A UN METODO DE TRATAMIENTO DE HEMOFILIA MEDIANTE LA ADMINISTRACION DE UNA CANTIDAD TERAPEUTICAMENTE EFICAZ DE FACTOR VIII RECOMBINANTE QUE HA SIDO PURIFICADO DE ACUERDO CON EL PRESENTE PROCEDIMIENTO.
PCT No. PCT/SE95/01350 Sec. 371 Date Mar. 27, 1997 Sec. 102(e) Date Mar. 27, 1997 PCT Filed Nov. 14, 1995 PCT Pub. No. WO96/15140 PCT Pub. Date May 23, 1996The present invention relates to a process for purifying recombinant coagulation factor VIII by loading an aqueous solution containing factor VIII onto a hydrophobic interaction chromatography (HIC) gel, wherein at least one surfactant is present in the aqueous solution and/or a buffer solution used to equilibrate the gel prior to loading the aqueous solution onto the gel. The presence of a surfactant when loading the solution containing factor VIII onto the HIC gel, makes it possible to efficiently separate the intact and active factor VIII molecules from molecules with structural deviations. With the present invention it is further possible to reduce the content of DNA and/or CHO cell contaminants considerably and increase the activity of the factor VIII product to a hitherto unknown extent. The invention further relates to an aqueous solution containing recombinant factor VIII which has been purified according to the present process and use of such an aqueous solution, for the manufacture of a medicament for administration to a patient having the symptoms of hemophilia. Also, the invention relates to a method for treatment of hemophilia by administration of a therapeutically effective amount of recombinant factor VIII which has been purified according to the present process.</description><subject>BEER</subject><subject>BIOCHEMISTRY</subject><subject>CHEMISTRY</subject><subject>COMPOSITIONS THEREOF</subject><subject>CULTURE MEDIA</subject><subject>ENZYMOLOGY</subject><subject>FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIREDCHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERSFROM A RACEMIC MIXTURE</subject><subject>HUMAN NECESSITIES</subject><subject>HYGIENE</subject><subject>MEDICAL OR VETERINARY SCIENCE</subject><subject>METALLURGY</subject><subject>MICROBIOLOGY</subject><subject>MICROORGANISMS OR ENZYMES</subject><subject>MUTATION OR GENETIC ENGINEERING</subject><subject>ORGANIC CHEMISTRY</subject><subject>PEPTIDES</subject><subject>PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES</subject><subject>PROCESSES USING MICROORGANISMS</subject><subject>PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS</subject><subject>SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS</subject><subject>SPIRITS</subject><subject>VINEGAR</subject><subject>WINE</subject><fulltext>true</fulltext><rsrctype>patent</rsrctype><creationdate>2003</creationdate><recordtype>patent</recordtype><sourceid>EVB</sourceid><recordid>eNrjZNANCPJ3dnXx9PV09QvxV3BxVQgIDfJ083R2dPb09wPyfRTcHJ1D_IMUwjw9PXkYWNMSc4pTeaE0N4Oim2uIs4duakF-fGpxQWJyal5qSbxrsJGhhZGloWlIiLExMWoAvO0lyg</recordid><startdate>20030316</startdate><enddate>20030316</enddate><creator>SMEDS, ANNA-LISA</creator><scope>EVB</scope></search><sort><creationdate>20030316</creationdate><title>PROCEDIMIENTO DE PURIFICACION DEL FACTOR VIII</title><author>SMEDS, ANNA-LISA</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-epo_espacenet_ES2182915TT33</frbrgroupid><rsrctype>patents</rsrctype><prefilter>patents</prefilter><language>spa</language><creationdate>2003</creationdate><topic>BEER</topic><topic>BIOCHEMISTRY</topic><topic>CHEMISTRY</topic><topic>COMPOSITIONS THEREOF</topic><topic>CULTURE MEDIA</topic><topic>ENZYMOLOGY</topic><topic>FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIREDCHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERSFROM A RACEMIC MIXTURE</topic><topic>HUMAN NECESSITIES</topic><topic>HYGIENE</topic><topic>MEDICAL OR VETERINARY SCIENCE</topic><topic>METALLURGY</topic><topic>MICROBIOLOGY</topic><topic>MICROORGANISMS OR ENZYMES</topic><topic>MUTATION OR GENETIC ENGINEERING</topic><topic>ORGANIC CHEMISTRY</topic><topic>PEPTIDES</topic><topic>PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES</topic><topic>PROCESSES USING MICROORGANISMS</topic><topic>PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS</topic><topic>SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS</topic><topic>SPIRITS</topic><topic>VINEGAR</topic><topic>WINE</topic><toplevel>online_resources</toplevel><creatorcontrib>SMEDS, ANNA-LISA</creatorcontrib><collection>esp@cenet</collection></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>SMEDS, ANNA-LISA</au><format>patent</format><genre>patent</genre><ristype>GEN</ristype><title>PROCEDIMIENTO DE PURIFICACION DEL FACTOR VIII</title><date>2003-03-16</date><risdate>2003</risdate><abstract>LA PRESENTE INVENCION SE REFIERE A UN PROCEDIMIENTO PARA PURIFICAR EL FACTOR VIII RECOMBINANTE DE COAGULACION MEDIANTE LA CARGA DE UNA SOLUCION ACUOSA QUE CONTIENE FACTOR VIII EN UN GEL DE CROMATOGRAFIA DE INTERACCION HIDROFOBA (HIC), EN DONDE AL MENOS HAY PRESENTE UN SURFACTANTE EN LA SOLUCION ACUOSA Y/O UNA SOLUCION DE TAMPON ES UTILIZADA PARA EQUILIBRAR EL GEL ANTES DE CARGAR LA SOLUCION ACUOSA EN EL GEL. LA PRESENCIA DE UN SURFACTANTE AL CARGAR LA SOLUCION QUE CONTIENE FACTOR VIII EN EL GEL HIC, HACE POSIBLE SEPARAR EFICAZMENTE LAS MOLECULAS DE FACTOR VIII INTACTAS Y ACTIVAS DE MOLECULAS CON DESVIOS ESTRUCTURALES. CON LA PRESENTE INVENCION ES ADEMAS POSIBLE REDUCIR EL CONTENIDO DE ADN Y/O CONTAMINANTES DE CELULA CHO DE FORMA CONSIDERABLE Y AUMENTAR LA ACTIVIDAD DEL PRODUCTO DE FACTOR VIII A UNA EXTENSION HASTA AHORA DESCONOCIDA. LA INVENCION SE REFIERE ADEMAS A UNA SOLUCION ACUOSA QUE CONTIENE FACTOR VIII RECOMBINANTE QUE HA SIDO PURIFICADO DE ACUERDO CON EL PRESENTE PROCEDIMIENTO Y ALUSO DE DICHA SOLUCION ACUOSA, PARA LA FABRICACION DE UN MEDICAMENTO PARA ADMINISTRACION A UN PACIENTE QUE TENGA LOS SINTOMAS DE HEMOFILIA. ADEMAS, LA INVENCION SE REFIERE A UN METODO DE TRATAMIENTO DE HEMOFILIA MEDIANTE LA ADMINISTRACION DE UNA CANTIDAD TERAPEUTICAMENTE EFICAZ DE FACTOR VIII RECOMBINANTE QUE HA SIDO PURIFICADO DE ACUERDO CON EL PRESENTE PROCEDIMIENTO.
PCT No. PCT/SE95/01350 Sec. 371 Date Mar. 27, 1997 Sec. 102(e) Date Mar. 27, 1997 PCT Filed Nov. 14, 1995 PCT Pub. No. WO96/15140 PCT Pub. Date May 23, 1996The present invention relates to a process for purifying recombinant coagulation factor VIII by loading an aqueous solution containing factor VIII onto a hydrophobic interaction chromatography (HIC) gel, wherein at least one surfactant is present in the aqueous solution and/or a buffer solution used to equilibrate the gel prior to loading the aqueous solution onto the gel. The presence of a surfactant when loading the solution containing factor VIII onto the HIC gel, makes it possible to efficiently separate the intact and active factor VIII molecules from molecules with structural deviations. With the present invention it is further possible to reduce the content of DNA and/or CHO cell contaminants considerably and increase the activity of the factor VIII product to a hitherto unknown extent. The invention further relates to an aqueous solution containing recombinant factor VIII which has been purified according to the present process and use of such an aqueous solution, for the manufacture of a medicament for administration to a patient having the symptoms of hemophilia. Also, the invention relates to a method for treatment of hemophilia by administration of a therapeutically effective amount of recombinant factor VIII which has been purified according to the present process.</abstract><edition>4</edition><oa>free_for_read</oa></addata></record> |
fulltext | fulltext_linktorsrc |
identifier | |
ispartof | |
issn | |
language | spa |
recordid | cdi_epo_espacenet_ES2182915TT3 |
source | esp@cenet |
subjects | BEER BIOCHEMISTRY CHEMISTRY COMPOSITIONS THEREOF CULTURE MEDIA ENZYMOLOGY FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIREDCHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERSFROM A RACEMIC MIXTURE HUMAN NECESSITIES HYGIENE MEDICAL OR VETERINARY SCIENCE METALLURGY MICROBIOLOGY MICROORGANISMS OR ENZYMES MUTATION OR GENETIC ENGINEERING ORGANIC CHEMISTRY PEPTIDES PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES PROCESSES USING MICROORGANISMS PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS SPIRITS VINEGAR WINE |
title | PROCEDIMIENTO DE PURIFICACION DEL FACTOR VIII |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-21T19%3A50%3A41IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-epo_EVB&rft_val_fmt=info:ofi/fmt:kev:mtx:patent&rft.genre=patent&rft.au=SMEDS,%20ANNA-LISA&rft.date=2003-03-16&rft_id=info:doi/&rft_dat=%3Cepo_EVB%3EES2182915TT3%3C/epo_EVB%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/&rfr_iscdi=true |