Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention

Pharmacodynamics of eptifibatide, a cyclic heptapeptide antagonist of platelet glycoprotein IIb/IIIa, are substantially altered by anticoagulants that chelate calcium, resulting in overestimation ex vivo of the in vivo effects of this agent. We conducted a dose-ranging study to characterize the phar...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Circulation (New York, N.Y.) N.Y.), 2001-07, Vol.104 (4), p.406-411
Hauptverfasser: GILCHRIST, Ian C, O'SHEA, J. Conor, RUNYON, John, TCHENG, James E, KOSOGLOU, Teddy, JENNINGS, Lisa K, LORENZ, Todd J, KITT, Michael M, KLEIMAN, Neal S, TALLEY, David, AGUIRRE, Frank, DAVIDSON, Charles
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 411
container_issue 4
container_start_page 406
container_title Circulation (New York, N.Y.)
container_volume 104
creator GILCHRIST, Ian C
O'SHEA, J. Conor
RUNYON, John
TCHENG, James E
KOSOGLOU, Teddy
JENNINGS, Lisa K
LORENZ, Todd J
KITT, Michael M
KLEIMAN, Neal S
TALLEY, David
AGUIRRE, Frank
DAVIDSON, Charles
description Pharmacodynamics of eptifibatide, a cyclic heptapeptide antagonist of platelet glycoprotein IIb/IIIa, are substantially altered by anticoagulants that chelate calcium, resulting in overestimation ex vivo of the in vivo effects of this agent. We conducted a dose-ranging study to characterize the pharmacodynamics and pharmacokinetics of eptifibatide under physiological conditions. Patients (n=39) undergoing elective percutaneous coronary intervention were randomly assigned to an eptifibatide bolus followed by an infusion (180-microgram/kg bolus followed by 2 microgram/kg per minute or 250-microgram/kg bolus followed by 3 microgram/kg per minute) for 18 to 24 hours. In a 2:1 ratio, these patients received either a second bolus of eptifibatide (90 microgram/kg or 125 microgram/kg for the initial 180-microgram/kg or 250-microgram/kg groups, respectively) or placebo 30 minutes after the initial bolus. Bleeding times, ex vivo platelet aggregation, receptor occupancy, and plasma eptifibatide levels at baseline and at 1, 2, 3, 4, 6, and 8 hours were evaluated. Platelet inhibition was dose dependent and >80% in all groups by steady state. The single-bolus regimens had a transient loss of inhibition at 1 hour, consistent with rapid distribution and drug elimination. Pharmacokinetic modeling suggested that optimal dosing of eptifibatide would be obtained with a 180-microgram/kg bolus and a 2-microgram/kg per minute infusion followed by a second 180-microgram/kg bolus 10 minutes later. A novel higher-dose, double-bolus regimen of eptifibatide in coronary intervention attains and maintains >90% inhibition of platelet aggregation in >90% of patients, providing the pharmacodynamic construct for the design of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of adjunctive eptifibatide in coronary stent implantation.
doi_str_mv 10.1161/hc2901.093504
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_71029635</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>71029635</sourcerecordid><originalsourceid>FETCH-LOGICAL-c425t-89925665d3bc8e195596c28f05a44fe8452400b7afa0e0a88780a8439a034eb3</originalsourceid><addsrcrecordid>eNpdkc1L5jAQxoMo-uruca9SRDxZd_LVNkcRPxYE9-C9pOl032ib1KRdeP97Iy0oXmaYmR8PM_MQ8ovCFaUF_b01TAG9AsUliD2yoZKJXEiu9skGAFRecsaOyHGML6kseCkPyRGloqgY0A2Z_251GLTx7c7pwZqYaddm49p8tQ6nj6bvsq39t8WQtz7iZdb6uekxb3w_xwzHyXa20ZNtMbMuGzGYedIOfRoaH7zTYZcGE4b_6Cbr3Q9y0Ok-4s81n5Dnu9vnm4f88en-z831Y24Ek1NeKcVkUciWN6ZCqqRUhWFVB1IL0WEl0q0ATak7DQi6qsoqRcGVBi6w4SfkYpEdg3-bMU71YKPBvl92q0sKTBVcJvDsG_ji5-DSajWjrARRCpagfIFM8DEG7Oox2CGdVlOoP7yoFy_qxYvEn66iczNg-0mvz0_A-QroaHTfBe2MjV9UFae84O_Az5I0</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>212704742</pqid></control><display><type>article</type><title>Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention</title><source>MEDLINE</source><source>American Heart Association Journals</source><source>Journals@Ovid Complete</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>GILCHRIST, Ian C ; O'SHEA, J. Conor ; RUNYON, John ; TCHENG, James E ; KOSOGLOU, Teddy ; JENNINGS, Lisa K ; LORENZ, Todd J ; KITT, Michael M ; KLEIMAN, Neal S ; TALLEY, David ; AGUIRRE, Frank ; DAVIDSON, Charles</creator><creatorcontrib>GILCHRIST, Ian C ; O'SHEA, J. Conor ; RUNYON, John ; TCHENG, James E ; KOSOGLOU, Teddy ; JENNINGS, Lisa K ; LORENZ, Todd J ; KITT, Michael M ; KLEIMAN, Neal S ; TALLEY, David ; AGUIRRE, Frank ; DAVIDSON, Charles</creatorcontrib><description>Pharmacodynamics of eptifibatide, a cyclic heptapeptide antagonist of platelet glycoprotein IIb/IIIa, are substantially altered by anticoagulants that chelate calcium, resulting in overestimation ex vivo of the in vivo effects of this agent. We conducted a dose-ranging study to characterize the pharmacodynamics and pharmacokinetics of eptifibatide under physiological conditions. Patients (n=39) undergoing elective percutaneous coronary intervention were randomly assigned to an eptifibatide bolus followed by an infusion (180-microgram/kg bolus followed by 2 microgram/kg per minute or 250-microgram/kg bolus followed by 3 microgram/kg per minute) for 18 to 24 hours. In a 2:1 ratio, these patients received either a second bolus of eptifibatide (90 microgram/kg or 125 microgram/kg for the initial 180-microgram/kg or 250-microgram/kg groups, respectively) or placebo 30 minutes after the initial bolus. Bleeding times, ex vivo platelet aggregation, receptor occupancy, and plasma eptifibatide levels at baseline and at 1, 2, 3, 4, 6, and 8 hours were evaluated. Platelet inhibition was dose dependent and &gt;80% in all groups by steady state. The single-bolus regimens had a transient loss of inhibition at 1 hour, consistent with rapid distribution and drug elimination. Pharmacokinetic modeling suggested that optimal dosing of eptifibatide would be obtained with a 180-microgram/kg bolus and a 2-microgram/kg per minute infusion followed by a second 180-microgram/kg bolus 10 minutes later. A novel higher-dose, double-bolus regimen of eptifibatide in coronary intervention attains and maintains &gt;90% inhibition of platelet aggregation in &gt;90% of patients, providing the pharmacodynamic construct for the design of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of adjunctive eptifibatide in coronary stent implantation.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/hc2901.093504</identifier><identifier>PMID: 11468201</identifier><identifier>CODEN: CIRCAZ</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams &amp; Wilkins</publisher><subject>Angioplasty, Balloon, Coronary ; Area Under Curve ; Biological and medical sciences ; Blood. Blood coagulation. Reticuloendothelial system ; Dose-Response Relationship, Drug ; Eptifibatide ; Female ; Humans ; Male ; Medical sciences ; Metabolic Clearance Rate ; Middle Aged ; Peptides - pharmacokinetics ; Pharmacology. Drug treatments ; Platelet Aggregation - drug effects ; Platelet Aggregation Inhibitors - pharmacokinetics ; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists &amp; inhibitors ; Time Factors</subject><ispartof>Circulation (New York, N.Y.), 2001-07, Vol.104 (4), p.406-411</ispartof><rights>2001 INIST-CNRS</rights><rights>Copyright American Heart Association, Inc. Jul 24, 2001</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c425t-89925665d3bc8e195596c28f05a44fe8452400b7afa0e0a88780a8439a034eb3</citedby><cites>FETCH-LOGICAL-c425t-89925665d3bc8e195596c28f05a44fe8452400b7afa0e0a88780a8439a034eb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,3689,27931,27932</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=1093136$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11468201$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>GILCHRIST, Ian C</creatorcontrib><creatorcontrib>O'SHEA, J. Conor</creatorcontrib><creatorcontrib>RUNYON, John</creatorcontrib><creatorcontrib>TCHENG, James E</creatorcontrib><creatorcontrib>KOSOGLOU, Teddy</creatorcontrib><creatorcontrib>JENNINGS, Lisa K</creatorcontrib><creatorcontrib>LORENZ, Todd J</creatorcontrib><creatorcontrib>KITT, Michael M</creatorcontrib><creatorcontrib>KLEIMAN, Neal S</creatorcontrib><creatorcontrib>TALLEY, David</creatorcontrib><creatorcontrib>AGUIRRE, Frank</creatorcontrib><creatorcontrib>DAVIDSON, Charles</creatorcontrib><title>Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>Pharmacodynamics of eptifibatide, a cyclic heptapeptide antagonist of platelet glycoprotein IIb/IIIa, are substantially altered by anticoagulants that chelate calcium, resulting in overestimation ex vivo of the in vivo effects of this agent. We conducted a dose-ranging study to characterize the pharmacodynamics and pharmacokinetics of eptifibatide under physiological conditions. Patients (n=39) undergoing elective percutaneous coronary intervention were randomly assigned to an eptifibatide bolus followed by an infusion (180-microgram/kg bolus followed by 2 microgram/kg per minute or 250-microgram/kg bolus followed by 3 microgram/kg per minute) for 18 to 24 hours. In a 2:1 ratio, these patients received either a second bolus of eptifibatide (90 microgram/kg or 125 microgram/kg for the initial 180-microgram/kg or 250-microgram/kg groups, respectively) or placebo 30 minutes after the initial bolus. Bleeding times, ex vivo platelet aggregation, receptor occupancy, and plasma eptifibatide levels at baseline and at 1, 2, 3, 4, 6, and 8 hours were evaluated. Platelet inhibition was dose dependent and &gt;80% in all groups by steady state. The single-bolus regimens had a transient loss of inhibition at 1 hour, consistent with rapid distribution and drug elimination. Pharmacokinetic modeling suggested that optimal dosing of eptifibatide would be obtained with a 180-microgram/kg bolus and a 2-microgram/kg per minute infusion followed by a second 180-microgram/kg bolus 10 minutes later. A novel higher-dose, double-bolus regimen of eptifibatide in coronary intervention attains and maintains &gt;90% inhibition of platelet aggregation in &gt;90% of patients, providing the pharmacodynamic construct for the design of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of adjunctive eptifibatide in coronary stent implantation.</description><subject>Angioplasty, Balloon, Coronary</subject><subject>Area Under Curve</subject><subject>Biological and medical sciences</subject><subject>Blood. Blood coagulation. Reticuloendothelial system</subject><subject>Dose-Response Relationship, Drug</subject><subject>Eptifibatide</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolic Clearance Rate</subject><subject>Middle Aged</subject><subject>Peptides - pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Platelet Aggregation - drug effects</subject><subject>Platelet Aggregation Inhibitors - pharmacokinetics</subject><subject>Platelet Glycoprotein GPIIb-IIIa Complex - antagonists &amp; inhibitors</subject><subject>Time Factors</subject><issn>0009-7322</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1L5jAQxoMo-uruca9SRDxZd_LVNkcRPxYE9-C9pOl032ib1KRdeP97Iy0oXmaYmR8PM_MQ8ovCFaUF_b01TAG9AsUliD2yoZKJXEiu9skGAFRecsaOyHGML6kseCkPyRGloqgY0A2Z_251GLTx7c7pwZqYaddm49p8tQ6nj6bvsq39t8WQtz7iZdb6uekxb3w_xwzHyXa20ZNtMbMuGzGYedIOfRoaH7zTYZcGE4b_6Cbr3Q9y0Ok-4s81n5Dnu9vnm4f88en-z831Y24Ek1NeKcVkUciWN6ZCqqRUhWFVB1IL0WEl0q0ATak7DQi6qsoqRcGVBi6w4SfkYpEdg3-bMU71YKPBvl92q0sKTBVcJvDsG_ji5-DSajWjrARRCpagfIFM8DEG7Oox2CGdVlOoP7yoFy_qxYvEn66iczNg-0mvz0_A-QroaHTfBe2MjV9UFae84O_Az5I0</recordid><startdate>20010724</startdate><enddate>20010724</enddate><creator>GILCHRIST, Ian C</creator><creator>O'SHEA, J. Conor</creator><creator>RUNYON, John</creator><creator>TCHENG, James E</creator><creator>KOSOGLOU, Teddy</creator><creator>JENNINGS, Lisa K</creator><creator>LORENZ, Todd J</creator><creator>KITT, Michael M</creator><creator>KLEIMAN, Neal S</creator><creator>TALLEY, David</creator><creator>AGUIRRE, Frank</creator><creator>DAVIDSON, Charles</creator><general>Lippincott Williams &amp; Wilkins</general><general>American Heart Association, Inc</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>U9A</scope><scope>7X8</scope></search><sort><creationdate>20010724</creationdate><title>Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention</title><author>GILCHRIST, Ian C ; O'SHEA, J. Conor ; RUNYON, John ; TCHENG, James E ; KOSOGLOU, Teddy ; JENNINGS, Lisa K ; LORENZ, Todd J ; KITT, Michael M ; KLEIMAN, Neal S ; TALLEY, David ; AGUIRRE, Frank ; DAVIDSON, Charles</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c425t-89925665d3bc8e195596c28f05a44fe8452400b7afa0e0a88780a8439a034eb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Angioplasty, Balloon, Coronary</topic><topic>Area Under Curve</topic><topic>Biological and medical sciences</topic><topic>Blood. Blood coagulation. Reticuloendothelial system</topic><topic>Dose-Response Relationship, Drug</topic><topic>Eptifibatide</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolic Clearance Rate</topic><topic>Middle Aged</topic><topic>Peptides - pharmacokinetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Platelet Aggregation - drug effects</topic><topic>Platelet Aggregation Inhibitors - pharmacokinetics</topic><topic>Platelet Glycoprotein GPIIb-IIIa Complex - antagonists &amp; inhibitors</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>GILCHRIST, Ian C</creatorcontrib><creatorcontrib>O'SHEA, J. Conor</creatorcontrib><creatorcontrib>RUNYON, John</creatorcontrib><creatorcontrib>TCHENG, James E</creatorcontrib><creatorcontrib>KOSOGLOU, Teddy</creatorcontrib><creatorcontrib>JENNINGS, Lisa K</creatorcontrib><creatorcontrib>LORENZ, Todd J</creatorcontrib><creatorcontrib>KITT, Michael M</creatorcontrib><creatorcontrib>KLEIMAN, Neal S</creatorcontrib><creatorcontrib>TALLEY, David</creatorcontrib><creatorcontrib>AGUIRRE, Frank</creatorcontrib><creatorcontrib>DAVIDSON, Charles</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>GILCHRIST, Ian C</au><au>O'SHEA, J. Conor</au><au>RUNYON, John</au><au>TCHENG, James E</au><au>KOSOGLOU, Teddy</au><au>JENNINGS, Lisa K</au><au>LORENZ, Todd J</au><au>KITT, Michael M</au><au>KLEIMAN, Neal S</au><au>TALLEY, David</au><au>AGUIRRE, Frank</au><au>DAVIDSON, Charles</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><addtitle>Circulation</addtitle><date>2001-07-24</date><risdate>2001</risdate><volume>104</volume><issue>4</issue><spage>406</spage><epage>411</epage><pages>406-411</pages><issn>0009-7322</issn><eissn>1524-4539</eissn><coden>CIRCAZ</coden><abstract>Pharmacodynamics of eptifibatide, a cyclic heptapeptide antagonist of platelet glycoprotein IIb/IIIa, are substantially altered by anticoagulants that chelate calcium, resulting in overestimation ex vivo of the in vivo effects of this agent. We conducted a dose-ranging study to characterize the pharmacodynamics and pharmacokinetics of eptifibatide under physiological conditions. Patients (n=39) undergoing elective percutaneous coronary intervention were randomly assigned to an eptifibatide bolus followed by an infusion (180-microgram/kg bolus followed by 2 microgram/kg per minute or 250-microgram/kg bolus followed by 3 microgram/kg per minute) for 18 to 24 hours. In a 2:1 ratio, these patients received either a second bolus of eptifibatide (90 microgram/kg or 125 microgram/kg for the initial 180-microgram/kg or 250-microgram/kg groups, respectively) or placebo 30 minutes after the initial bolus. Bleeding times, ex vivo platelet aggregation, receptor occupancy, and plasma eptifibatide levels at baseline and at 1, 2, 3, 4, 6, and 8 hours were evaluated. Platelet inhibition was dose dependent and &gt;80% in all groups by steady state. The single-bolus regimens had a transient loss of inhibition at 1 hour, consistent with rapid distribution and drug elimination. Pharmacokinetic modeling suggested that optimal dosing of eptifibatide would be obtained with a 180-microgram/kg bolus and a 2-microgram/kg per minute infusion followed by a second 180-microgram/kg bolus 10 minutes later. A novel higher-dose, double-bolus regimen of eptifibatide in coronary intervention attains and maintains &gt;90% inhibition of platelet aggregation in &gt;90% of patients, providing the pharmacodynamic construct for the design of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of adjunctive eptifibatide in coronary stent implantation.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams &amp; Wilkins</pub><pmid>11468201</pmid><doi>10.1161/hc2901.093504</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0009-7322
ispartof Circulation (New York, N.Y.), 2001-07, Vol.104 (4), p.406-411
issn 0009-7322
1524-4539
language eng
recordid cdi_proquest_miscellaneous_71029635
source MEDLINE; American Heart Association Journals; Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals
subjects Angioplasty, Balloon, Coronary
Area Under Curve
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Dose-Response Relationship, Drug
Eptifibatide
Female
Humans
Male
Medical sciences
Metabolic Clearance Rate
Middle Aged
Peptides - pharmacokinetics
Pharmacology. Drug treatments
Platelet Aggregation - drug effects
Platelet Aggregation Inhibitors - pharmacokinetics
Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors
Time Factors
title Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-05T12%3A54%3A22IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Pharmacodynamics%20and%20pharmacokinetics%20of%20higher-dose,%20double-bolus%20eptifibatide%20in%20percutaneous%20coronary%20intervention&rft.jtitle=Circulation%20(New%20York,%20N.Y.)&rft.au=GILCHRIST,%20Ian%20C&rft.date=2001-07-24&rft.volume=104&rft.issue=4&rft.spage=406&rft.epage=411&rft.pages=406-411&rft.issn=0009-7322&rft.eissn=1524-4539&rft.coden=CIRCAZ&rft_id=info:doi/10.1161/hc2901.093504&rft_dat=%3Cproquest_cross%3E71029635%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=212704742&rft_id=info:pmid/11468201&rfr_iscdi=true