Loading…

Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide

Brain edema after a large stroke causes significant morbidity and mortality. Here, we seek to identify pharmacodynamic markers of edema that are modified by intravenous (i.v.) glibenclamide (glyburide; BIIB093) treatment. Using metabolomic profiling of 399 plasma samples from patients enrolled in th...

Full description

Saved in:
Bibliographic Details
Published in:Cell reports. Medicine 2022-06, Vol.3 (6), p.100654-100654, Article 100654
Main Authors: Irvine, Hannah J., Acharjee, Animesh, Wolcott, Zoe, Ament, Zsuzsanna, Hinson, H.E., Molyneaux, Bradley J., Simard, J. Marc, Sheth, Kevin N., Kimberly, W. Taylor
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c455t-7a6954f8cc5778b3921bc5a7aa59bb629b871f18a0a94398546a7a51e5d57c193
cites cdi_FETCH-LOGICAL-c455t-7a6954f8cc5778b3921bc5a7aa59bb629b871f18a0a94398546a7a51e5d57c193
container_end_page 100654
container_issue 6
container_start_page 100654
container_title Cell reports. Medicine
container_volume 3
creator Irvine, Hannah J.
Acharjee, Animesh
Wolcott, Zoe
Ament, Zsuzsanna
Hinson, H.E.
Molyneaux, Bradley J.
Simard, J. Marc
Sheth, Kevin N.
Kimberly, W. Taylor
description Brain edema after a large stroke causes significant morbidity and mortality. Here, we seek to identify pharmacodynamic markers of edema that are modified by intravenous (i.v.) glibenclamide (glyburide; BIIB093) treatment. Using metabolomic profiling of 399 plasma samples from patients enrolled in the phase 2 Glyburide Advantage in Malignant Edema and Stroke (GAMES)-RP trial, 152 analytes are measured using liquid chromatography-tandem mass spectrometry. Associations with midline shift (MLS) and the matrix metalloproteinase-9 (MMP-9) level that are further modified by glibenclamide treatment are compared with placebo. Hypoxanthine is the only measured metabolite that associates with MLS and MMP-9. In sensitivity analyses, greater hypoxanthine levels also associate with increased net water uptake (NWU), as measured on serial head computed tomography (CT) scans. Finally, we find that treatment with i.v. glibenclamide reduces plasma hypoxanthine levels across all post-treatment time points. Hypoxanthine, which has been previously linked to inflammation, is a biomarker of brain edema and a treatment response marker of i.v. glibenclamide treatment. [Display omitted] •Hypoxanthine is associated with brain edema, including midline shift•Hypoxanthine is reduced by i.v. glibenclamide treatment•Hypoxanthine mediates the association between i.v. glibenclamide and midline shift In this study, Irvine et al. demonstrate that hypoxanthine, a metabolite linked to hypoxia and inflammation, is associated with brain edema and attenuated by i.v. glibenclamide treatment in patients with large ischemic stroke. These findings provide insight into markers of brain edema, which causes secondary neurologic injury after stroke.
doi_str_mv 10.1016/j.xcrm.2022.100654
format article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9244997</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S2666379122001860</els_id><sourcerecordid>2676925127</sourcerecordid><originalsourceid>FETCH-LOGICAL-c455t-7a6954f8cc5778b3921bc5a7aa59bb629b871f18a0a94398546a7a51e5d57c193</originalsourceid><addsrcrecordid>eNp9Uc9vFCEUJkZjm7b_QA-Go5ddgRlgSIyJadSaNPFSL72QB7zpss4MK8w23f9eJlubevEEed8PHt9HyCVna864-rBdP_o8rgUTog6Yku0rciqUUqtGG_76xf2EXJSyZYwJyXnXsLfkpJGaMd3yU3J3fdilR5jmTZyQxkKB7jaQR_ApHCYYo6cj5F-Yaeor7De4jFyGOFEMOAIdU4h9xEDdgd4P0eHkh6oLeE7e9DAUvHg6z8jPr19ur65XNz--fb_6fLPyrZTzSoMysu0776XWnWuM4M5L0ADSOKeEcZ3mPe-AgWkb08lWVVBylEFqz01zRj4dfXd7N2LwOM0ZBrvLsW5-sAmi_ReZ4sbepwdrRNsao6vB-yeDnH7vscx2rD_FYYAJ075YobQyNTyxUMWR6nMqJWP__AxndunFbu3Si116scdequjdywWfJX9bqISPRwLWmB4iZlt8rDliiBn9bEOK__P_A6tCn-s</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2676925127</pqid></control><display><type>article</type><title>Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide</title><source>ScienceDirect</source><source>PubMed Central</source><creator>Irvine, Hannah J. ; Acharjee, Animesh ; Wolcott, Zoe ; Ament, Zsuzsanna ; Hinson, H.E. ; Molyneaux, Bradley J. ; Simard, J. Marc ; Sheth, Kevin N. ; Kimberly, W. Taylor</creator><creatorcontrib>Irvine, Hannah J. ; Acharjee, Animesh ; Wolcott, Zoe ; Ament, Zsuzsanna ; Hinson, H.E. ; Molyneaux, Bradley J. ; Simard, J. Marc ; Sheth, Kevin N. ; Kimberly, W. Taylor</creatorcontrib><description>Brain edema after a large stroke causes significant morbidity and mortality. Here, we seek to identify pharmacodynamic markers of edema that are modified by intravenous (i.v.) glibenclamide (glyburide; BIIB093) treatment. Using metabolomic profiling of 399 plasma samples from patients enrolled in the phase 2 Glyburide Advantage in Malignant Edema and Stroke (GAMES)-RP trial, 152 analytes are measured using liquid chromatography-tandem mass spectrometry. Associations with midline shift (MLS) and the matrix metalloproteinase-9 (MMP-9) level that are further modified by glibenclamide treatment are compared with placebo. Hypoxanthine is the only measured metabolite that associates with MLS and MMP-9. In sensitivity analyses, greater hypoxanthine levels also associate with increased net water uptake (NWU), as measured on serial head computed tomography (CT) scans. Finally, we find that treatment with i.v. glibenclamide reduces plasma hypoxanthine levels across all post-treatment time points. Hypoxanthine, which has been previously linked to inflammation, is a biomarker of brain edema and a treatment response marker of i.v. glibenclamide treatment. [Display omitted] •Hypoxanthine is associated with brain edema, including midline shift•Hypoxanthine is reduced by i.v. glibenclamide treatment•Hypoxanthine mediates the association between i.v. glibenclamide and midline shift In this study, Irvine et al. demonstrate that hypoxanthine, a metabolite linked to hypoxia and inflammation, is associated with brain edema and attenuated by i.v. glibenclamide treatment in patients with large ischemic stroke. These findings provide insight into markers of brain edema, which causes secondary neurologic injury after stroke.</description><identifier>ISSN: 2666-3791</identifier><identifier>EISSN: 2666-3791</identifier><identifier>DOI: 10.1016/j.xcrm.2022.100654</identifier><identifier>PMID: 35700741</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Administration, Intravenous ; Biomarkers ; brain edema ; Brain Edema - diagnostic imaging ; glibenclamide ; Glyburide - administration &amp; dosage ; Humans ; hypoxanthine ; Hypoxanthine - blood ; inflammation ; Matrix Metalloproteinase 9 - therapeutic use ; metabolism ; metabolomics ; stroke ; Stroke - complications</subject><ispartof>Cell reports. Medicine, 2022-06, Vol.3 (6), p.100654-100654, Article 100654</ispartof><rights>2022 The Author(s)</rights><rights>Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.</rights><rights>2022 The Author(s) 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-7a6954f8cc5778b3921bc5a7aa59bb629b871f18a0a94398546a7a51e5d57c193</citedby><cites>FETCH-LOGICAL-c455t-7a6954f8cc5778b3921bc5a7aa59bb629b871f18a0a94398546a7a51e5d57c193</cites><orcidid>0000-0002-0316-4348 ; 0000-0002-2519-8530 ; 0000-0003-2735-7010 ; 0000-0002-3377-1229 ; 0000-0003-1598-9782</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9244997/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S2666379122001860$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,3549,27924,27925,45780,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35700741$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Irvine, Hannah J.</creatorcontrib><creatorcontrib>Acharjee, Animesh</creatorcontrib><creatorcontrib>Wolcott, Zoe</creatorcontrib><creatorcontrib>Ament, Zsuzsanna</creatorcontrib><creatorcontrib>Hinson, H.E.</creatorcontrib><creatorcontrib>Molyneaux, Bradley J.</creatorcontrib><creatorcontrib>Simard, J. Marc</creatorcontrib><creatorcontrib>Sheth, Kevin N.</creatorcontrib><creatorcontrib>Kimberly, W. Taylor</creatorcontrib><title>Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide</title><title>Cell reports. Medicine</title><addtitle>Cell Rep Med</addtitle><description>Brain edema after a large stroke causes significant morbidity and mortality. Here, we seek to identify pharmacodynamic markers of edema that are modified by intravenous (i.v.) glibenclamide (glyburide; BIIB093) treatment. Using metabolomic profiling of 399 plasma samples from patients enrolled in the phase 2 Glyburide Advantage in Malignant Edema and Stroke (GAMES)-RP trial, 152 analytes are measured using liquid chromatography-tandem mass spectrometry. Associations with midline shift (MLS) and the matrix metalloproteinase-9 (MMP-9) level that are further modified by glibenclamide treatment are compared with placebo. Hypoxanthine is the only measured metabolite that associates with MLS and MMP-9. In sensitivity analyses, greater hypoxanthine levels also associate with increased net water uptake (NWU), as measured on serial head computed tomography (CT) scans. Finally, we find that treatment with i.v. glibenclamide reduces plasma hypoxanthine levels across all post-treatment time points. Hypoxanthine, which has been previously linked to inflammation, is a biomarker of brain edema and a treatment response marker of i.v. glibenclamide treatment. [Display omitted] •Hypoxanthine is associated with brain edema, including midline shift•Hypoxanthine is reduced by i.v. glibenclamide treatment•Hypoxanthine mediates the association between i.v. glibenclamide and midline shift In this study, Irvine et al. demonstrate that hypoxanthine, a metabolite linked to hypoxia and inflammation, is associated with brain edema and attenuated by i.v. glibenclamide treatment in patients with large ischemic stroke. These findings provide insight into markers of brain edema, which causes secondary neurologic injury after stroke.</description><subject>Administration, Intravenous</subject><subject>Biomarkers</subject><subject>brain edema</subject><subject>Brain Edema - diagnostic imaging</subject><subject>glibenclamide</subject><subject>Glyburide - administration &amp; dosage</subject><subject>Humans</subject><subject>hypoxanthine</subject><subject>Hypoxanthine - blood</subject><subject>inflammation</subject><subject>Matrix Metalloproteinase 9 - therapeutic use</subject><subject>metabolism</subject><subject>metabolomics</subject><subject>stroke</subject><subject>Stroke - complications</subject><issn>2666-3791</issn><issn>2666-3791</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9Uc9vFCEUJkZjm7b_QA-Go5ddgRlgSIyJadSaNPFSL72QB7zpss4MK8w23f9eJlubevEEed8PHt9HyCVna864-rBdP_o8rgUTog6Yku0rciqUUqtGG_76xf2EXJSyZYwJyXnXsLfkpJGaMd3yU3J3fdilR5jmTZyQxkKB7jaQR_ApHCYYo6cj5F-Yaeor7De4jFyGOFEMOAIdU4h9xEDdgd4P0eHkh6oLeE7e9DAUvHg6z8jPr19ur65XNz--fb_6fLPyrZTzSoMysu0776XWnWuM4M5L0ADSOKeEcZ3mPe-AgWkb08lWVVBylEFqz01zRj4dfXd7N2LwOM0ZBrvLsW5-sAmi_ReZ4sbepwdrRNsao6vB-yeDnH7vscx2rD_FYYAJ075YobQyNTyxUMWR6nMqJWP__AxndunFbu3Si116scdequjdywWfJX9bqISPRwLWmB4iZlt8rDliiBn9bEOK__P_A6tCn-s</recordid><startdate>20220621</startdate><enddate>20220621</enddate><creator>Irvine, Hannah J.</creator><creator>Acharjee, Animesh</creator><creator>Wolcott, Zoe</creator><creator>Ament, Zsuzsanna</creator><creator>Hinson, H.E.</creator><creator>Molyneaux, Bradley J.</creator><creator>Simard, J. Marc</creator><creator>Sheth, Kevin N.</creator><creator>Kimberly, W. Taylor</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>6I.</scope><scope>AAFTH</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0316-4348</orcidid><orcidid>https://orcid.org/0000-0002-2519-8530</orcidid><orcidid>https://orcid.org/0000-0003-2735-7010</orcidid><orcidid>https://orcid.org/0000-0002-3377-1229</orcidid><orcidid>https://orcid.org/0000-0003-1598-9782</orcidid></search><sort><creationdate>20220621</creationdate><title>Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide</title><author>Irvine, Hannah J. ; Acharjee, Animesh ; Wolcott, Zoe ; Ament, Zsuzsanna ; Hinson, H.E. ; Molyneaux, Bradley J. ; Simard, J. Marc ; Sheth, Kevin N. ; Kimberly, W. Taylor</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-7a6954f8cc5778b3921bc5a7aa59bb629b871f18a0a94398546a7a51e5d57c193</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Administration, Intravenous</topic><topic>Biomarkers</topic><topic>brain edema</topic><topic>Brain Edema - diagnostic imaging</topic><topic>glibenclamide</topic><topic>Glyburide - administration &amp; dosage</topic><topic>Humans</topic><topic>hypoxanthine</topic><topic>Hypoxanthine - blood</topic><topic>inflammation</topic><topic>Matrix Metalloproteinase 9 - therapeutic use</topic><topic>metabolism</topic><topic>metabolomics</topic><topic>stroke</topic><topic>Stroke - complications</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Irvine, Hannah J.</creatorcontrib><creatorcontrib>Acharjee, Animesh</creatorcontrib><creatorcontrib>Wolcott, Zoe</creatorcontrib><creatorcontrib>Ament, Zsuzsanna</creatorcontrib><creatorcontrib>Hinson, H.E.</creatorcontrib><creatorcontrib>Molyneaux, Bradley J.</creatorcontrib><creatorcontrib>Simard, J. Marc</creatorcontrib><creatorcontrib>Sheth, Kevin N.</creatorcontrib><creatorcontrib>Kimberly, W. Taylor</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell reports. Medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Irvine, Hannah J.</au><au>Acharjee, Animesh</au><au>Wolcott, Zoe</au><au>Ament, Zsuzsanna</au><au>Hinson, H.E.</au><au>Molyneaux, Bradley J.</au><au>Simard, J. Marc</au><au>Sheth, Kevin N.</au><au>Kimberly, W. Taylor</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide</atitle><jtitle>Cell reports. Medicine</jtitle><addtitle>Cell Rep Med</addtitle><date>2022-06-21</date><risdate>2022</risdate><volume>3</volume><issue>6</issue><spage>100654</spage><epage>100654</epage><pages>100654-100654</pages><artnum>100654</artnum><issn>2666-3791</issn><eissn>2666-3791</eissn><abstract>Brain edema after a large stroke causes significant morbidity and mortality. Here, we seek to identify pharmacodynamic markers of edema that are modified by intravenous (i.v.) glibenclamide (glyburide; BIIB093) treatment. Using metabolomic profiling of 399 plasma samples from patients enrolled in the phase 2 Glyburide Advantage in Malignant Edema and Stroke (GAMES)-RP trial, 152 analytes are measured using liquid chromatography-tandem mass spectrometry. Associations with midline shift (MLS) and the matrix metalloproteinase-9 (MMP-9) level that are further modified by glibenclamide treatment are compared with placebo. Hypoxanthine is the only measured metabolite that associates with MLS and MMP-9. In sensitivity analyses, greater hypoxanthine levels also associate with increased net water uptake (NWU), as measured on serial head computed tomography (CT) scans. Finally, we find that treatment with i.v. glibenclamide reduces plasma hypoxanthine levels across all post-treatment time points. Hypoxanthine, which has been previously linked to inflammation, is a biomarker of brain edema and a treatment response marker of i.v. glibenclamide treatment. [Display omitted] •Hypoxanthine is associated with brain edema, including midline shift•Hypoxanthine is reduced by i.v. glibenclamide treatment•Hypoxanthine mediates the association between i.v. glibenclamide and midline shift In this study, Irvine et al. demonstrate that hypoxanthine, a metabolite linked to hypoxia and inflammation, is associated with brain edema and attenuated by i.v. glibenclamide treatment in patients with large ischemic stroke. These findings provide insight into markers of brain edema, which causes secondary neurologic injury after stroke.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>35700741</pmid><doi>10.1016/j.xcrm.2022.100654</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-0316-4348</orcidid><orcidid>https://orcid.org/0000-0002-2519-8530</orcidid><orcidid>https://orcid.org/0000-0003-2735-7010</orcidid><orcidid>https://orcid.org/0000-0002-3377-1229</orcidid><orcidid>https://orcid.org/0000-0003-1598-9782</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 2666-3791
ispartof Cell reports. Medicine, 2022-06, Vol.3 (6), p.100654-100654, Article 100654
issn 2666-3791
2666-3791
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9244997
source ScienceDirect; PubMed Central
subjects Administration, Intravenous
Biomarkers
brain edema
Brain Edema - diagnostic imaging
glibenclamide
Glyburide - administration & dosage
Humans
hypoxanthine
Hypoxanthine - blood
inflammation
Matrix Metalloproteinase 9 - therapeutic use
metabolism
metabolomics
stroke
Stroke - complications
title Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T19%3A27%3A22IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Hypoxanthine%20is%20a%20pharmacodynamic%20marker%20of%20ischemic%20brain%20edema%20modified%20by%20glibenclamide&rft.jtitle=Cell%20reports.%20Medicine&rft.au=Irvine,%20Hannah%20J.&rft.date=2022-06-21&rft.volume=3&rft.issue=6&rft.spage=100654&rft.epage=100654&rft.pages=100654-100654&rft.artnum=100654&rft.issn=2666-3791&rft.eissn=2666-3791&rft_id=info:doi/10.1016/j.xcrm.2022.100654&rft_dat=%3Cproquest_pubme%3E2676925127%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c455t-7a6954f8cc5778b3921bc5a7aa59bb629b871f18a0a94398546a7a51e5d57c193%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2676925127&rft_id=info:pmid/35700741&rfr_iscdi=true