@article{1f46a0dba33a448f9ad6b91764e15b3e,
title = "Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide",
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.",
keywords = "brain edema, glibenclamide, hypoxanthine, inflammation, metabolism, metabolomics, stroke",
author = "Irvine, {Hannah J.} and Animesh Acharjee and Zoe Wolcott and Zsuzsanna Ament and Hinson, {H. E.} and Molyneaux, {Bradley J.} and Simard, {J. Marc} and Sheth, {Kevin N.} and Kimberly, {W. Taylor}",
note = "Funding Information: The GAMES-RP Trial was originally funded by Remedy Pharmaceuticals, Inc . J.M.S. is supported by grants from NHLBI ( R01 HL082517 ) and NINDS ( R01 NS060801 ). W.T.K. is supported by grants from NINDS ( R01 NS099209 , R21 NS120002 , and 3U01 NS106513-S1 ) and AHA ( AHA 20SRG35540018 ). A.A. was supported by the National Institute for Health Research (NIHR) Surgical Reconstruction and Microbiology Research Center ( SRMRC ), Birmingham, UK. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, the Medical Research Council, or the Department of Health. Funding Information: The GAMES-RP Trial was originally funded by Remedy Pharmaceuticals, Inc. J.M.S. is supported by grants from NHLBI (R01 HL082517) and NINDS (R01 NS060801). W.T.K. is supported by grants from NINDS (R01 NS099209, R21 NS120002, and 3U01 NS106513-S1) and AHA (AHA 20SRG35540018). A.A. was supported by the National Institute for Health Research (NIHR) Surgical Reconstruction and Microbiology Research Center (SRMRC), Birmingham, UK. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, the Medical Research Council, or the Department of Health. Conceptualization, H.J.I. A.A. and W.T.K.; methodology, H.J.I. A.A. Z.W. Z.A. and W.T.K.; investigation, H.J.I. A.A. Z.A. and W.T.K.; writing – original draft, H.J.I. and W.T.K.; writing – review & editing, H.J.I. A.A. Z.W. Z.A. H.E.H. B.J.M. J.M.S. K.N.S. and W.T.K.; funding acquisition, K.N.S. and W.T.K.; supervision, K.N.S. and W.T.K. J.M.S. has a patent related to the study and serves on the Board of Directors for Remedy Pharmaceuticals. H.E.H. B.J.M. W.T.K. and K.N.S. received grants from Remedy Pharmaceuticals outside the submitted work. H.E.H. K.N.S. and W.T.K. received research grants from Biogen and the American Heart Association. W.T.K. received grants and personal fees from NControl Therapeutics outside the submitted work. K.N.S. received grants from Bard, Hyperfine, and Astrocyte outside the submitted work. H.E.H. B.J.M. J.M.S. and W.T.K. received personal fees from Biogen outside the submitted work. During the peer review process, Biogen had the opportunity to review the manuscript. The authors retained full editorial control of the manuscript and provided their final approval of all content. Funding Information: J.M.S. has a patent related to the study and serves on the Board of Directors for Remedy Pharmaceuticals. H.E.H., B.J.M., W.T.K., and K.N.S. received grants from Remedy Pharmaceuticals outside the submitted work. H.E.H., K.N.S., and W.T.K. received research grants from Biogen and the American Heart Association. W.T.K. received grants and personal fees from NControl Therapeutics outside the submitted work. K.N.S. received grants from Bard, Hyperfine, and Astrocyte outside the submitted work. H.E.H., B.J.M., J.M.S., and W.T.K. received personal fees from Biogen outside the submitted work. During the peer review process, Biogen had the opportunity to review the manuscript. The authors retained full editorial control of the manuscript and provided their final approval of all content. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = jun,
day = "21",
doi = "10.1016/j.xcrm.2022.100654",
language = "English (US)",
volume = "3",
journal = "Cell Reports Medicine",
issn = "2666-3791",
publisher = "Cell Press",
number = "6",
}