Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide
Irvine, Hannah J Acharjee, Animesh Wolcott, Zoe Ament, Zsuzsanna Hinson, H E Molyneaux, Bradley J Simard, J Marc Sheth, Kevin N Kimberly, W Taylor
Irvine, Hannah J
Acharjee, Animesh
Wolcott, Zoe
Ament, Zsuzsanna
Hinson, H E
Molyneaux, Bradley J
Simard, J Marc
Sheth, Kevin N
Kimberly, W Taylor
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2022-06-13
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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.
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Irvine HJ, Acharjee A, Wolcott Z, Ament Z, Hinson HE, Molyneaux BJ, Simard JM, Sheth KN, Kimberly WT. Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide. Cell Rep Med. 2022 Jun 21;3(6):100654. doi: 10.1016/j.xcrm.2022.100654. Epub 2022 Jun 13
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