Exploratory Analysis of Glyburide as a Novel Therapy for Preventing Brain Swelling

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• 作者：Kevin N. Sheth (1)
  W. Taylor Kimberly (3)
  Jordan J. Elm (4)
  Thomas A. Kent (5)
  Albert J. Yoo (6)
  G?tz Thomalla (7)
  Bruce Campbell (8)
  Geoffrey A. Donnan (8)
  Stephen M. Davis (8)
  Gregory W. Albers (9)
  Sven Jacobson (10)
  Gregory del Zoppo (11)
  J. Marc Simard (12) (13)
  Barney J. Stern (12)
  Pitchaiah Mandava (5)
  
• 关键词：Malignant edema ; Stroke ; Cerebral edema ; Brain swelling ; Hemorrhage ; Hemorrhagic transformation ; Clinical trial ; Decompressive craniectomy
• 刊名：Neurocritical Care
• 出版年：2014
• 出版时间：August 2014
• 年：2014
• 卷：21
• 期：1
• 页码：43-51
• 全文大小：579 KB
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• 作者单位：Kevin N. Sheth (1)
  W. Taylor Kimberly (3)
  Jordan J. Elm (4)
  Thomas A. Kent (5)
  Albert J. Yoo (6)
  G?tz Thomalla (7)
  Bruce Campbell (8)
  Geoffrey A. Donnan (8)
  Stephen M. Davis (8)
  Gregory W. Albers (9)
  Sven Jacobson (10)
  Gregory del Zoppo (11)
  J. Marc Simard (12) (13)
  Barney J. Stern (12)
  Pitchaiah Mandava (5)
  
  1. Departments of Neurology and Neurosurgery, Yale University School of Medicine, 15 York Street, LCI 710A, New Haven, CT, 06520, USA
  3. Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
  4. Medical University of South Carolina, Columbia, SC, USA
  5. Michael E. DeBakey VA Medical Center Stroke Program and the Stroke Outcomes Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX, USA
  6. Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
  7. Klinik Und Poliklinik für Neurologie, Kopf- Und Neurozentrum, Universit?tsklinikum Hamburg-Eppendorf, Hamburg, Germany
  8. Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia
  9. Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA
  10. Remedy Pharmaceuticals, Inc, New York, NY, USA
  11. Department of Hematology, University of Washington School of Medicine, Seattle, WA, USA
  12. Departments of Neurology, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, MD, USA
  13. Department of Neurosurgery, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, MD, USA
  
• ISSN：1556-0961

文摘

Background Malignant infarction is characterized by the formation of cerebral edema, and medical treatment is limited. Preclinical data suggest that glyburide, an inhibitor of SUR1-TRPM4, is effective in preventing edema. We previously reported feasibility of the GAMES-Pilot study, a two-center prospective, open label, phase IIa trial of 10 subjects at high risk for malignant infarction based on diffusion weighted imaging (DWI) threshold of 82?cm3 treated with RP-1127 (glyburide for injection). In this secondary analysis, we tested the hypothesis that RP-1127 may be efficacious in preventing poor outcome when compared to controls. Methods Controls suffering large hemispheric infarction were obtained from the EPITHET and MMI-MRI studies. We first screened subjects for controls with the same DWI threshold used for enrollment into GAMES-Pilot, 82?cm3. Next, to address imbalances, we applied a weighted Euclidean matching. Ninety day mRS 0-, rate of decompressive craniectomy, and mortality were the primary clinical outcomes of interest. Results The mean age of the GAMES cohort was 51?years and initial DWI volume was 102?±?23?cm3. After Euclidean matching, GAMES subjects showed similar NIHSS, higher DWI volume, younger age and had mRS 0--0?% versus 50?% in controls p?=?0.049; with a similar trend in mRS 0- (40 vs. 25?%; p?=?0.43) and trend toward lower mortality (10 vs. 35?%; p?=?0.21). Conclusions In this pilot study, RP-1127-treated subjects showed better clinical outcomes when compared to historical controls. An adequately powered and randomized phase II trial of patients at risk for malignant infarction is needed to evaluate the potential efficacy of RP-1127.