Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Neurocritical Care Aims and scope Submit manuscript

Abstract

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 0–4, 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 0–4—90 % versus 50 % in controls p = 0.049; with a similar trend in mRS 0–3 (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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Woo SK, Kwon MS, Ivanov A, Gerzanich V, Simard JM. The sulfonylurea receptor 1 (Sur1)-transient receptor potential melastatin 4 (Trpm4) channel. J Biol Chem. 2013;288(5):3655–67.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Simard JM, Chen M, Tarasov KV, Bhatta S, Ivanova S, Melnitchenko L, Tsymbalyuk N, West GA, Gerzanich V. Newly expressed SUR1-regulated NC(ca-ATP) channel mediates cerebral edema after ischemic stroke. Nat Med. 2006;12(4):433–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Simard JM, Kent TA, Chen M, Tarasov KV, Gerzanich V. Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol. 2007;6(3):258–68.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Simard JM, Yurovsky V, Tsymbalyuk N, Melnichenko L, Ivanova S, Gerzanich V. Protective effect of delayed treatment with low-dose glibenclamide in three models of ischemic stroke. Stroke. 2009;40(2):604–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Simard JM, Tsymbalyuk N, Tsymbalyuk O, Ivanova S, Yurovsky V, Gerzanich V. Glibenclamide is superior to decompressive craniectomy in a rat model of malignant stroke. Stroke. 2010;41(3):531–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Simard JM, Woo SK, Tsymbalyuk N, Voloshyn O, Yurovsky V, Ivanova S, Lee R, Gerzanich V. Glibenclamide-10-h treatment window in a clinically relevant model of stroke. Transl Stroke Res. 2012;3(2):286–95.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Wali B, Ishrat T, Atif F, Hua F, Stein DG, Sayeed I. Glibenclamide administration attenuates infarct volume, hemispheric swelling, and functional impairments following permanent focal cerebral ischemia in rats. Stroke Res Treat. 2012;2012:460909.

    PubMed Central  PubMed  Google Scholar 

  8. Kunte H, Schmidt S, Eliasziw M, del Zoppo GJ, Simard JM, Masuhr F, Weih M, Dirnagl U. Sulfonylureas improve outcome in patients with type 2 diabetes and acute ischemic stroke. Stroke. 2007;38(9):2526–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Kunte H, Busch M, Trostdorf K, Vollnberg B, Harms L, Mehta R, Castellani R, Kent T, Mandava P, Simard J. Hemorrhagic transformation of ischemic stroke in diabetics on sulfonylureas. Ann Neurol. 2012;72:799–806.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Mlynash M, Lansberg MG, De Silva DA, Lee J, Christensen S, Straka M, Campbell BC, Bammer R, Olivot JM, Desmond P, Donnan GA, Davis SM, Albers GW, DEFUSE-EPITHET Investigators. Refining the definition of the malignant profile: insights from the DEFUSE-EPITHET pooled data set. Stroke. 2011;42(5):1270–5.

    Article  PubMed Central  PubMed  Google Scholar 

  11. The national institute of neurological disorders and stroke rt-PA stroke study group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581–7.

    Article  Google Scholar 

  12. Yoo AJ, Verduzco LA, Schaefer PW, Hirsch JA, Rabinov JD, Gonzalez RG. MRI-based selection for intra-arterial stroke therapy: value of pretreatment diffusion-weighted imaging lesion volume in selecting patients with acute stroke who will benefit from early recanalization. Stroke. 2009;40(6):2046–54.

    PubMed Central  PubMed  Google Scholar 

  13. Mlynash M, Lansberg MG, Straka M, Kemp S, Wechsler LR, Jovin TG, Wilder MJ, Lutsep HL, Czartoski T, Bernstein RA, Chang CW, Warach S, Fazekas F, Thai D, Inoue M. The malignant MRI profile: implications for endovascular therapy. Stroke. 2012;43:A53.

    Google Scholar 

  14. Sanak D, Nosal’ V, Horak D, Bartkova A, Zelenak K, Herzig R, Bucil J, Skoloudik D, Burval S, Cisarikova V, Vlachova I, Kocher M, Zapletalova J, Kurca E, Kanovsky P. Impact of diffusion-weighted MRI-measured initial cerebral infarction volume on clinical outcome in acute stroke patients with middle cerebral artery occlusion treated by thrombolysis. Neuroradiology. 2006;48(9):632–9.

    PubMed  Google Scholar 

  15. Sheth KN, Kimberly WT, Elm JJ, Kent TA, Mandava P, Yoo AJ, Thomalla G, Campbell B, Donnan GA, Davis SM, Albers GW, Jacobson S, Simard JM, Stern BJ. Pilot study of intravenous glyburide in patients with a large ischemic stroke. Stroke. 2014;45(1):281–3.

    CAS  PubMed  Google Scholar 

  16. Kimberly WT, Battey TW, Pham L, Wu O, Yoo AJ, Furie KL, Singhal AB, Elm JJ, Stern BJ, Sheth KN. Glyburide is associated with attenuated vasogenic edema in stroke patients. Neurocrit Care. 2014;20(2):193–201.

    Google Scholar 

  17. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317–29.

    CAS  PubMed  Google Scholar 

  18. Thomalla G, Hartmann F, Juettler E, Singer OC, Lehnhardt FG, Kohrmann M, Kersten JF, Krutzelmann A, Humpich MC, Sobesky J, Gerloff C, Villringer A, Fiehler J, Neumann-Haefelin T, Schellinger PD, Rother J, Clinical Trial Net of the German Competence Network Stroke. Prediction of malignant middle cerebral artery infarction by magnetic resonance imaging within 6 hours of symptom onset: a prospective multicenter observational study. Ann Neurol. 2010;68(4):435–45.

    PubMed  Google Scholar 

  19. Sims JR, Gharai LR, Schaefer PW, Vangel M, Rosenthal ES, Lev MH, Schwamm LH. ABC/2 for rapid clinical estimate of infarct, perfusion, and mismatch volumes. Neurology. 2009;72(24):2104–10.

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, Barber PA, Bladin C, De Silva DA, Byrnes G, Chalk JB, Fink JN, Kimber TE, Schultz D, Hand PJ, Frayne J, Hankey G, Muir K, Gerraty R, Tress BM, Desmond PM, EPITHET investigators. Effects of alteplase beyond 3 h after stroke in the echoplanar imaging thrombolytic evaluation trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol. 2008;7(4):299–309.

    PubMed  Google Scholar 

  21. Yoo AJ, Sheth KN, Kimberly WT, Chaudhry ZA, Elm JJ, Jacobson S, Davis SM, Donnan GA, Albers GW, Stern BJ, Gonzalez RG. Validating imaging biomarkers of cerebral edema in patients with severe ischemic stroke. J Stroke Cerebrovasc Dis. 2012;22(6):742–9.

    PubMed  Google Scholar 

  22. Kimberly WT, Sheth KN. Approach to severe hemispheric stroke. Neurology. 2011;76(7 Suppl 2):S50–6.

    PubMed  Google Scholar 

  23. Simard JM, Sahuquillo J, Sheth KN, Kahle KT, Walcott BP. Managing malignant cerebral infarction. Curr Treat Options Neurol. 2011;13(2):217–29.

    PubMed Central  PubMed  Google Scholar 

  24. Vahedi K, Hofmeijer J, Juettler E, Vicaut E, George B, Algra A, Amelink GJ, Schmiedeck P, Schwab S, Rothwell PM, Bousser MG, van der Worp HB, Hacke W. DECIMAL, DESTINY, and HAMLET investigators. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol. 2007;6(3):215–22.

    PubMed  Google Scholar 

  25. Bergstralh EJ, Kosanke JL. Computerized matching of cases to controls. Technical report 56; 1995. http://www.mayo.edu/research/documents/biostat-56pdf/doc-10026923. Accessed 10 Mar 2014.

  26. Mandava P, Kalkonde YV, Rochat RH, Kent TA. A matching algorithm to address imbalances in study populations: application to the national institute of neurological diseases and stroke recombinant tissue plasminogen activator acute stroke trial. Stroke. 2010;41(4):765–70.

    PubMed  Google Scholar 

  27. Friedman JH, Bentley JL, Finkel RA. An algorithm for finding best matches in logarithmic time. ACM Trans Math Softw. 1977;3(3):209–26.

    Google Scholar 

  28. Matlab ® (homepage on the internet). Classification using nearest neighbors. Statistics toolbox; 2013. http://www.mathworks.com/help/stats/classification-using-nearest-neighbors.html#bsehylk. Accessed 10 Mar 2014.

  29. Mandava P, Dalmeida W, Anderson JA, Thiagarajan P, Fabian RH, Weir RU, Kent TA. A pilot trial of low-dose intravenous abciximab and unfractionated heparin for acute ischemic stroke: translating GP IIb/IIIa receptor inhibition to clinical practice. Transl Stroke Res. 2010;1(3):170–7.

    CAS  PubMed  Google Scholar 

  30. Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R. ‘Malignant’ middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol. 1996;53(4):309–15.

    CAS  PubMed  Google Scholar 

  31. Berrouschot J, Sterker M, Bettin S, Koster J, Schneider D. Mortality of space-occupying (‘malignant’) middle cerebral artery infarction under conservative intensive care. Intensiv Care Med. 1998;24(6):620–3.

    CAS  Google Scholar 

  32. Simard JM, Geng Z, Silver FL, Sheth KN, Kimberly WT, Stern BJ, Colucci M, Gerzanich V. Does inhibiting Sur1 complement rt-PA in cerebral ischemia? Ann N Y Acad Sci. 2012;1268:95–107.

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Woo SK, Kwon MS, Geng Z, Chen Z, Ivanov A, Bhatta S, Gerzanich V, Simard JM. Sequential activation of hypoxia-inducible factor 1 and specificity protein 1 is required for hypoxia-induced transcriptional stimulation of Abcc8. J Cereb Blood Flow Metab. 2011;32(3):525–36.

    PubMed Central  PubMed  Google Scholar 

  34. Dowlatshahi D, Demchuk AM, Flaherty ML, Ali M, Lyden PL, Smith EE, VISTA Collaboration. Defining hematoma expansion in intracerebral hemorrhage: relationship with patient outcomes. Neurology. 2011;76(14):1238–44.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Videen TO, Zazulia AR, Manno EM, Derdeyn CP, Adams RE, Diringer MN, Powers WJ. Mannitol bolus preferentially shrinks non-infarcted brain in patients with ischemic stroke. Neurology. 2001;57(11):2120–2.

    CAS  PubMed  Google Scholar 

  36. Lo EH, Broderick JP, Moskowitz MA. tPA and proteolysis in the neurovascular unit. Stroke. 2004;35(2):354–6.

    PubMed  Google Scholar 

  37. Hofmeijer J, Kappelle LJ, Algra A, Amelink GJ, van Gijn J, van der Worp HB. HAMLET investigators. Surgical decompression for space-occupying cerebral infarction (the hemicraniectomy after middle cerebral artery infarction with life-threatening edema trial [HAMLET]): a multicentre, open, randomised trial. Lancet Neurol. 2009;8(4):326–33.

    PubMed  Google Scholar 

  38. Steiner T, Mendoza G, De Georgia M, Schellinger P, Holle R, Hacke W. Prognosis of stroke patients requiring mechanical ventilation in a neurological critical care unit. Stroke. 1997;28(4):711–5.

    CAS  PubMed  Google Scholar 

  39. Rabinstein AA, Wijdicks EF. Outcome of survivors of acute stroke who require prolonged ventilatory assistance and tracheostomy. Cerebrovasc Dis. 2004;18(4):325–31.

    PubMed  Google Scholar 

  40. Golestanian E, Liou JI, Smith MA. Long-term survival in older critically ill patients with acute ischemic stroke. Crit Care Med. 2009;37(12):3107–13.

    PubMed Central  PubMed  Google Scholar 

  41. Frank JI. Large hemispheric infarction, deterioration, and intracranial pressure. Neurology. 1995;45(7):1286–90.

    CAS  PubMed  Google Scholar 

  42. Mandava P, Krumpelman CS, Shah JN, White DL, Kent TA. Quantification of errors in ordinal outcome scales using Shannon entropy: effect on sample size calculations. PLoS One. 2013;8(7):e67754.

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Hankey GJ, Spiesser J, Hakimi Z, Bego G, Carita P, Gabriel S. Rate, degree, and predictors of recovery from disability following ischemic stroke. Neurology. 2007;68(19):1583–7.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The study PI (KNS) made all decisions regarding analysis and publication and assumes responsibility for the manuscript. The Stroke Outcomes Laboratory (TAK, PM) was supported by a Pilot Grant from the Institute for Clinical and Translational Research at the Baylor College of Medicine.

Clinical Trial Registration

URL: www.clinicaltrials.gov Identifier: NCT01268683.

Funding

The sponsor for this study was Remedy Pharmaceuticals, Inc.

Author information

Authors and Affiliations

  1. Departments of Neurology and Neurosurgery, Yale University School of Medicine, 15 York Street, LCI 710A, New Haven, CT, 06520, USA

    Kevin N. Sheth

  2. Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

    W. Taylor Kimberly

  3. Medical University of South Carolina, Columbia, SC, USA

    Jordan J. Elm

  4. Michael E. DeBakey VA Medical Center Stroke Program and the Stroke Outcomes Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX, USA

    Thomas A. Kent & Pitchaiah Mandava

  5. Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA

    Albert J. Yoo

  6. Klinik Und Poliklinik für Neurologie, Kopf- Und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

    Götz Thomalla

  7. Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia

    Bruce Campbell, Geoffrey A. Donnan & Stephen M. Davis

  8. Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA

    Gregory W. Albers

  9. Remedy Pharmaceuticals, Inc, New York, NY, USA

    Sven Jacobson

  10. Department of Hematology, University of Washington School of Medicine, Seattle, WA, USA

    Gregory del Zoppo

  11. Departments of Neurology, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, MD, USA

    J. Marc Simard & Barney J. Stern

  12. Department of Neurosurgery, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, MD, USA

    J. Marc Simard

Authors
  1. Kevin N. Sheth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. Taylor Kimberly
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jordan J. Elm
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas A. Kent
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Albert J. Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Götz Thomalla
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bruce Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Geoffrey A. Donnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stephen M. Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gregory W. Albers
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sven Jacobson
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Gregory del Zoppo
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J. Marc Simard
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Barney J. Stern
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Pitchaiah Mandava
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kevin N. Sheth.

Additional information

W. Taylor Kimberly has contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sheth, K.N., Taylor Kimberly, W., Elm, J.J. et al. Exploratory Analysis of Glyburide as a Novel Therapy for Preventing Brain Swelling. Neurocrit Care 21, 43–51 (2014). https://doi.org/10.1007/s12028-014-9970-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12028-014-9970-2

Keywords

Search

Navigation