Advertisement

Current Cardiology Reports

, Volume 10, Issue 1, pp 37–42 | Cite as

Neuroprotection in cerebral ischemia: Emphasis on the SAINT trial

  • Marcus R. Chacon
  • Matt B. Jensen
  • Justin A. Sattin
  • Justin A. Zivin
Article

Abstract

Acute ischemic stroke (AIS) is a significant cause of death and disability in the United States. It has been 10 years since tissue plasminogen activator became the first medication approved by the US Food and Drug Administration for treatment for AIS. However, this treatment simply reopens arteries. The identification of deleterious cellular reactions that occur secondary to cerebral ischemia has led investigators to search for neuroprotection strategies to complement reperfusion. More than 100 human trials, including a handful of phase III trials, had failed to produce an efficacious neuroprotective agent. In 2006, the first positive trial of neuroprotection was published: the SAINT I (Stroke-Acute Ischemic NXY Treatment) study. In February 2008, the SAINT II study was published, indicating that NXY-059 was not effective for AIS treatment.

Keywords

Cerebral Ischemia Middle Cerebral Artery Occlusion Acute Ischemic Stroke Neuroprotective Agent Nalmefene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Thom T, Haase N, Rosamond W, et al.: Heart disease and stroke statistics—2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2006, 113:e85–e151.PubMedCrossRefGoogle Scholar
  2. 2.
    Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group [no authors listed]. N Engl J Med 1995, 333:1581–1587.Google Scholar
  3. 3.
    Lyden P, Wahlgren NG: Mechanisms of action of neuroprotectants in stroke. J Stroke Cerebrovasc Dis 2000, 9:9–14.PubMedCrossRefGoogle Scholar
  4. 4.
    O’Collins VE, Macleod MR, Donnan GA, et al.: 1,026 experimental treatments in acute stroke. Ann Neurol 2006, 59:467–477.PubMedCrossRefGoogle Scholar
  5. 5.
    Kidwell CS, Liebeskind DS, Starkman S, Saver JL: Trends in acute ischemic stroke trials through the 20th century. Stroke 2001, 32:1349–1359.PubMedGoogle Scholar
  6. 6.
    Lees KR, Zivin JA, Ashwood T, et al.: NXY-059 for acute ischemic stroke. N Engl J Med 2006, 354:588–600.PubMedCrossRefGoogle Scholar
  7. 7.
    Labiche LA, Grotta JC: Clinical trials for cytoprotection in stroke. NeuroRx 2004, 1:46–70.PubMedCrossRefGoogle Scholar
  8. 8.
    Davis SM, Lees KR, Albers GW, et al.: Selfotel in acute ischemic stroke: possible neurotoxic effects of an NMDA antagonist. Stroke 2000, 31:347–354.PubMedGoogle Scholar
  9. 9.
    Albers GW, Goldstein LB, Hall D, Lesko LM: Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial. JAMA 2001, 286:2673–2682.PubMedCrossRefGoogle Scholar
  10. 10.
    Lees KR, Asplund K, Carolei A, et al.: Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. GAIN International Investigators. Lancet 2000, 355:1949–1954.PubMedCrossRefGoogle Scholar
  11. 11.
    Sacco RL, DeRosa JT, Haley EC Jr, et al.: Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. JAMA 2001, 285:1719–1728.PubMedCrossRefGoogle Scholar
  12. 12.
    Lyden P, Shuaib A, Ng K, et al.: Clomethiazole Acute Stroke Study in ischemic stroke (CLASS-I): final results. Stroke 2002, 33:122–128.PubMedCrossRefGoogle Scholar
  13. 13.
    Clark WM, Raps EC, Tong DC, Kelly RE: Cervene (Nalmefene) in acute ischemic stroke: final results of a phase III efficacy study. The Cervene Stroke Study Investigators. Stroke 2000, 31:1234–1239.PubMedGoogle Scholar
  14. 14.
    Clark WM, Williams BJ, Selzer KA, et al.: A randomized efficacy trial of citicoline in patients with acute ischemic stroke. Stroke 1999, 30:2592–2597.PubMedGoogle Scholar
  15. 15.
    Clark WM, Wechsler LR, Sabounjian LA, Schwiderski UE: A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients. Neurology 2001, 57:1595–1602.PubMedGoogle Scholar
  16. 16.
    Davalos A, Castillo J, Alvarez-Sabin J, et al.: Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials. Stroke 2002, 33:2850–2857.PubMedCrossRefGoogle Scholar
  17. 17.
    Gladstone DJ, Black SE, Hakim AM: Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 2002, 33:2123–2136.PubMedCrossRefGoogle Scholar
  18. 18.
    Cheng YD, Al-Khoury L, Zivin JA: Neuroprotection for ischemic stroke: two decades of success and failure. NeuroRx 2004, 1:36–45.PubMedCrossRefGoogle Scholar
  19. 19.
    Lyden PD, Krieger D, Yenari M, Dietrich WD: Therapeutic hypothermia for acute stroke. Int J Stroke 2006, 1:9–19.CrossRefPubMedGoogle Scholar
  20. 20.
    Barone FC, Feuerstein GZ, White RF: Brain cooling during transient focal ischemia provides complete neuroprotection. Neurosci Biobehav Rev 1997, 21:31–44.PubMedCrossRefGoogle Scholar
  21. 21.
    Hoffman WE, Thomas C: Effects of graded hypothermia on outcome from brain ischemia. Neurol Res 1996, 18:185–189.PubMedCrossRefGoogle Scholar
  22. 22.
    Hoffman WE, Werner C, Baughman VL, et al.: Postischemic treatment with hypothermia improves outcome from incomplete cerebral ischemia in rats. J Neurosurg Anesthesiol 1991, 3:34–38.PubMedCrossRefGoogle Scholar
  23. 23.
    Huh PW, Belayev L, Zhao W, et al.: Comparative neuroprotective efficacy of prolonged moderate intraischemic and postischemic hypothermia in focal cerebral ischemia. J Neurosurg 2000, 92:91–99.PubMedCrossRefGoogle Scholar
  24. 24.
    Guluma KZ, Hemmen TM, Olsen SE, et al.: A trial of therapeutic hypothermia via endovascular approach in awake patients with acute ischemic stroke: methodology. Acad Emerg Med 2006, 13:820–827.PubMedCrossRefGoogle Scholar
  25. 25.
    Lyden PD, Allgren RL, Ng K, et al.: Intravascular Cooling in the Treatment of Stroke (ICTuS): early clinical experience. J Stroke Cerebrovasc Dis 2005, 14:107.PubMedCrossRefGoogle Scholar
  26. 26.
    ClinicalTrials.gov: Phase 1 Study of Intravenous Thrombolysis Plus Hypothermia for Acute Treatment of Ischemic Stroke. Available at http://www.clinicaltrials.gov/ct/show/NCT00283088. Accessed July 28, 2006.
  27. 27.
    ClinicalTrials.gov: Combined Neuroprotective Modalities: Caffeinol & Hypothermia Coupled With TPA. Available at http://www.clinicaltrials.gov/ct/show/NCT00299416. Accessed August 4, 2007.
  28. 28.
    Belayev L, Khoutorova L, Zhang Y, et al.: Caffeinol confers cortical but not subcortical neuroprotection after transient focal cerebral ischemia in rats. Brain Res 2004, 1008:278–283.PubMedCrossRefGoogle Scholar
  29. 29.
    Lapchak PA, Song D, Wei J, Zivin JA: Pharmacology of caffeinol in embolized rabbits: clinical rating scores and intracerebral hemorrhage incidence. Exp Neurol 2004, 188:286–291.PubMedCrossRefGoogle Scholar
  30. 30.
    ClinicalTrials.gov: A Phase III Randomized Multicenter Clinical Trial of High-Dose Human Albumin Therapy For Neuroprotection in Acute Ischemic Stroke. Available at http://www.clinicaltrials.gov/ct/show/NCT00235495. Accessed August 4, 2007.
  31. 31.
    Ginsberg MD, Hill MD, Palesch YY, et al.: The ALIAS Pilot Trial: a dose-escalation and safety study of albumin therapy for acute ischemic stroke—I: Physiological responses and safety results. Stroke 2006, 37:2100–2106.PubMedCrossRefGoogle Scholar
  32. 32.
    ClinicalTrials.gov: A Multicentre, Double-Blind, Placebo-Controlled, Ascending-Dose, Clinical Trial of Intravenous Microplasmin Administration in Patients With Acute Ischemic Stroke. Available at http://www.clinicaltrials.gov/ct/show/NCT00123305. Accessed August 4, 2007.
  33. 33.
    ClinicalTrials.gov: Controlled Study of ONO-2506 in Patients With Acute Ischemic Stroke. Available at http://www.clinicaltrials.gov/ct/show/NCT00229177. Accessed August 4, 2007.
  34. 34.
    ClinicalTrials.gov: A Multicentre, Double-Blind, Randomised, Placebo-Controlled, Dose-Escalating Parallel-Group Study to Investigate the Tolerability of Enecadin (INN) in Acute Ischemic Stroke. Available at http://www.clinicaltrials.gov/ct/show/NCT00331721. Accessed August 4, 2007.
  35. 35.
    Collen D: Revival of plasmin as a therapeutic agent? Thromb Haemost 2001, 86:731–732.PubMedGoogle Scholar
  36. 36.
    Lapchak PA, Araujo DM, Pakola S, et al.: Microplasmin: a novel thrombolytic that improves behavioral outcome after embolic strokes in rabbits. Stroke 2002, 33:2279–2284.PubMedCrossRefGoogle Scholar
  37. 37.
    Muir KW: Magnesium in stroke treatment. Postgrad Med J 2002, 78:641–645.PubMedCrossRefGoogle Scholar
  38. 38.
    Muir KW, Lees KR, Ford I, Davis S: Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. Lancet 2004, 363:439–445.PubMedCrossRefGoogle Scholar
  39. 39.
    Zivin JA: Slow-Mag. Stroke 2004, 35:1776–1777.PubMedCrossRefGoogle Scholar
  40. 40.
    ClinicalTrials.gov: Field Administration of Stroke Therapy-Magnesium Trial: A Randomized, Double-Blind, Placebo Controlled Trial of Neuroprotective Magnesium Sulfate Therapy for Acute Stroke Initiated Within 2 Hours of Onset by Paramedics in the Field. Available at http://www.clinicaltrials.gov/ct/show/NCT00059332. Accessed August 4, 2007.
  41. 41.
    Maples KR, Green AR, Floyd RA: Nitrone-related therapeutics: potential of NXY-059 for the treatment of acute ischaemic stroke. CNS Drugs 2004, 18:1071–1084.PubMedCrossRefGoogle Scholar
  42. 42.
    Chan PH: Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 2001, 21:2–14.PubMedCrossRefGoogle Scholar
  43. 43.
    Kontos HA: Oxygen radicals in cerebral ischemia: the 2001 Willis lecture. Stroke 2001, 32:2712–2716.PubMedCrossRefGoogle Scholar
  44. 44.
    Kuroda S, Tsuchidate R, Smith ML, et al.: Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 1999, 19:778–787.PubMedCrossRefGoogle Scholar
  45. 45.
    Sydserff SG, Borelli AR, Green AR, Cross AJ: Effect of NXY-059 on infarct volume after transient or permanent middle cerebral artery occlusion in the rat; studies on dose, plasma concentration and therapeutic time window. Br J Pharmacol 2002, 135:103–112.PubMedCrossRefGoogle Scholar
  46. 46.
    Zhao Z, Cheng M, Maples KR, et al.: NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal cerebral ischemia in the rat. Brain Res 2001, 909:46–50.PubMedCrossRefGoogle Scholar
  47. 47.
    Lapchak PA, Araujo DM, Song D, et al.: Effects of the spin trap agent disodium-[tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (generic NXY-059) on intracerebral hemorrhage in a rabbit large clot embolic stroke model: combination studies with tissue plasminogen activator. Stroke 2002, 33:1665–1670.PubMedCrossRefGoogle Scholar
  48. 48.
    Lapchak PA, Araujo DM, Song D, et al.: Neuroprotective effects of the spin trap agent disodium-[(tert-butylimino)m ethyl]benzene-1,3-disulfonate N-oxide (generic NXY-059) in a rabbit small clot embolic stroke model: combination studies with the thrombolytic tissue plasminogen activator. Stroke 2002, 33:1411–1415.PubMedCrossRefGoogle Scholar
  49. 49.
    Marshall JW, Duffin KJ, Green AR, Ridley RM: NXY-059, a free radical-trapping agent, substantially lessens the functional disability resulting from cerebral ischemia in a primate species. Stroke 2001, 32:190–198.PubMedGoogle Scholar
  50. 50.
    Marshall JW, Cummings RM, Bowes LJ, et al.: Functional and histological evidence for the protective effect of NXY-059 in a primate model of stroke when given 4 hours after occlusion. Stroke 2003, 34:2228–2233.PubMedCrossRefGoogle Scholar
  51. 51.
    Lees KR, Barer D, Ford GA, et al.: Tolerability of NXY-059 at higher target concentrations in patients with acute stroke. Stroke 2003, 34:482–487.PubMedCrossRefGoogle Scholar
  52. 52.
    Lees KR, Sharma AK, Barer D, et al.: Tolerability and pharmacokinetics of the nitrone NXY-059 in patients with acute stroke. Stroke 2001, 32:675–680.PubMedGoogle Scholar
  53. 53.
    Lyden PD, Shuaib A, Lees KR, et al.: Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: the CHANT Trial. Stroke 2007, 38:2262–2269.PubMedCrossRefGoogle Scholar
  54. 54.
    Adams HP Jr, Davis PH, Leira EC, et al.: Baseline NIH Stroke Scale score strongly predicts outcome after stroke: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology 1999, 53:126–131.PubMedGoogle Scholar
  55. 55.
    Shuaib A, Lees KR, Lyden P, et al.: NXY-059 for the treatment of acute ischemic stroke. N Engl J Med 2007, 357:562–571.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2008

Authors and Affiliations

  • Marcus R. Chacon
  • Matt B. Jensen
  • Justin A. Sattin
    • 1
  • Justin A. Zivin
  1. 1.Department of NeurosciencesUniversity of California San DiegoLa JollaUSA

Personalised recommendations