Emerging drugs for acute ischemic stroke

Expert Opinion on Emerging Drugs

Volumn 14, Issue 1, 2009, Pages 33-42

  Sicard, Kenneth M ^b   Fisher, Marc ^a  

^a UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

^b St Vincent Hospital   (United States)

Author keywords

Albumin; CT; Diffusion; Erythropoietin; G CSF; Magnesium; MERCI retriever; MRI; Neuroprotection; Penumbra; Perfusion; Reperfusion; Thrombolysis; tPA

Indexed keywords

ACETYLSALICYLIC ACID; ALBUMIN; ALTEPLASE; ANCROD; AX 200; CITICOLINE; DESMOTEPLASE; DISUFENTON SODIUM; ERYTHROPOIETIN; GRANULOCYTE COLONY STIMULATING FACTOR; HEPARIN; MAGNESIUM; MAGNESIUM SULFATE; PLACEBO; PROUROKINASE; SARUPLASE; TISSUE PLASMINOGEN ACTIVATOR; UNCLASSIFIED DRUG; UROKINASE; FIBRINOLYTIC AGENT;

ACUTE DISEASE; BRAIN HEMORRHAGE; BRAIN INFARCTION; BRAIN INFARCTION SIZE; BRAIN ISCHEMIA; CEREBROVASCULAR ACCIDENT; CLINICAL TRIAL; DISABILITY; DOSE RESPONSE; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; DRUG SAFETY; FIBRINOLYTIC THERAPY; FUNCTIONAL STATUS; HUMAN; LOW DRUG DOSE; LUNG EDEMA; MORTALITY; NEUROIMAGING; NEUROPROTECTION; NONHUMAN; OUTCOME ASSESSMENT; PATHOPHYSIOLOGY; PROGNOSIS; RECANALIZATION; REPERFUSION; REVIEW; UNSPECIFIED SIDE EFFECT; ANIMAL; HOSPITAL SUBDIVISIONS AND COMPONENTS; METHODOLOGY; STROKE; TREATMENT OUTCOME;

ACUTE DISEASE; ANIMALS; BRAIN ISCHEMIA; CLINICAL TRIALS AS TOPIC; FIBRINOLYTIC AGENTS; HOSPITAL UNITS; HUMANS; STROKE; THROMBOLYTIC THERAPY; TREATMENT OUTCOME;

EID: 65649092057     PISSN: 14728214     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728210902748365     Document Type: Review

References (83)

1. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 1997;339:342-344 (Pubitemid 27192468)
2. Heuschmann PU, Kolominsky-Rabas PL, Roether J, et al. Predictors of in-hospital mortality in patients with acute ischemic stroke treated with thrombolytic therapy. J Am Med Assoc 2004;292:1831-1838 (Pubitemid 40169293)
3. Hankey GJ, Jamrozik K, Broadhurst RJ, et al. Long-term risk of first recurrent stroke in the Perth Community Stroke Study. Stroke 1998;29:2491-2500 (Pubitemid 28543996)
4. Hacke W, Albers G, Al-Rawi Y, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 2005;36:66-73 (Pubitemid 40054177)
5. Baron JC, Warach S. Imaging. Stroke 2005;36:196-199
6. Jahan R. Hyperacute therapy of acute ischemic stroke: intraarterial thrombolysis and mechanical revascularization strategies. Tech Vasc Interv Radiol 2005;8:87-91 (Pubitemid 41368560)
7. Schabitz WR, Fisher M. Perspectives on neuroprotective stroke therapy. Biochem Soc Trans 2006;34:1271-1276 (Pubitemid 46769036)
8. 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;333:1581-1588
9. Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST). Lancet 2007;369:275-82 • The results of tPA use in clinical practice among approximately 6400 patients demonstrated safety and efficacy in routine clinical practice.
10. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). J Am Med Assoc 1995;274:1017-1025
11. Hacke W, Kaste M, Fieschi C, et al. Randomized double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 1998;352:1245-1251 (Pubitemid 28470336)
12. Clark WN, Wissman S, Albers GW, et al. Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial, Alteplase Thrombolysis for acute noninterventional therapy in ischemic stroke. J Am Med Assoc 1999;282:2019-2026
13. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768-74 •• This important pooled analysis of several tPA trials demonstrated that very early treatment, within 90 min of AIS onset, was highly efficacious, but treatment within 3- 4.5 h may offer additional benefit.
14. Hacke W, Kaste M, Bluhmki E, et al. (for the ECASS Investigators). Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. N Engl J Med 2008;359:1317-29 •• This recently reported study demonstrated that the time window for i.v. tPA could be extended to 4.5 h after stroke onset.
15. Fisher M, Bastan B. Treating acute ischemic stroke. Curr Opin Drug Discov Devel 2008;11:626-632
16. Ribo M, Molina CA, Rovira A, et al. Safety and efficacy of intravenous tissue plasminogen activator in the 3- to 6-hour window using multimodal transcranial Doppler/MRI selection protocol. Stroke 2005;36:602-606 (Pubitemid 40344163)
17. Schellinger PD, Thomalla G, Fiehler J, et al. MRI-based and CT-based thrombolytic therapy in acute stroke within and beyond established time windows: an analysis of 1210 patients. Stroke 2007;38:2640-45 •• This large case series of tPA-treated patients demonstrated that selection of patients for treatment in the 3- 6 h time window based upon diffusion/perfusion mismatch identifies a group likely to respond. (Pubitemid 47493997)
18. Davis SM, Donnan GA, Parsons MW, et al. Effects of alteplase beyond 3h after stroke onset in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomized trial. Lancet Neurol 2008;7:299-399 •• An important MRI-based, randomized, placebo-controlled study of tPA in the 3- 6 h time window that will serve as the basis of a future Phase III pivotal trial.
19. Furlan AJ, Eyding D, Albers GW, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 2006;37:1227-1231 (Pubitemid 43731867)
20. Forest Laboratories Inc. Topline results of phase III study in acute ischemic stroke (DIAS-2) do not demonstrate difference between desmoteplase and placebo. Press Release 31 May 2007
21. Warach S. Clinical benefit of desmoteplase treatment in patients with moderate to severe stroke: Further results of the DIAS-2 Trial. International Stroke Conference 2008, New Orleans, LA, USA (2008): LBP2 Meeting dates: 20-22 February 2008.
22. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. J Am Med Assoc 1999;282:2003-2011
23. Ogawa A, Mori E, Minematsu K, et al. Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: The middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan. Stroke 2007;38:2633-2639 (Pubitemid 47493996)
24. Lisboa RC, Jovanovic BD, Alberts MJ. Analysis of the safety and efficacy on intra-arterial thrombolytic therapy in ischemic stroke. Stroke 2002;33:2866-2871 (Pubitemid 35462858)
25. Lindsberg PJ, Mattle HP. Therapy of basilar artery occlusion: a systematic analysis comparing intra-arterial and intravenous thrombolysis. Stroke 2006;37:922-928 (Pubitemid 43731936)
26. Mandava P, Kent TA. Intra-arterial therapies for acute ischemic stroke. Neurology 2007;68:2132-39 • This analysis of a case series of patients treated with IA thrombolysis concludes that the studies were highly variable and so do not provide evidence that such treatment is beneficial.
27. IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: The Interventional Management of Stroke Study. Stroke 2004;35:904-911 (Pubitemid 38419800)
28. The IMS II Trial Investigators. The Interventional Management of Stroke (IMS) Study. Stroke 2007;38:2127-2135
29. Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: Results of the MERCI trial. Stroke 2005;36:1432-40 • Presents the data that led to FDA approval of the MERCI device for the removal of intracranial clots. (Pubitemid 40967507)
30. Smith WS, Sung G, Saver J, et al. Mechanical thrombectomy for acute ischemic stroke: Final results of the Multi MERCI trial. Stroke 2008;39:1205-1211
31. The Penumbra Stroke Trial. Penumbra Inc, Alameda, CA, USA. Available from: www.penumbrainc.com/physicians/ clinical-trial
32. Fisher M, Ratan R. New perspectives on developing acute stroke therapy. Ann Neurol 2003;53:10-20 (Pubitemid 36083824)
33. Lo EH, Moskowitz MA, Jacobs TP. Exciting, radical, suicidal: how brain cells die after stroke. Stroke 2005;36:189-192 (Pubitemid 40170779)
34. Hossman KA. Pathophysiology and therapy of experimental stroke. Cell Mol Neurobiol 2006;26:1055-1081
35. Lo EH. Experimental models, neurovascular mechanisms and translational issues in stroke research. Br J Pharmacol 2008;153:S396-405 (Pubitemid 351341004)
36. Bardutzky J, Meng X, Bouley J, et al. Effects of intravenous dimethyl sulfoxide on ischemia evolution in a rat permanent occlusion model. J Cereb Blood Flow Metab 2005;25:968-977 (Pubitemid 41061712)
37. Ning M, Furie KL, Koroshetz WJ, et al. Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke. Neurology 2006;66:1550-1555 (Pubitemid 43958553)
38. Belayev L, Busto R, Zhao W, et al. Effect of delayed albumin hemodilution on infarction volume and brain edema after transient middle cerebral artery occlusion in rats. J Neurosurg 1997;87:595-601 (Pubitemid 27430403)
39. Belayev L, Zhao W, Pattany PM, et al. Diffusion-weighted magnetic resonance imaging confirms marked neuroprotective efficacy of albumin therapy in focal cerebral ischemia. Stroke 1998;29:2587-2599 (Pubitemid 28544011)
40. Belayev L, Liu Y, Zhao W, et al. Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke 2001;32:553-560 (Pubitemid 32155250)
41. Ginsberg MD, Belayev L, Bazan NG, et al. Albumin-based neurotherapeutics for acute ischemic stroke: from bench to bedside. In: Krieglstein J, Klumpp S, Editors, Pharmacology of Cerebral Ischemia, Medpharm Scientific Publishers, Stuttgart, Germany; 2004 . p. 421-433
42. Wayner DD, Burton GW, Ingold KU, et al. Quantitative measurement of the total, peroxyl radical-trapping antioxidant capability of human blood plasma by controlled peroxidation. The important contribution made by plasma proteins. FEBS Lett 1985;187:33-37
43. He P, Curry FE. Albumin modulation of capillary permeability: role of endothelial cell [Ca2+]i. Am J Physiol 1993;265:H74-82 (Pubitemid 23224692)
44. Huh PW, Belayev L, Zhao W, et al. The effect of high-dose albumin therapy on local cerebral perfusion after transient focal cerebral ischemia in rats. Brain Res 1998;804:105-113 (Pubitemid 28410484)
45. Belayev L, Pinard E, Nallet H, et al. Albumin therapy of transient focal cerebral ischemia: in vivo analysis of dynamic microvascular responses. Stroke 2002;33:1077-1084 (Pubitemid 34293595)
46. Rodriguez de Turco EB, Belayev L, Liu Y, et al. Systemic fatty acid responses to transient focal cerebral ischemia: influence of neuroprotectant therapy with human albumin. J Neurochem 2002;83:515-524 (Pubitemid 35231805)
47. Palesch YY, Hill MD, Ryckborst KJ, et al. The ALIAS Pilot Trial: a dose-escalation and safety study of albumin therapy for acute ischemic stroke. II. Neurological outcome and efficacy-analysis. Stroke 2006;37:2107-2114
48. 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
49. Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology 2008;55:363-389
50. Ovbiagele B, Kidwell CS, Starkman S, et al. Neuroprotective agents for the treatment of acute ischemic stroke. Curr Neurol Neurosci Rep 2003;3:9-20 (Pubitemid 38898978)
51. Izumi Y, Roussel S, Pinard E, et al. Reduction of infarct volume by magnesium after middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab 1991;11:1025-1030
52. Yang Y, Li Q, Ahmad F, et al. Survival and histological evaluation of therapeutic window of post-ischemia treatment with magnesium sulfate in embolic stroke model of rat. Neurosci Lett 2000;285:119-122 (Pubitemid 30227634)
53. Westermaier T, Zausinger S, Baethmann A, et al. Dose finding study of intravenous magnesium sulphate in transient focal cerebral ischemia in rats. Acta Neurochir (Wien) 2005;147:525-532 (Pubitemid 40603116)
54. Marinov MB, Harbaugh KS, Hoopes PJ, et al. Neuroprotective effects of preischemia intraarterial magnesium sulfate in reversible focal cerebral ischemia. J Neurosurg 1996;85:117-124 (Pubitemid 26195046)
55. Meloni BP, Zhu H, Knuckey NW. Is magnesium neuroprotective following global and focal cerebral ischaemia? A review of published studies. Magn Res 2006;19:123-137 (Pubitemid 44229159)
56. Stewart D, Marder VJ, Starkman S, et al. Magnesium sulfate neither potentiates nor inhibits tissue plasminogen activator-induced thrombolysis. J Thromb Haemost 2006;4:1575-1579 (Pubitemid 43919186)
57. Muir KW, Lees KR, Ford I, et al. Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. Lancet 2004;363:439-445 (Pubitemid 38210060)
58. Saver JL, Kidwell C, Eckstein M, et al. Prehospital neuroprotective therapy for acute stroke: results of the Field Administration of Stroke Therapy-Magnesium (FAST-MAG) pilot trial. Stroke 2004;35:e106-08
59. Internet Stroke Center, Stroke Trials Registry. 2007. Available from: http://www.strokecenter.org/trials/index.aspx.
60. FAST-MAG Trial website. 2007. Available from: http://www.fastmag.info/p- summ.htm.
61. Sherman DG, Atkinson RP, Chippendale T, et al. Intravenous ancrod for treatment of acute ischemic stroke: the STAT study: a randomized controlled trial. Stroke Treatment with Ancrod Trial. JAMA 2000;283:2395-2403 (Pubitemid 30257538)
62. Hennerici MG, Kay R, Bogousslavsky J, et al. Intravenous ancrod for acute ischaemic stroke in the European Stroke Treatment with Ancrod Trial: a randomised controlled trial. Lancet 2006;368:1871-1878 (Pubitemid 44794528)
63. Ntaios G, Savopoulos C, Chatzinikolaou A, et al. The neuroprotective role of erythropoietin in the management of acute ischaemic stroke: from bench to bedside. Acta Neurol Scand 2008;118:362-368.
64. NIH Clinical Trials Registry. 2008. Available from: www.clinicaltrials. gov.
65. Schabitz WR, Schneider A. New targets for established proteins: exploring G-CSF for the treatment of stroke. Trends Pharmacol Sci 2007;28:157-161 (Pubitemid 46483721)
66. Schneider A, Kruger C, Steigleder T, et al. The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 2005;115:569-573 (Pubitemid 41134150)
67. Gibson CL, Bath PM, Murphy SP, et al. G-CSF reduces infarct volume and improves functional outcome after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 2005;25:431-439 (Pubitemid 40502992)
68. Komine-Kobayashi M, Zhang N, Liu M, et al. Neuroprotective effect of recombinant human granulocyte colony stimulating factor in transient focal ischemia of mice. J Cereb Blood Flow Metab 2006;26:402-413 (Pubitemid 43297921)
69. Schabitz WR, Kollmar R, Schwaninger M, et al. Neuroprotective effect of granulocyte colony stimulating factor after focal cerebral ischemia. Stroke 2003;34:745-751 (Pubitemid 36307405)
70. Schneider A, Wysocki R, Pitzer C, et al. An extended window of opportunity for G-CSF treatment in cerebral ischemia. BMC Biol 2006;4:36 (Pubitemid 44697094)
71. Shyu WC, Lin SZ, Yang HI, et al. Functional recovery of stroke rats induced by granulocyte colony stimulating factor-stimulated stem cells. Circulation 2004;110:1847-1854 (Pubitemid 39299228)
72. Minnerup J, Heidrich J, Wellman J, et al. Meta-Analysis of the efficacy of granulocyte colony stimulating factor in the animal models of focal cerebral ischemia. Stroke 2008;39:1855-1861
73. Rogalweski A, Schneider A, Ringelstein EB, et al. Toward a multimodal neuroprotective treatment of stroke. Stroke 2006;37:1129-1136
74. Shyu WC, Lin SZ, Lee CC, et al. Granulocyte colony stimulating factor for acute ischemic stroke: a randomized controlled trial. CMAJ 2006;174:927-933
75. Sprigg N, Bath PM, Zhao L, et al. Granulocyte colony stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: the Stem cell Trial of recovery Enhancement after Stroke (STEMS) pilot randomized, controlled trial (ISRCTN 16784092). Stroke 2006;37:2979-2983
76. Secades JJ, Lorenzo JL. Citicoline: pharmacological profile and clinical review, 2006 update. Methods Find Exp Clin Pharmacol 2006;28(Suppl B):1-56 (Pubitemid 44569736)
77. 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 (Pubitemid 35462855)
78. Fisher M, Albers GW, Donnan GA, et al. Enhancing the development and approval of acute stroke therapies: Stroke Therapy Academic Industry roundtable. Stroke 2005;36:1808-1813 (Pubitemid 41098783)
79. Donnan GA. A new road map for neuroprotection. Stroke 2008;39:242-48 •• The continued failure of neuroprotective drugs led to this assessment of what steps should be considered in the future to increase the chance of success with such agents.
80. Phan TG, Donnan GA, Davis SM, et al. Proof-of-principle phase II MRI studies in stroke: Sample size estimates from dichotomous and continuous data. Stroke 2006;37:2521-2525 (Pubitemid 44454672)
81. Fisher M, Cheung K, Howard G, et al. New pathways forevaluating potential acute stroke therapies. Int J Stroke 2006;1:52-8 • Provides suggestions for the design and implementation of future Phase II stroke trials.
82. Lees KR, Zivin JA, Ashwood T, et al. NXY-059 for acute ischemic stroke. N Engl J Med 2006;354:588-600 (Pubitemid 43209106)
83. 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 (Pubitemid 47236281)