Clinical trials for cytoprotection in stroke.
To date, many cytoprotective drugs have reached the stage of pivotal phase 3 efficacy trials in acute stroke patients. (Table 1) Unfortunately, throughout the neuroprotective literature, the phrase "failure to demonstrate efficacy" prevails as a common thread among the many neutral or negative trials, despite the largely encouraging results encountered in preclinical studies. The reasons for this discrepancy are multiple, and have been discussed by Dr. Zivin in his review. Many of the recent trials have addressed deficiencies of the previous ones with more rigorous trial design, including more specific patient selection criteria (ensure homogeneity of stroke location and severity), stratified randomization algorithms (time-to-treat), narrowed therapeutic time-window and pharmacokinetic monitoring. Current trials have also incorporated biologic surrogate markers of toxicity and outcome such as drug levels and neuroimaging. Lastly, multi-modal therapies and coupled cytoprotection/reperfusion strategies are being investigated to optimize tissue salvage. This review will focus on individual therapeutic strategies and we will emphasize what we have learned from these trials both in terms of trial design and the biologic effect (or lack thereof) of these agents.
Labiche
Lise A
LA
Stroke Program, University of Texas at Houston Medical School, 6431 Fannin Street, Houston, Texas 77030, USA.
Grotta
James C
JC
D000818:Animals; D001921:Brain / Q000187:drug effects*; D002986:Clinical Trials as Topic; D006801:Humans; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D012107:Research Design; D020521:Stroke / Q000628:therapy*; D016896:Treatment Outcome
D018696:Neuroprotective Agents
J Pharmacol Exp Ther. 2002 May;301(2):605-10
11961063
JAMA. 2001 Dec 5;286(21):2673-82
11730442
Cerebrovasc Dis. 2002;14(3-4):239-51
12403958
J Cereb Blood Flow Metab. 1992 Nov;12(6):971-6
1400651
Stroke. 1991 Sep;22(9):1137-42
1926256
J Neurosci. 1990 Jan;10(1):311-6
2405111
J Cell Sci. 1996 Oct;109 ( Pt 10):2571-80
8923218
Circulation. 1996 Sep 1;94(5):939-45
8790029
Cochrane Database Syst Rev. 2000;(2):CD000064
10796290
J Pharmacobiodyn. 1987 Oct;10(10):595-7
2831335
Stroke. 1995 Nov;26(11):2040-3
7482646
Stroke. 2001 Dec 1;32(12):2833-5
11739982
Stroke. 2000 Feb;31(2):404-9
10657413
Neuropharmacology. 1996 Jun;35(6):689-93
8887977
Cerebrovasc Dis. 2000 Nov-Dec;10(6):431-6
11070372
Stroke. 1995 Aug;26(8):1361-4
7543222
Lancet. 2000 Jun 3;355(9219):1949-54
10859040
Stroke. 1990 May;21(5):721-5
2339451
Cerebrovasc Dis. 2001;12(3):258-63
11641593
Exp Neurol. 1999 Mar;156(1):121-9
10192783
Brain Res. 1997 Feb 7;747(2):304-12
9046006
Clin Neuropharmacol. 1991 Oct;14(5):373-90
1742747
Lancet. 1996 Feb 17;347(8999):422-5
8618482
Stroke. 1997 Nov;28(11):2238-42; discussion 2243
9368571
Stroke. 1995 Apr;26(4):602-5
7709405
J Neurosurg. 1991 Jan;74(1):8-13
1984511
Brain Res. 1999 May 1;826(2):210-9
10224298
Stroke. 2001 Aug;32(8):1847-54
11486115
J Pharmacol Exp Ther. 1996 Nov;279(2):759-66
8930181
Crit Care Med. 2000 Aug;28(8):2831-6
10966258
J Biol Chem. 1999 Nov 26;274(48):34450-8
10567426
Neuropharmacology. 2000 Feb 14;39(4):691-702
10728890
J Cereb Blood Flow Metab. 1998 Dec;18(12):1336-45
9850146
J Cereb Blood Flow Metab. 1991 Nov;11(6):1025-30
1939380
Brain Res. 2000 Jan 17;853(1):68-73
10627309
N Engl J Med. 2002 Feb 21;346(8):557-63
11856794
Stroke. 2000 Sep;31(9):2251-6
10978060
Neurology. 1997 Sep;49(3):671-8
9305321
Cerebrovasc Dis. 1998 May-Jun;8(3):188-90
9619704
Stroke. 1998 Jun;29(6):1256-7
9626304
Acta Neurol Scand. 1984 Apr;69(4):232-9
6377803
Stroke. 1998 Oct;29(10):2171-80
9756600
Neurology. 1997 Nov;49(5 Suppl 4):S66-9
9371155
Neurology. 2001 Oct 23;57(8):1428-34
11673584
Neurosurgery. 1987 Apr;20(4):518-24
3587541
Ann Neurol. 1990 Jun;27(6):606-11
2163236
Acta Neurochir Suppl. 1996;66:107-13
8780807
Stroke. 1988 Feb;19(2):211-6
3278412
J Stroke Cerebrovasc Dis. 1996 Sep-Oct;6(1):35-40
17894963
J Neurosurg. 1963 Oct;20:849-59
14186080
Exp Neurol. 2000 May;163(1):200-6
10785459
Stroke. 1998 Jan;29(1):12-7
9445321
Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13496-500
10557349
Clin Ter. 1982 Aug 31;102(4):379-86
6754218
Exp Neurol. 1997 Jun;145(2 Pt 1):425-33
9217078
Stroke. 1993 Jul;24(7):1063-7
8100654
Stroke. 1990 Dec;21(12 Suppl):IV81-4
2260153
Stroke. 2001 Nov;32(11):2665-74
11692032
BMJ. 1989 Mar 11;298(6674):636-42
2496789
Br J Pharmacol. 2001 Jun;133(3):345-50
11375250
Stroke. 1995 Feb;26(2):254-8
7831698
J Pharmacol Exp Ther. 1996 Nov;279(2):748-58
8930180
Br Med J (Clin Res Ed). 1986 Jan 4;292(6512):21-3
3080050
Stroke. 1997 Dec;28(12):2338-46
9412611
Stroke. 1991 Jul;22(7):877-83
1677219
Stroke. 1994 Jan;25(1):202-11
7505494
Neuropharmacology. 2000 Jul 10;39(9):1483-94
10854894
Ann N Y Acad Sci. 2002 May;962:423-37
12076993
Stroke. 1994 Feb;25(2):418-23
8303754
Stroke. 1997 Mar;28(3):564-73
9056612
Stroke. 2001 Feb;32(2):461-5
11157183
Stroke. 1996 Jan;27(1):76-81
8553408
Ann Neurol. 1990 Jun;27(6):612-9
2163237
J Neurosci Res. 1999 Dec 1;58(5):697-705
10561698
Stroke. 2001 Feb;32(2):553-60
11157196
J Neurosurg. 1989 Jul;71(1):98-104
2661744
Ann Neurol. 2002 Nov;52(5):617-22
12402259
Stroke. 2001 Mar;32(3):675-80
11239186
Brain Res. 2001 Aug 3;909(1-2):46-50
11478919
Neurosci Lett. 2000 Sep 22;291(3):196-200
10984640
Biochem Pharmacol. 1988 Jun 1;37(11):2267-71
3377822
Stroke. 1984 Jan-Feb;15(1):36-9
6364463
Mol Endocrinol. 1997 Aug;11(9):1245-55
9259316
Stroke. 2000 Jun;31(6):1250-5
10835440
Stroke. 1995 Jan;26(1):117-21; discussion 121-2
7839380
Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8179-84
9223335
Magn Reson Imaging. 2001 Feb;19(2):153-60
11358652
Brain Res. 1995 Jun 5;682(1-2):182-8
7552309
Eur J Pharmacol. 1998 Oct 23;359(2-3):251-60
9832397
Brain Res Mol Brain Res. 2001 Feb 19;87(1):71-80
11223161
Stroke. 1995 Aug;26(8):1438-42; discussion 1443
7631350
Eur Neurol. 1998 Aug;40(2):78-83
9693236
Brain Pathol. 2000 Apr;10(2):283-92
10764048
Circulation. 2001 Oct 9;104(15):1799-804
11591617
Brain Res. 1990 Nov 5;532(1-2):336-8
2282527
Stroke. 1986 May-Jun;17(3):404-9
3715936
Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4635-40
9539790
Br J Pharmacol. 1996 Aug;118(7):1592-6
8842419
Postgrad Med J. 2002 Nov;78(925):641-5
12496316
Neuropharmacology. 2002 May;42(6):846-54
12015211
Ann Neurol. 2000 Nov;48(5):713-22
11079534
Undersea Hyperb Med. 2000 Winter;27(4):185-90
11419358
J Clin Invest. 2002 Dec;110(11):1729-38
12464678
J Pharmacol Exp Ther. 2001 Feb;296(2):312-21
11160612
Stroke. 1998 Jan;29(1):152-8
9445345
Stroke. 1999 May;30(5):986-92
10229732
Neurology. 2002 Jan 8;58(1):133-5
11781420
Stroke. 2000 Jun;31(6):1234-9
10835438
Stroke. 1991 Apr;22(4):437-41
2024271
Brain Res. 1992 Aug 7;587(2):233-40
1525659
Stroke. 2003 May;34(5):1242-5
12690224
J Nucl Med. 2001 Dec;42(12):1833-40
11752082
Brain Res. 1987 Oct 13;423(1-2):347-52
3119155
Ital J Neurol Sci. 1991 Dec;12(6):557-63
1783533
Stroke. 2001 Mar;32(3):783-7
11239202
Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6687-92
8692879
Acad Emerg Med. 1998 Jan;5(1):18-24
9444337
Neurol Res. 2001 Oct;23(7):755-60
11680517
Stroke. 1995 Jul;26(7):1183-8
7541572
Cerebrovasc Dis. 1998 May-Jun;8(3):172-81
9619701
Stroke. 2000 Jan;31(1):82-5
10625720
J Neurosurg. 1988 Apr;68(4):505-17
3280746
Transplant Proc. 2001 May;33(3):2390-2
11377571
Stroke. 1999 Jan;30(1):134-9
9880401
Neurology. 2001 Nov 13;57(9):1595-602
11706098
Stroke. 1994 Jul;25(7):1348-53
8023348
J Neurochem. 2002 Jan;80(1):12-23
11796739
Brain Pathol. 2002 Oct;12(4):488-98
12408236
Stroke. 2000 Feb;31(2):347-54
10657404
Indian J Physiol Pharmacol. 1998 Oct;42(4):555-8
10874361
Cochrane Database Syst Rev. 2002;(1):CD001924
11869612
Science. 1989 Jun 16;244(4910):1360-2
2660263
Stroke. 1999 Oct;30(10):2038-42
10512904
Surg Neurol. 1987 Oct;28(4):265-8
3629458
Eur J Pharmacol. 1994 Apr 15;267(2):R1-2
7519560
J Pharmacol Exp Ther. 1999 Feb;288(2):653-9
9918571
Stroke. 1992 Jan;23(1):3-8
1731418
J Cereb Blood Flow Metab. 1987 Dec;7(6):729-38
3693428
Neurosci Biobehav Rev. 1997 Jan;21(1):31-44
8994207
Stroke. 1994 Aug;25(8):1552-8
8042206
Proc Natl Acad Sci U S A. 1984 Oct;81(20):6388-92
6093100
J Neurosurg. 1996 Mar;84(3):405-14
8609551
Jpn J Psychiatry Neurol. 1986 Mar;40(1):61-79
3773354
Adv Pharmacol. 1997;37:319-48
8891106
Anesthesiology. 1993 Feb;78(2):335-42
8439029
Neurology. 1993 Feb;43(2):397-403
7679781
Stroke. 1995 Aug;26(8):1369-72
7631339
Brain Res. 2000 Apr 17;862(1-2):59-62
10799669
Stroke. 1998 Dec;29(12):2461-6
9836751
Brain Res Brain Res Rev. 1999 Aug;30(2):176-88
10525174
Acta Neurol Scand. 1989 Oct;80(4):282-6
2683557
N Engl J Med. 2002 Feb 21;346(8):549-56
11856793
Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10526-31
10984541
Brain Res. 2001 Oct 19;916(1-2):85-90
11597594
Stroke. 2003 May;34(5):1246-51
12690223
Stroke. 2000 Aug;31(8):1982-9; discussion 1989
10926967
J Cereb Blood Flow Metab. 1990 May;10(3):365-74
2329123
Stroke. 1999 May;30(5):993-6
10229733
J Neurosurg. 1986 May;64(5):780-6
3701424
Stroke. 1986 Sep-Oct;17(5):953-6
3532439
Exp Neurol. 2002 Oct;177(2):531-7
12429198
Stroke. 2001 Jan;32(1):190-8
11136936
Stroke. 1996 May;27(5):913-8
8623113
Stroke. 1999 Feb;30(2):427-31; discussion 431-2
9933283
Stroke. 2000 Jan;31(1):86-94
10625721
Stroke. 2002 Dec;33(12):2850-7
12468781
Neurology. 2002 Mar 26;58(6):945-52
11914413
Stroke. 1988 Aug;19(8):997-1002
3400111
Eur J Pharmacol. 1997 Nov 12;338(3):243-51
9424018
Stroke. 1999 Jan;30(1):21-8
9880383
Br J Pharmacol. 1991 Oct;104(2):406-11
1797307
Acta Physiol Scand. 1992 Dec;146(4):543-4
1492573
Stroke. 2001 Sep;32(9):2033-5
11546893
Brain Res. 1994 May 30;647(1):131-8
8069695
Eur J Appl Physiol. 2002 Mar;86(5):401-5
11882925
J Neuroimmunol. 2000 Sep 22;109(2):66-74
10996208
Eur J Pharmacol. 1989 May 2;164(1):153-8
2546785
J Neurochem. 2002 Nov;83(3):515-24
12390513
Stroke. 1999 Jul;30(7):1464-71
10390324
Stroke. 2000 Sep;31(9):2257-65
10978061
Neuropharmacology. 2000 Jan 4;39(2):211-7
10670416
Exp Neurol. 2000 Dec;166(2):298-306
11085895
Br J Pharmacol. 2002 Jan;135(1):103-12
11786485
Stroke. 1984 Jul-Aug;15(4):627-9
6087500
JAMA. 2001 Apr 4;285(13):1719-28
11277826
Neuroscience. 1997 Jan;76(1):105-16
8971763
J Neural Transm Suppl. 1998;53:299-311
9700666
Stroke. 1999 Nov;30(11):2416-21; discussion 2422
10548679
Stroke. 2001 Nov;32(11):2550-3
11692015
Brain Res. 2000 Nov 10;883(1):41-50
11063986
BMC Neurol. 2002 Apr 18;2:2
11960560
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4044-9
11259643
Am J Physiol. 1992 Sep;263(3 Pt 2):R734-7
1384353
Eur Arch Psychiatry Clin Neurosci. 2001 Aug;251(4):179-84
11697582
Neuropeptides. 1985 Feb;5(4-6):307-10
2860592
Stroke. 1996 Sep;27(9):1453-8
8784112
Stroke. 1998 May;29(5):918-23
9596235
Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15769-74
9861045
Stroke. 1999 Aug;30(8):1679-86
10436121
Neurosci Lett. 2000 May 12;285(2):119-22
10793241
Stroke. 1997 Nov;28(11):2214-8
9368567
J Cereb Blood Flow Metab. 1999 Jul;19(7):742-9
10413028
Cochrane Database Syst Rev. 2000;(2):CD000277
10796337
Brain Res. 2003 Jan 3;959(1):169-72
12480171
J Stroke Cerebrovasc Dis. 1999 Jul-Aug;8(4):224-30
17895169
Stroke. 1994 Nov;25(11):2253-7
7974553
Stroke. 1998 Oct;29(10):2129-35
9756594
Br Med J. 1978 Oct 7;2(6143):994-6
361156
Stroke. 2003 Jan;34(1):207-13
12511776
Neuropharmacology. 2000 Jan 28;39(3):515-22
10698017
Brain Res. 1997 Feb 21;749(1):131-4
9070637
Stroke. 1999 Dec;30(12):2592-7
10582983
Lancet. 1996 Jul 20;348(9021):193
8684167
Stroke. 2002 Jan;33(1):122-8
11779900
Stroke. 1999 Mar;30(3):624-9
10066862