Combination therapy for ischemic stroke: Potential of neuroprotectants plus thrombolytics

American Journal of Cardiovascular Drugs

Volumn 2, Issue 5, 2002, Pages 303-313

  Chen, Shang Der ^a,b   Lee, Jin Moo ^a   Yang, Ding I ^a,c   Nassief, Abdullah ^a   Hsu, Chung Y ^a  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b CHANG GUNG MEMORIAL HOSPITAL   (Taiwan)

^c TZU CHI UNIVERSITY   (Taiwan)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINOBUTYRIC ACID RECEPTOR STIMULATING AGENT; 4 PHOSPHONOMETHYLPIPECOLIC ACID; ALTEPLASE; AMPA RECEPTOR ANTAGONIST; ANTIINFLAMMATORY AGENT; APTIGANEL; CALCIUM CHANNEL BLOCKING AGENT; CITICOLINE; CLOMETHIAZOLE; CYCLOHEXIMIDE; EBSELEN; ELIPRODIL; FIBRINOLYTIC AGENT; FIBROBLAST GROWTH FACTOR; FLUNARIZINE; GAVESTINEL; GLUTAMATE RECEPTOR ANTAGONIST; GLYCINE RECEPTOR ANTAGONIST; LAMOTRIGINE; MAGNESIUM SULFATE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; NEUROPROTECTIVE AGENT; NEUTROPHIL INHIBITORY FACTOR; NIMODIPINE; NITRIC OXIDE SYNTHASE INHIBITOR; PD 152247; PROUROKINASE; SCAVENGER; TIRILAZAD; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANTIINFLAMMATORY ACTIVITY; APOPTOSIS; ARTICLE; BLOOD CLOT LYSIS; BRAIN INJURY; BRAIN ISCHEMIA; CELL DEATH; CEREBROVASCULAR ACCIDENT; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DRUG EFFICACY; ENZYME ACTIVATION; HUMAN; INDUCED HYPOTHERMIA; NEUROPROTECTION; NONHUMAN; OXIDATIVE STRESS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; SIDE EFFECT;

EID: 0036399717     PISSN: 11753277     EISSN: None     Source Type: Journal    
DOI: 10.2165/00129784-200202050-00003     Document Type: Article

References (130)

1. Mortality patterns - United States 1997. MMWR Morb Mortal Wkly Rep 1999; 48 (30): 664-8
2. Fisher M, Bogousslavsky J. Further evolution toward effective therapy for acute ischemic stroke [comment in: JAMA 1998 Apr 22-29; 279 (16): 1304-6]. JAMA 1998; 279 (16): 1298-303
3. Lee JM, Zipfel GJ, Choi DW. The changing landscape of ischaemic brain injury mechanisms. Nature 1999 Jun 24; 399 (6738 Suppl.): A7-A14
4. 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
5. Goldberg MP. Stroke trials data base [online] in Internet Stroke Center at Washington University. Available from URL: http://www.neuro.wustl.edu/stroke/stroke-trials.htm [Accessed 2001 Jun 15]
6. Clark WM, 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. JAMA 1999 Dec 1; 282 (21): 2019-26
7. Hacke W, Brott T, Caplan L, et al. Thrombolysis in acute ischemic stroke: controlled trials and clinical experience. Neurology 1999; 53 (7 Suppl. 4): S3-S14
8. 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. JAMA 1999 Dec 1; 282 (21): 2003-11
9. Lutsep HL, Albers GW, DeCrespigny A, et al. Clinical utility of diffusion-weighted magnetic resonance imaging in the assessment of ischemic stroke. Ann Neurol 1997 May; 41 (5): 574-80
10. Fisher M, Warach S. New magnetic resonance imaging techniques for stroke diagnosis and treatment. In: Hsu CY, editor. Ischemic stroke: from basic mechanisms to new drug development. Switzerland: Karger, 1998: 139-50
11. Marks MP, Tong DC, Beaulieu C, et al. Evaluation of early reperfusion and i.v. tPA therapy using diffusion- and perfusion-weighted MRI. Neurology 1999 Jun 10; 52 (9): 1792-8
12. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999 Sep; 22 (9): 391-7
13. Lipton P. Ischemic cell death in brain neurons. Physiol Rev 1999 Oct; 79 (4): 1431-568
14. Choi DW, Rothman SM. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci 1990; 13: 171-82
15. Choi DW, Koh JY. Zinc and brain injury. Annu Rev Neurosci 1998; 21: 347-75
16. Koh JY, Suh SW, Gwag BJ, et al. The role of zinc in selective neuronal death after transient global cerebral ischemia. Science 1996 May 17; 272 (5264): 1013-6
17. Chan PH. Role of oxidants in ischemic brain damage. Stroke 1996 Jun; 27 (6): 1124-9
18. Iadecola C. Bright and dark sides of nitric oxide in ischemic brain injury. Trends Neurosci 1997; 20 (3): 132-9
19. Dalkara T, Moskowitz MA. Nitric oxide in cerebrovascular regulation and ischemia. In: Hsu CY, editor. Ischemic stroke: from basic mechanisms to new drug development. Switzerland: Karger, 1998: 28-45
20. Beckman JS, Beckman TW, Chen J, et al. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A 1990 Feb; 87 (4): 1620-4
21. Huang Z, Huang PL, Panahian N, et al. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 1994 Sep 23; 265 (5180): 1883-5
22. Huang Z, et al. Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine. J Cereb Blood Flow Metab 1996 Sep; 16 (5): 981-7
23. Iadecola C, Zhang F, Casey R, et al. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci 1997 Dec 1; 17 (23): 9157-64
24. Charriaut-Marlangue C, Margail I, Represa A, et al. Apoptosis and necrosis after reversible focal ischemia: an in situ DNA fragmentation analysis. J Cereb Blood Flow Metab 1996; 16 (2): 186-94
25. MacManus JP, Linnik MD. Gene expression induced by cerebral ischemia: an apoptotic perspective. J Cereb Blood Flow Metab 1997 Aug; 17 (8): 815-32
26. Martin LJ, Al-Abdullah NA, Brambrink AM, et al. Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: a perspective on the contributions of apoptosis and necrosis. Brain Res Bull 1998; 46 (4): 281-309
27. Green DR, Reed JC. Mitochondria and apoptosis. Science 1998 Aug 28; 281 (5381): 1309-12
28. Kroemer G, Dallaporta B, Resche-Rigon M. The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol 1998; 60: 619-42
29. Lorenzo HK, Susin A, Penninger J, et al. Apoptosis inducing factor (AIF): a phylogenetically old caspase-independent effector of cell death. Cell Death Differ 1999; 6 (6): 516-24
30. Li K, Li Y, Shelton JM, et al. Cytochrome c deficiency causes embryonic lethality and attenuates stress-induced apoptosis. Cell 2000; 101 (4): 389-99
31. Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91 (4): 479-89
32. Zou H, Li Y, Liu X, et al. An APAF-1 cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 1999; 274 (17): 11549-56
33. Budihardjo I, Oliver H, Lutter M, et al. Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 1999; 15: 269-90
34. Narita M, Shimizu S, Ito T, et al. Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. Proc Natl Acad Sci U S A 1998; 95 (25): 14681-6
35. Shimizu S, Narita M, Tsujimoto Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 1999 Jun 3; 399 (6735): 483-7
36. Pastorino JG, Chen S-T, Tafani M, et al. The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition. J Biol Chem 1998; 273 (44): 7770-5
37. Pastorino JG, Tafani M, Rothman RJ, et al. Functional consequences of the sustained or transient activation by Bax of the mitochondrial permeability transition pore. J Biol Chem 1999; 274 (44): 31734-9
38. Hengartner MO. The biochemistry of apoptosis [comment in: Nature 2000 Oct 12; 407 (6805): 685-687]. Nature 2000 Oct 12; 407 (6805): 770-6
39. Ranger AM, Malynn BA, Korsmeyer SJ. Mouse models of cell death. Nat Genet 2001 Jun; 28 (2): 113-8
40. Liu X, Kim CN, Yang J, et al. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 1996; 86 (1): 147-57
41. Darmon AJ, Nicholson DW, Bleackley RC. Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B. Nature 1995 Oct 5; 377 (6548): 446-8
42. Nicholson DW, Ali A, Thomberry NA, et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 1995; 376 (6535):37-43
43. Krajewski S, Krajewska M, Ellerby LM, et al. Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci U S A 1999; 96 (10): 5752-7
44. Ouyang YB, Tan Y, Comb M, et al. Survival- and death-promoting events after transient cerebral ischemia: phosphorylation of Akt, release of cytochrome C and activation of caspase-like proteases. J Cereb Blood Flow Metab 1999; 19 (10): 1126-35
45. Velier JJ, et al. Caspase-8 and caspase-3 are expressed by different populations of cortical neurons undergoing delayed cell death after focal stroke in the rat. J Neurosci 1999 Jul 15; 19 (14): 5932-41
46. Schulz JB, Weller M, Moskowitz MA. Caspases as treatment targets in stroke and neurodegenerative diseases. Ann Neurol 1999 Apr; 45 (4): 421-9
47. Endres M, Wang ZQ, Namura S, et al. Ischemic brain injury is mediated by, the activation of poly (ADP-ribose) polymerase. J Cereb Blood Flow Metab 1997; 17 (11): 1143-51
48. Takahashi K, Pieper AA, Croul SE, et al. Post-treatment with an inhibitor of poly (ADP-ribose) polymerase attenuates cerebral damage in focal ischemia. Brain Res 1999; 829 (1-2): 46-54
49. Abdelkarim GE, Gertz K, Harms C, et al. Protective effects of PJ34, a novel, potent inhibitor of poly (ADP-ribose) polymerase (PARP) in in vitro and in vivo models of stroke. Int J Mol Med 2001; 7 (3): 255-60
50. Hsu CY, An G, Liu JS, et al. Expression of immediate early gene and growth factor mRNAs in a focal cerebral ischemia model in the rat. Stroke 1993; 24 (12): I78-81
51. An G, Lin TN, Liu JS, et al. Expression of c-fos and c-jun family genes after focal cerebral ischemia. Ann Neurol 1993; 33 (5): 457-64
52. Akins PT, Liu PK, Hsu CY. Immediate early gene expression in response to cerebral ischemia. Friend or foe? Stroke 1996 Sep; 27 (9): 1682-7
53. Chen J, Graham SH, Nakayama M, et al. Apoptosis repressor genes Bcl-2 and Bcl-x-long are expressed in the rat brain following global ischemia. J Cereb Blood Flow Metab 1997; 17 (1): 2-10
54. Gillardon F, Lenz C, Wasche KF, et al. Altered expression of Bcl-2, Bcl-X, Bax, and c-Fos colocalizes with DNA fragmentation and ischemic cell damage following middle cerebral artery occlusion in rats. Brain Res Mol Brain Res 1996; 40 (2): 254-60
55. Barone FC, Feuerstein GZ. Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 1999 Aug; 19 (8): 819-34
56. Kochanek PM, Hallenbeck JM. Polymorphonuclear leukocytes and monocytes/macrophages in the pathogenesis of cerebral ischemia and stroke. Stroke 1992 Sep; 23 (9): 1367-79
57. Iadecola C, Ross ME. Molecular pathology of cerebral ischemia: delayed gene expression and strategies for neuroprotection. Ann N Y Acad Sci 1997; 825: 203-17
58. del Zoppo G, Ginis I, Hallenbrook JM, et al. Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol 2000; 10 (1): 95-112
59. Nogawa S, Zhang F, Ross ME, et al. Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci 1997 Apr 15; 17 (8): 2746-55
60. Nogawa S, Forster C, Zhang F, et al. Interaction between inducible nitric oxide synthase and cyclooxygenase-2 after cerebral ischemia. Proc Natl Acad Sci U S A 1998 Sep 1; 95 (18): 10966-71
61. Ginsberg MD. Temperature influences on ischemic brain injury. In: Hsu CY, editor. Ischemic stroke: from basic mechanisms to new drug development. Basel, Switzerland, Karger, 1998;16: 65-88
62. Jorgensen HS, Reith J, Pedersen PM, et al. Body temperature and outcome in stroke patients [letter]. Lancet 1996; 348 (9021): 193
63. Reith J, Jorgensen HS, Pedersen PM, et al. Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet 1996; 347 (8999): 422-5
64. Boysen G, Christensen H. Stroke severity determines body temperature in acute stroke. Stroke 2001; 32 (2): 413-7
65. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346 (8): 549-56
66. Raichle ME. The pathophysiology of brain ischemia. Ann Neurol 1983 Jan; 13 (1): 2-10
67. Siesjo BK. Historical overview. Calcium, ischemia, and death of brain cells. Ann N Y Acad Sci 1988; 522: 638-61
68. Mohamed AA, Mendelow AD, Teasdale GM, et al. Effect of the calcium antagonist nimodipine on local cerebral blood flow and metabolic coupling. J Cereb Blood Flow Metab 1985; 5 (1): 26-33
69. Meyer FB, Sundt Jr TM, Yanagihara T, et al. Ischemic vasoconstriction and parenchymal brain pH. In: Vanhoutte PM, Paoletti R, Govoni S, editors. Calcium antagonists: pharmacology and clinical research. New York: New York Academy of Science, 1988: 502-15
70. Deshpande JK, Wieloch T. Flunarizine, a calcium entry blocker, ameliorates ischemic brain damage in the rat. Anesthesiology 1986 Feb; 64 (2): 215-24
71. Gotoh O, Mohamed AA, McCulloch J, et al. Nimodipine and the haemodynamic and histopathological consequences of middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 1986; 6 (3): 321-31
72. Petruk KC, West M, Mohr G, et al. Nimodipine treatment in poor-grade aneurysm patients. Results of a multicenter double-blind placebo-controlled trial. J Neurosurg 1988; 68 (4): 505-17
73. The American Nimodipine Study Group. Clinical trial of nimodipine in acute ischemic stroke. Stroke 1992; 23 (1): 3-8
74. Ahmed N, Nasman P, Wahlgren NG. Effect of intravenous nimodipine on blood pressure and outcome after acute stroke. Stroke 2000 Jun; 31 (6): 1250-5
75. Horn J, de Haan RJ, Vermeulen M, et al. Very Early Nimodipine Use in Stroke (VENUS): a randomized, double-blind, placebo-controlled trial. Stroke 2001; 32 (2): 461-5
76. Simon RP, Swan JH, Griffiths T, et al. Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain. Science 1984; 226 (4676): 850-2
77. Park CK, Nehls DG, Graham DI, et al. The glutamate antagonist MK-801 reduces focal ischemic brain damage in the rat. Ann Neurol 1988 Oct; 24 (4): 543-51
78. Bordi F, Pietra C, Ziviani L, et al. The glycine antagonist GV150526 protects somatosensory evoked potentials and reduces the infarct area in the MCAo model of focal ischemia in the rat. Exp Neurol 1997 Jun; 145 (2 Pt 1): 425-33
79. Lees KR, Lavelle JF, Cunha L, et al. Glycine antagonist (GV150526) in acute stroke: a multicentre, double-blind placebo-controlled phase II trial. Cerebrovasc Dis 2001; 11 (1): 20-9
80. Sacco RL, DeRosa JT, Haley Jr EC, et al. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. JAMA 2001; 285 (13): 1719-28
81. Li H, Buchan AM. Treatment with an AMPA antagonist 12 hours following severe normothermic forebrain ischemia prevents CA1 neuronal injury. J Cereb Blood Flow Metab 1993 Nov; 13 (6): 933-9
82. Schielke GP, Kupina NC, Boxer PA, et al. The neuroprotective effect of the novel AMPA receptor antagonist PD 152247 (PNQX) in temporary focal ischemia in the rat. Stroke 1999 Jul; 30 (7): 1472-7
83. Muir KW, Lees KR. A randomized, double-blind, placebo-controlled pilot trial of intravenous magnesium sulfate in acute stroke. Ann N Y Acad Sci 1995 Sep 15; 765: 315-6
84. Muir KW, Lees KR. A randomized, double-blind, placebo-controlled pilot trial of intravenous magnesium sulfate in acute stroke. Stroke 1995; 26: 1183-8
85. Smith SE, Meldrum BS. Cerebroprotective effect of lamotrigine after focal ischemia in rats. Stroke 1995 Jan; 26 (1): 117-121; discussion 121-2
86. Gotti B, Duverger D, Bertin J, et al. Ifenprodil and SL 82.0715 as cerebral anti-ischemic agents. I. Evidence for efficacy in models of focal cerebral ischemia. J Pharmacol Exp Ther 1988 Dec; 247 (3): 1211-21
87. Poignet, H, Beaughard M, Lecoin G, et al. Functional, behavioral, and histological changes induced by transient global cerebral ischemia in rats, effects of cinnarizine and flunarizine. J Cereb Blood Flow Metab; 1989 Oct. 9 (5): 646-54
88. Lazarewicz JW, Pluta R, Puka M, et al. Diverse mechanisms of neuronal protection by nimodipine in experimental rabbit brain ischemia. Stroke 1990 Dec; 21 (12): IV108-10
89. Chan SA, Reid KH, Schurr A, et al. Fosphenytoin reduces hippocampal neuronal damage in rat following transient global ischemia. Acta Neurochir 1998; 140 (2): 175-80
90. Marshall JW, Cross JA, Ridley RM. Functional benefit from clomethiazole treatment after focal cerebral ischemia in a nonhuman primate species. Exp Neurol 1999 Mar; 156 (1): 121-9
91. Wahlgren NG, Ranasinha KW, Rosolacci T, et al. Clomethiazole acute stroke study (CLASS): results of a randomized, controlled trial of clomethiazole versus placebo in 1360 acute stroke patients. Stroke 1999 Jan; 30 (1): 21-8
92. Lyden P, Shuaib A, Ng K, et al. Clomethiazole Acute Stroke Study in ischemic stroke (CLASS-I): final results. Stroke 2002; 33 (1): 122-8
93. Lesiuk H, Sutherland G, Peeling J, et al. Effect of U74006F on forebrain ischemia in rats. Stroke 1991 Jul; 22 (7): 896-901
94. The RANTTAS Investigators. A randomized trial of tirilazad mesylate in patients with acute stroke (RANTTAS). Stroke 1996; 27 (9): 1453-8
95. Haley Jr EC. High-dose tirilazad for acute stroke (RANTTAS II). RANTTAS II Investigators. Stroke 1998; 29 (6): 1256-7
96. Peters GR, Hwang L-J, Musch B. Safety and efficacy of 6 mg/kg/day tirilazad mesylate with acute ischemic stroke (TESS study) [abstract]. Stroke 1996; 27: 195
97. Tirilazad International Steering Committee. Tirilazad mesylate in acute ischemic stroke: a systematic review. Stroke 2000; 31 (9): 2257-65
98. Parnham M, Sies H. Ebselen: prospective therapy for cerebral ischaemia. Expert Opin Investig Drugs 2000 Mar; 9 (3): 607-19
99. Yamaguchi T, Sano K, Takakura K, et al. Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group. Stroke 1998 Jan; 29 (1): 12-7
100. Matsuo Y, Onodera H, Shiga Y, et al. Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat. Effects of neutrophil depletion. Stroke 1994 Jul; 25 (7): 1469-75
101. Jiang N, Moyle M, Soule HR, et al. Neutrophil inhibitory factor is neuroprotective after focal ischemia in rats. Ann Neurol 1995 Dec; 38 (6): 935-42
102. Chen H, Chopp M, Zhang RL, et al. Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann Neurol 1994 Apr; 35 (4): 458-63
103. Zhang RL, Chopp M, Li Y, et al. Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat. Neurology 1994 Sep; 44 (9): 1747-51
104. Stroemer RP, Rothwell NJ. Cortical protection by localized striatal injection of IL-1ra following cerebral ischemia in the rat. J Cereb Blood Flow Metab 1997 Jun; 17 (6): 597-604
105. Sherman DG. The Enlimomab acute stroke trial: final results [abstract]. Neurology 1997, 48 (S33 001): A270
106. Use of anti-ICAM-1 therapy in ischemic, stroke: results of the Enlimomab Acute Stroke Trial. Neurology 2001; 57 (8): 1428-34
107. D'Orlando, KJ, Sandage Jr BW. Citicoline (CDP-choline): mechanisms of action and effects in ischemic brain injury. Neurol Res 1995 Aug; 17 (4): 281-4
108. Chen ST, Hsu CY, Hogan EL, et al. Thromboxane, prostacyclin, and leukotrienes in cerebral ischemia. Neurology 1986 Apr; 36 (4): 466-70
109. Warach S, Pettigrew LC, Dashe JF, et al. Effect of citicoline on ischemic lesions as measured by diffusion- weighted magnetic resonance imaging. Citicoline 010 Investigators. Ann Neurol 2000 Nov; 48 (5): 713-22
110. Clark WM, Warach SJ, Pettigrew LC, et al. A randomized dose-response trial of citicoline in acute ischemic stroke patients. Citicoline Stroke Study Group. Neurology 1997 Sep; 49 (3): 671-8
111. Clark WM, Williams BJ, Selzer KA, et al. A randomized efficacy trial of citicoline in patients with acute ischemic stroke. Stroke 1999 Dec; 30 (12): 2592-7
112. Moore PK, Wallace P, Gaffen Z, et al. Characterization of the novel nitric oxide synthase inhibitor 7-nitro indazole and related indazoles: antinociceptive and cardiovascular effects. Br J Pharmacol 1993 Sep; 110 (1): 219-24
113. Coert BA, Anderson RE, Meyer FB. A comparative study of the effects of two nitric oxide synthase inhibitors and two nitric oxide donors on temporary focal cerebral ischemia in the Wistar rat. J Neurosurg 1999 Feb; 90 (2): 332-8
114. Nagayama M, Zhang F, Iadecola C. Delayed treatment with aminoguanidine decreases focal cerebral ischemic damage and enhances neurologic recovery in rats. J Cereb Blood Flow Metab 1998 Oct; 18 (10): 1107-13
115. Chen K, Finklestein SP. Neurotrophic factors. In: Hsu CY, editor. Ischemic stroke: from basic mechanisms to new drug development. Switzerland: Karger, 1998: 116-26
116. Jiang N, Finklestein SP, Do T, et al. Delayed intravenous administration of basic fibroblast growth factor (bFGF) reduces infarct volume in a model of focal cerebral ischemia/reperfusion in the rat. J Neurol Sci 1996 Aug; 139 (2): 173-9
117. Fink K, Zhu J, Namura S, et al. Prolonged therapeutic window for ischemic brain damage caused by delayed caspase activation. J Cereb Blood Flow Metab 1998 Oct; 18 (10): 1071-6
118. Fink KB, Andrews LJ, Butler We, et al. Reduction of post-traumatic brain injury and free radical production by inhibition of the caspase-1 cascade. Neuroscience 1999; 94 (4): 1213-8
119. Rabuffetti M, Sciorati C, Tarozzo G, et al. Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-chloromethyl ketone induces long-lasting neuroprotection in cerebral ischemia through apoptosis reduction and decrease of proinflammatory cytokines. J Neurosci 2000 Jun 15; 20 (12): 4398-404
120. Schabitz WR, et al. Synergistic effects of a combination of low-dose basic fibroblast growth factor and citicoline after temporary experimental focal ischemia. Stroke 1999 Feb; 30 (2): 427-431; discussion 431-2
121. Schmid-Elsaesser R, Zausinger S, Hungerhuber E, et al. Neuroprotective effects of combination therapy with tirilazad and magnesium in rats subjected to reversible focal cerebral ischemia. Neurosurgery 1999 Jan; 44 (1): 163-171; discussion 171-2
122. Suzuki J, S Fujimoto, Mizoi K, et al. The protective effect of combined administration of anti-oxidants and perfluorochemicals on cerebral ischemia. Stroke 1984 Jul-Aug; 15 (4): 672-9
123. Du C, Hu R, Csernansky CA, et al. Very delayed infarction after mild focal cerebral ischemia: a role for apoptosis? J Cereb Blood Flow Metab 1996 Mar; 16 (2): 195-201
124. Du C, Hu R, Csernansky CA, et al. Additive neuroprotective effects of dextrorphan and cycloheximide in rats subjected to transient focal cerebral ischemia. Brain Res 1996; 718 (1-2): 233-6
125. Schulz JB, Weller M, Matthews RT, et al. Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia. Cell Death Differ 1998 Oct; 5 (10): 847-57
126. Ma J, Qui J, Dalkara T, et al. Synergistic protective effect of caspase inhibitors and bFGF against brain injury induced by transient focal ischaemia. Br J Pharmacol 2001 Jun; 133 (3): 345-50
127. Li H, Colbourne F, Sun P, et al. Caspase inhibitors reduce neuronal injury after focal but not global cerebral ischemia in rats. Stroke 2000; 31: 176-82
128. Andersen M, Overgaard K, Meden P, et al. Effects of citicoline combined with thrombolytic therapy in a rat embolic stroke model. Stroke 1999 Jul; 30 (7): 1464-71
129. Grotta J. Combination therapy stroke trial. rt-PA +/- lubeluzole. Ann N Y Acad Sci 2001; 939: 309-10
130. Lyden P, Jacoby M, Schim J, et al. The Clomethiazole Acute Stroke Study in tissue-type plasminogen activator-treated stroke (CLASS-T): final results. Neurology 2001; 57 (7): 1199-205