Pre-clinical to Clinical Translational Failures and Current Status of Clinical Trials in Stroke Therapy: A Brief Review

Author(s): Neha Dhir, Bikash Medhi*, Ajay Prakash, Manoj Kumar Goyal, Manish Modi, Sandeep Mohindra

Journal Name: Current Neuropharmacology

Volume 18 , Issue 7 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

In stroke (cerebral ischemia), despite continuous efforts both at the experimental and clinical level, the only approved pharmacological treatment has been restricted to tissue plasminogen activator (tPA). Stroke is the leading cause of functional disability and mortality throughout worldwide. Its pathophysiology starts with energy pump failure, followed by complex signaling cascade that ultimately ends in neuronal cell death. Ischemic cascade involves excessive glutamate release followed by raised intracellular sodium and calcium influx along with free radicals’ generation, activation of inflammatory cytokines, NO synthases, lipases, endonucleases and other apoptotic pathways leading to cell edema and death. At the pre-clinical stage, several agents have been tried and proven as an effective neuroprotectant in animal models of ischemia. However, these agents failed to show convincing results in terms of efficacy and safety when the trials were conducted in humans following stroke. This article highlights the various agents which have been tried in the past but failed to translate into stroke therapy along with key points that are responsible for the lagging of experimental success to translational failure in stroke treatment.

Keywords: Stroke, cerebral ischemia, neuroprotection, pathophysiology, pharmacotherapy, pre-clinical studies, clinical trials, STAIR criteria.

[1]
Musuka, T.D.; Wilton, S.B.; Traboulsi, M.; Hill, M.D. Diagnosis and management of acute ischemic stroke: speed is critical. CMAJ, 2015, 187(12), 887-893.
[http://dx.doi.org/10.1503/cmaj.140355] [PMID: 26243819]
[2]
Woodruff, T.M.; Thundyil, J.; Tang, S.C.; Sobey, C.G.; Taylor, S.M.; Arumugam, T.V. Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Mol. Neurodegener., 2011, 6(1), 11.
[http://dx.doi.org/10.1186/1750-1326-6-11] [PMID: 21266064]
[3]
Deb, P.; Sharma, S.; Hassan, K.M. Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology, 2010, 17(3), 197-218.
[http://dx.doi.org/10.1016/j.pathophys.2009.12.001] [PMID: 20074922]
[4]
Seifert, H.A.; Offner, H. The splenic response to stroke: from rodents to stroke subjects. J. Neuroinflammation, 2018, 15(1), 195.
[http://dx.doi.org/10.1186/s12974-018-1239-9] [PMID: 29970193]
[5]
Shuaib, A.; Hussain, M.S. The past and future of neuroprotection in cerebral ischaemic stroke. Eur. Neurol., 2008, 59(1-2), 4-14.
[http://dx.doi.org/10.1159/000109254] [PMID: 17917451]
[6]
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), 1581-1587.
[http://dx.doi.org/10.1056/NEJM199512143332401] [PMID: 7477192]
[7]
Cheng, Y.D.; Al-Khoury, L.; Zivin, J.A. Neuroprotection for ischemic stroke: two decades of success and failure. NeuroRx, 2004, 1(1), 36-45.
[http://dx.doi.org/10.1602/neurorx.1.1.36] [PMID: 15717006]
[8]
Prentice, H.; Modi, J.P.; Wu, J-Y. Mechanisms of neuronal protection against excitotoxicity, endoplasmic reticulum stress, and mitochondrial dysfunction in stroke and neurodegenerative diseases. Oxid. Med. Cell. Longev., 2015, 2015964518
[http://dx.doi.org/10.1155/2015/964518] [PMID: 26576229]
[9]
Weinberger, J.M. Evolving therapeutic approaches to treating acute ischemic stroke. J. Neurol. Sci., 2006, 249(2), 101-109.
[http://dx.doi.org/10.1016/j.jns.2006.06.010] [PMID: 17005205]
[10]
Froehler, M.T.; Ovbiagele, B. Therapeutic hypothermia for acute ischemic stroke. Expert Rev. Cardiovasc. Ther., 2010, 8(4), 593-603.
[http://dx.doi.org/10.1586/erc.09.129] [PMID: 20397832]
[11]
Tănăsescu, R.; Nicolau, A.; Ticmeanu, M.; Luca, D.; Caraiola, S.; Cojocaru, I.M.; Frăsineanu, A.; Ionescu, R.; Hristea, A.; Ene, A.; Tănăsescu, R.; Baicuş, C. An immunological approach to cerebral ischemia (I). Immune cells and adhesion molecules. Rom. J. Intern. Med., 2008, 46(1), 3-8.
[PMID: 19157265]
[12]
Neumar, R.W.; Hagle, S.M.; DeGracia, D.J.; Krause, G.S.; White, B.C. Brain μ-calpain autolysis during global cerebral ischemia. J. Neurochem., 1996, 66(1), 421-424.
[http://dx.doi.org/10.1046/j.1471-4159.1996.66010421.x] [PMID: 8522983]
[13]
Astrup, J.; Siesjö, B.K.; Symon, L. Thresholds in cerebral ischemia - the ischemic penumbra. Stroke, 1981, 12(6), 723-725.
[http://dx.doi.org/10.1161/01.STR.12.6.723] [PMID: 6272455]
[14]
Ginsberg, M.D.; Belayev, L.; Zhao, W.; Huh, P.W.; Busto, R. The acute ischemic penumbra: topography, life span, and therapeutic response. Acta Neurochir. Suppl. (Wien), 1999, 73, 45-50.
[http://dx.doi.org/10.1007/978-3-7091-6391-7_7] [PMID: 10494340]
[15]
Jhelum, P.; Karisetty, B.C.; Kumar, A.; Chakravarty, S. Implications of epigenetic mechanisms and their targets in cerebral ischemia models. Curr. Neuropharmacol., 2017, 15(6), 815-830.
[http://dx.doi.org/10.2174/1570159X14666161213143907] [PMID: 27964703]
[16]
Kassis, H.; Shehadah, A.; Chopp, M.; Zhang, Z.G. Epigenetics in stroke recovery. Genes (Basel), 2017, 8(3)E89
[http://dx.doi.org/10.3390/genes8030089] [PMID: 28264471]
[17]
Endres, M.; Meisel, A.; Biniszkiewicz, D.; Namura, S.; Prass, K.; Ruscher, K.; Lipski, A.; Jaenisch, R.; Moskowitz, M.A.; Dirnagl, U. DNA methyltransferase contributes to delayed ischemic brain injury. J. Neurosci., 2000, 20(9), 3175-3181.
[http://dx.doi.org/10.1523/JNEUROSCI.20-09-03175.2000] [PMID: 10777781]
[18]
Zhao, S.; Yan, F.; Cheng, J.; Huang, L.; Chen, H. HDAC2 selectively regulates FOXO3a-mediated gene transcription during oxidative stress-induced neuronal cell death. J. Neurosci., 2015, 35(3), 1250-9.
[19]
Kim, H.J.; Leeds, P.; Chuang, D.M. The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain. J. Neurochem., 2009, 110(4), 1226-1240.
[http://dx.doi.org/10.1111/j.1471-4159.2009.06212.x] [PMID: 19549282]
[20]
Kassis, H.; Shehadah, A.; Li, C.; Zhang, Y.; Cui, Y.; Roberts, C.; Sadry, N.; Liu, X.; Chopp, M.; Zhang, Z.G. Class IIa histone deacetylases affect neuronal remodeling and functional outcome after stroke. Neurochem. Int., 2016, 96, 24-31.
[http://dx.doi.org/10.1016/j.neuint.2016.04.006] [PMID: 27103167]
[21]
Lapchak, P.A.; Araujo, D.M. Advances in ischemic stroke treatment: neuroprotective and combination therapies. Expert Opin. Emerg. Drugs, 2007, 12(1), 97-112.
[http://dx.doi.org/10.1517/14728214.12.1.97] [PMID: 17355216]
[22]
George, P.M.; Steinberg, G.K. Novel stroke therapeutics: unraveling stroke pathophysiology and its impact on clinical treatments. Neuron, 2015, 87(2), 297-309.
[http://dx.doi.org/10.1016/j.neuron.2015.05.041] [PMID: 26182415]
[23]
Kaur, H.; Prakash, A.; Medhi, B. Drug therapy in stroke: from preclinical to clinical studies. Pharmacology, 2013, 92(5-6), 324-334.
[http://dx.doi.org/10.1159/000356320] [PMID: 24356194]
[24]
Lees, K.R.; Barer, D.; Ford, G.A.; Hacke, W.; Kostulas, V.; Sharma, A.K.; Odergren, T. SA-NXY-0004 Investigators Tolerability of NXY-059 at higher target concentrations in patients with acute stroke. Stroke, 2003, 34(2), 482-487.
[http://dx.doi.org/10.1161/01.STR.0000053032.14223.81] [PMID: 12574564]
[25]
Martínez-Vila, E.; Sieira, P.I. Current status and perspectives of neuroprotection in ischemic stroke treatment. Cerebrovasc. Dis., 2001, 11(Suppl. 1), 60-70.
[http://dx.doi.org/10.1159/000049127] [PMID: 11244202]
[26]
Muir, K.W.; Lees, K.R.; Hamilton, S.J.C.A.; George, C.F.; Hobbiger, S.F.; Lunnon, M.W. A randomized, double-blind, placebo-controlled ascending dose tolerance study of 619C89 in acute stroke. Ann. N. Y. Acad. Sci., 1995, 765(1), 328-329.
[http://dx.doi.org/10.1111/j.1749-6632.1995.tb16605.x] [PMID: 7486634]
[27]
Grotta, J. The US and Canadian Lubeluzole Ischemic Stroke Study Group Lubeluzole treatment of acute ischemic stroke. Stroke, 1997, 28(12), 2338-2346.
[http://dx.doi.org/10.1161/01.STR.28.12.2338] [PMID: 9412611]
[28]
Diener, H.C. European and Australian Lubeluzole Ischaemic Stroke Study Group Multinational randomised controlled trial of lubeluzole in acute ischaemic stroke. Cerebrovasc. Dis., 1998, 8(3), 172-181.
[http://dx.doi.org/10.1159/000015847] [PMID: 9619701]
[29]
Pulsinelli, W.; Mann, M.; Welch, K.; Zivin, J.; Biller, J. Fosphenytoin in acute ischemic stroke: efficacy results. Neurology, 1999, 52(Suppl. 2), A384.
[30]
Squire, I.B.; Lees, K.R.; Pryse-Phillips, W.; Kertesz, A.; Bamford, J. Lifarizine Study Group Efficacy and tolerability of lifarizine in acute ischemic stroke. A pilot study. Ann. N. Y. Acad. Sci., 1995, 765(1), 317-318.
[http://dx.doi.org/10.1111/j.1749-6632.1995.tb16599.x] [PMID: 7486628]
[31]
Scatton, B.; Carter, C.; Benavides, J.; Giroux, C. N-Methyl-D-Aspartate receptor antagonists: a novel therapeutic perspective for the treatment of ischemic brain injury. Cerebrovasc. Dis., 1991, 1(3), 121-135.
[http://dx.doi.org/10.1159/000108829]
[32]
Block, F.; Schwarz, M. Dextromethorphan reduces functional deficits and neuronal damage after global ischemia in rats. Brain Res., 1996, 741(1-2), 153-159.
[http://dx.doi.org/10.1016/S0006-8993(96)00916-X] [PMID: 9001717]
[33]
Olney, J.W.; Labruyere, J.; Price, M.T. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science, 1989, 244(4910), 1360-1362.
[http://dx.doi.org/10.1126/science.2660263] [PMID: 2660263]
[34]
Buchan, A.M.; Slivka, A.; Xue, D. The effect of the NMDA receptor antagonist MK-801 on cerebral blood flow and infarct volume in experimental focal stroke. Brain Res., 1992, 574(1-2), 171-177.
[http://dx.doi.org/10.1016/0006-8993(92)90814-P] [PMID: 1386274]
[35]
Lees, K.R. Cerestat and other NMDA antagonists in ischemic stroke. Neurology, 1997, 49(5)(Suppl. 4), S66-S69.
[http://dx.doi.org/10.1212/WNL.49.5_Suppl_4.S66] [PMID: 9371155]
[36]
Pitsikas, N.; Brambilla, A.; Besozzi, C.; Bonali, P.; Fodritto, F.; Grippa, N.; Scandroglio, A.; Borsini, F. Effects of cerestat and NBQX on functional and morphological outcomes in rat focal cerebral ischemia. Pharmacol. Biochem. Behav., 2001, 68(3), 443-447.
[http://dx.doi.org/10.1016/S0091-3057(00)00469-X] [PMID: 11325397]
[37]
Giroux, C.; Rosen, P.; Scatton, B. In: Pharmacology of Cerebral Ischemia. Krieglstein J, Oberpichler-Schwenk H, editor. Stuttgart: Wissenschaftliche Verglagsgesellschaft; Preclinical, pharmacology and clinical safety profile of eliprodil, an atypical nmda receptor antagonist. Pharmacol. Cerebral Ischemia, 1994, 643-648.
[38]
Ibarrola, D.; Seegers, H.; Jaillard, A.; Hommel, M.; Décorps, M.; Massarelli, R. The effect of eliprodil on the evolution of a focal cerebral ischaemia in vivo. Eur. J. Pharmacol., 1998, 352(1), 29-35.
[http://dx.doi.org/10.1016/S0014-2999(98)00330-6] [PMID: 9718264]
[39]
Takahashi, M.; Ni, J.W.; Kawasaki-Yatsugi, S.; Toya, T.; Ichiki, C.; Yatsugi, S.I.; Koshiya, K.; Shimizu-Sasamata, M.; Yamaguchi, T. Neuroprotective efficacy of YM872, an α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, after permanent middle cerebral artery occlusion in rats. J. Pharmacol. Exp. Ther., 1998, 287(2), 559-566.
[PMID: 9808681]
[40]
Takahashi, M.; Kohara, A.; Shishikura, J.; Kawasaki-Yatsugi, S.; Ni, J.W.; Yatsugi, S.; Sakamoto, S.; Okada, M.; Shimizu-Sasamata, M.; Yamaguchi, T. YM872: a selective, potent and highly water-soluble alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist. CNS Drug Rev., 2002, 8(4), 337-352.
[http://dx.doi.org/10.1111/j.1527-3458.2002.tb00232.x] [PMID: 12481190]
[41]
A Study to Evaluate the Effects of YM872 on Stroke Lesion Volume in Acute Stroke Patients - Full Text View, https://clinicaltrials.gov/ct2/show/NCT00044070
[42]
Akins, P.T.; Atkinson, R.P. Glutamate AMPA receptor antagonist treatment for ischaemic stroke. Curr. Med. Res. Opin., 2002, 18(Suppl. 2), s9-s13.
[http://dx.doi.org/10.1185/030079902125000660] [PMID: 12365832]
[43]
Muir, K.W.; Lees, K.R.A. A randomized, double-blind, placebo-controlled pilot trial of intravenous magnesium sulfate in acute stroke. Ann. N. Y. Acad. Sci., 1995, 765, 315-316.
[http://dx.doi.org/10.1111/j.1749-6632.1995.tb16598.x] [PMID: 7486627]
[44]
Grotta, J.C.; Pettigrew, L.C.; Rosenbaum, D.; Reid, C.; Rhoades, H.; McCandless, D. Efficacy and mechanism of action of a calcium channel blocker after global cerebral ischemia in rats. Stroke, 1988, 19(4), 447-454.
[http://dx.doi.org/10.1161/01.STR.19.4.447] [PMID: 3363573]
[45]
Lukic-Panin, V.; Kamiya, T.; Zhang, H.; Hayashi, T.; Tsuchiya, A.; Sehara, Y.; Deguchi, K.; Yamashita, T.; Abe, K. Prevention of neuronal damage by calcium channel blockers with antioxidative effects after transient focal ischemia in rats. Brain Res., 2007, 1176, 143-150.
[http://dx.doi.org/10.1016/j.brainres.2007.07.038] [PMID: 17904110]
[46]
Gelmers, H.J. Calcium-channel blockers: effects on cerebral blood flow and potential uses for acute stroke. Am. J. Cardiol., 1985, 55(3), 144B-148B.
[http://dx.doi.org/10.1016/0002-9149(85)90623-X] [PMID: 2578724]
[47]
Abe, K.; Kogure, K.; Watanabe, T. Prevention of ischemic and postischemic brain edema by a novel calcium antagonist (PN200-110). J. Cereb. Blood Flow Metab., 1988, 8(3), 436-439.
[http://dx.doi.org/10.1038/jcbfm.1988.81] [PMID: 2966804]
[48]
Meyer, J.S.; Takashima, S.; Terayama, Y. Calcium channel blockers prevent delayed cerebral ischemia after intracranial aneurysmal subarachnoid hemorrhage.Cerebral Ischemia and Basic Mechanisms; Springer: in Berlin, Heidelberg, 1994, pp. 113-124.
[http://dx.doi.org/10.1007/978-3-642-78151-3_12]
[49]
Lyden, P.D.; Zivin, J.A.; Kochhar, A.; Mazzarella, V. Effects of calcium channel blockers on neurologic outcome after focal ischemia in rabbits. Stroke, 1988, 19(8), 1020-1026.
[http://dx.doi.org/10.1161/01.STR.19.8.1020] [PMID: 3400100]
[50]
Horn, J.; Limburg, M. Calcium antagonists for ischemic stroke: a systematic review. Stroke, 2001, 32(2), 570-576.
[http://dx.doi.org/10.1161/01.STR.32.2.570] [PMID: 11157199]
[51]
Zhang, J.; Yang, J.; Zhang, C.; Jiang, X.; Zhou, H.; Liu, M. Calcium antagonists for acute ischemic stroke. Cochrane Database Syst. Rev., 2012, (5)CD001928
[http://dx.doi.org/10.1002/14651858.cd001928.pub2] [PMID: 22592678]
[52]
Wahlgren, N.G.; MacMahon, D.G.; De Keyser, J. Intravenous nimodipine west european stroke trial (inwest) of nimodipine in the treatment of acute ischaemic stroke. Cerebrovasc. Dis., 1994, 4(3), 204-210.
[http://dx.doi.org/10.1159/000108483]
[53]
Oczkowski, W.J.; Hachinski, V.C.; Bogousslavsky, J.; Barnett, H.J.; Carruthers, S.G.A. A double-blind, randomized trial of PY108-068 in acute ischemic cerebral infarction. Stroke, 1989, 20(5), 604-608.
[http://dx.doi.org/10.1161/01.STR.20.5.604] [PMID: 2655184]
[54]
Franke, C.L.; Palm, R.; Dalby, M.; Schoonderwaldt, H.C.; Hantson, L.; Eriksson, B.; Lang-Jenssen, L.; Smakman, J. Flunarizine in stroke treatment (FIST): a double-blind, placebo-controlled trial in Scandinavia and the Netherlands. Acta Neurol. Scand., 1996, 93(1), 56-60.
[http://dx.doi.org/10.1111/j.1600-0404.1996.tb00171.x] [PMID: 8825274]
[55]
Paik, N-J.; Yang, E. Role of GABA plasticity in stroke recovery. Neural Regen. Res., 2014, 9(23), 2026-2028.
[http://dx.doi.org/10.4103/1673-5374.147920] [PMID: 25657711]
[56]
Chi, O.Z.; Hunter, C.; Liu, X.; Chi, Y.; Weiss, H.R. Effects of GABA(A) receptor blockade on regional cerebral blood flow and blood-brain barrier disruption in focal cerebral ischemia. J. Neurol. Sci., 2011, 301(1-2), 66-70.
[http://dx.doi.org/10.1016/j.jns.2010.10.024] [PMID: 21094956]
[57]
Schwartz-Bloom, R.D.; Sah, R. γ-Aminobutyric acid(A) neurotransmission and cerebral ischemia. J. Neurochem., 2001, 77(2), 353-371.
[http://dx.doi.org/10.1046/j.1471-4159.2001.00274.x] [PMID: 11299298]
[58]
He, W-M.; Ying-Fu, L.; Wang, H.; Peng, Y-P. Delayed treatment of α5 GABAA receptor inverse agonist improves functional recovery by enhancing neurogenesis after cerebral ischemia-reperfusion injury in rat MCAO model. Sci. Rep., 2019, 9(1), 2287.
[http://dx.doi.org/10.1038/s41598-019-38750-0] [PMID: 30783142]
[59]
Wahlgren, N.G. The Clomethiazole Acute Stroke Study Collaborative Group. The Clomethiazole Acute Stroke Study (CLASS): Results of a Randomised Controlled Study of Clomethiazole versus Placebo in 1360 Acute Stroke Patients. Cerebrovasc. Dis. 1997, 7(Suppl. 4), 24-30.
[http://dx.doi.org/10.1159/000108249]
[60]
Liu, J.; Wang, L-N.; Ma, X.; Ji, X. Gamma aminobutyric acid (GABA) receptor agonists for acute stroke. Cochrane Database Syst. Rev., 2016, 10CD009622
[http://dx.doi.org/10.1002/14651858.CD009622.pub4] [PMID: 27701753]
[61]
Gribkoff, V.K.; Starrett, J.E., Jr; Dworetzky, S.I.; Hewawasam, P.; Boissard, C.G.; Cook, D.A.; Frantz, S.W.; Heman, K.; Hibbard, J.R.; Huston, K.; Johnson, G.; Krishnan, B.S.; Kinney, G.G.; Lombardo, L.A.; Meanwell, N.A.; Molinoff, P.B.; Myers, R.A.; Moon, S.L.; Ortiz, A.; Pajor, L.; Pieschl, R.L.; Post-Munson, D.J.; Signor, L.J.; Srinivas, N.; Taber, M.T.; Thalody, G.; Trojnacki, J.T.; Wiener, H.; Yeleswaram, K.; Yeola, S.W. Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels. Nat. Med., 2001, 7(4), 471-477.
[http://dx.doi.org/10.1038/86546] [PMID: 11283675]
[62]
Jensen, B.S. BMS-204352: a potassium channel opener developed for the treatment of stroke. CNS Drug Rev., 2002, 8(4), 353-360.
[http://dx.doi.org/10.1111/j.1527-3458.2002.tb00233.x] [PMID: 12481191]
[63]
Lapchak, P.A.; Araujo, D.M. Development of the nitrone-based spin trap agent NXY-059 to treat acute ischemic stroke. CNS Drug Rev., 2003, 9(3), 253-262.
[http://dx.doi.org/10.1111/j.1527-3458.2003.tb00252.x] [PMID: 14530797]
[64]
Sydserff, S.G.; Borelli, A.R.; Green, A.R.; Cross, A.J. 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(1), 103-112.
[http://dx.doi.org/10.1038/sj.bjp.0704449] [PMID: 11786485]
[65]
Zhao, Z.; Cheng, M.; Maples, K.R.; Ma, J.Y.; Buchan, A.M. NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal cerebral ischemia in the rat. Brain Res., 2001, 909(1-2), 46-50.
[http://dx.doi.org/10.1016/S0006-8993(01)02618-X] [PMID: 11478919]
[66]
Okamura, K.; Tsubokawa, T.; Johshita, H.; Miyazaki, H.; Shiokawa, Y. Edaravone, a free radical scavenger, attenuates cerebral infarction and hemorrhagic infarction in rats with hyperglycemia. Neurol. Res., 2014, 36(1), 65-69.
[http://dx.doi.org/10.1179/1743132813Y.0000000259] [PMID: 24074041]
[67]
Fujiwara, N.; Som, A.T.; Pham, L-D.D.; Lee, B.J.; Mandeville, E.T.; Lo, E.H.; Arai, K. A free radical scavenger edaravone suppresses systemic inflammatory responses in a rat transient focal ischemia model. Neurosci. Lett., 2016, 633, 7-13.
[http://dx.doi.org/10.1016/j.neulet.2016.08.048] [PMID: 27589890]
[68]
Yagi, K.; Kitazato, K.T.; Uno, M.; Tada, Y.; Kinouchi, T.; Shimada, K.; Nagahiro, S. Edaravone, a free radical scavenger, inhibits MMP-9-related brain hemorrhage in rats treated with tissue plasminogen activator. Stroke, 2009, 40(2), 626-631.
[http://dx.doi.org/10.1161/STROKEAHA.108.520262] [PMID: 19095969]
[69]
He, M.; Xing, S.; Yang, B.; Zhao, L.; Hua, H.; Liang, Z.; Zhou, W.; Zeng, J.; Pei, Z. Ebselen attenuates oxidative DNA damage and enhances its repair activity in the thalamus after focal cortical infarction in hypertensive rats. Brain Res., 2007, 1181, 83-92.
[http://dx.doi.org/10.1016/j.brainres.2007.08.072] [PMID: 17920569]
[70]
Namura, S.; Nagata, I.; Takami, S.; Masayasu, H.; Kikuchi, H. Ebselen reduces cytochrome c release from mitochondria and subsequent DNA fragmentation after transient focal cerebral ischemia in mice. Stroke, 2001, 32(8), 1906-1911.
[http://dx.doi.org/10.1161/01.STR.32.8.1906] [PMID: 11486124]
[71]
Sena, E.; Wheble, P.; Sandercock, P.; Macleod, M. Systematic review and meta-analysis of the efficacy of tirilazad in experimental stroke. Stroke, 2007, 38(2), 388-394.
[http://dx.doi.org/10.1161/01.STR.0000254462.75851.22] [PMID: 17204689]
[72]
Enomoto, M.; Endo, A.; Yatsushige, H.; Fushimi, K.; Otomo, Y. Clinical effects of early edaravone use in acute ischemic stroke patients treated by endovascular reperfusion therapy. Stroke, 2019, 50(3), 652-658.
[http://dx.doi.org/10.1161/STROKEAHA.118.023815] [PMID: 30741623]
[73]
Yamaguchi, T.; Sano, K.; Takakura, K.; Saito, I.; Shinohara, Y.; Asano, T.; Yasuhara, H. Ebselen Study Group Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Stroke, 1998, 29(1), 12-17.
[http://dx.doi.org/10.1161/01.STR.29.1.12] [PMID: 9445321]
[74]
Bath, P.M.; Iddenden, R.; Bath, F.J.; Orgogozo. M.J. M. International Steering. T. Tirilazad for Acute Ischaemic Stroke of Systematic Reviews. 2001, (4), CD002087.
[75]
Tirilazad mesylate in acute ischemic stroke: A systematic review. Stroke, 2000, 31(9), 2257-2265.
[http://dx.doi.org/10.1161/01.STR.31.9.2257] [PMID: 10978061]
[76]
Kuschinsky, W.; Gillardon, F. Apoptosis and cerebral ischemia. Cerebrovasc. Dis., 2000, 10(3), 165-169.
[http://dx.doi.org/10.1159/000016052] [PMID: 10773641]
[77]
Prunell, G.F.; Arboleda, V.A.; Troy, C.M. Caspase function in neuronal death: delineation of the role of caspases in ischemia. Curr. Drug Targets CNS Neurol. Disord., 2005, 4(1), 51-61.
[http://dx.doi.org/10.2174/1568007053005082] [PMID: 15723613]
[78]
Hara, H.; Friedlander, R.M.; Gagliardini, V.; Ayata, C.; Fink, K.; Huang, Z.; Shimizu-Sasamata, M.; Yuan, J.; Moskowitz, M.A. Inhibition of interleukin 1β converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc. Natl. Acad. Sci. USA, 1997, 94(5), 2007-2012.
[http://dx.doi.org/10.1073/pnas.94.5.2007] [PMID: 9050895]
[79]
Lin, X.; Ye, H.; Siaw-Debrah, F.; Pan, S.; He, Z.; Ni, H.; Xu, Z.; Jin, K.; Zhuge, Q.; Huang, L. AC-YVAD-CMK inhibits pyroptosis and improves functional outcome after intracerebral hemorrhage. BioMed Res. Int., 2018, 20183706047
[http://dx.doi.org/10.1155/2018/3706047] [PMID: 30410928]
[80]
Sun, Y.; Xu, Y.; Geng, L. Caspase-3 inhibitor prevents the apoptosis of brain tissue in rats with acute cerebral infarction. Exp. Ther. Med., 2015, 10(1), 133-138.
[http://dx.doi.org/10.3892/etm.2015.2462] [PMID: 26170924]
[81]
Zhang, R.L.; Chopp, M.; Jiang, N.; Tang, W.X.; Prostak, J.; Manning, A.M.; Anderson, D.C. Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke, 1995, 26(8), 1438-1442.
[http://dx.doi.org/10.1161/01.STR.26.8.1438] [PMID: 7631350]
[82]
Schneider, D.; Berrouschot, J.; Brandt, T.; Hacke, W.; Ferbert, A.; Norris, S.H.; Polmar, S.H.; Schäfer, E. Safety, pharmacokinetics and biological activity of enlimomab (anti-ICAM-1 antibody): an open-label, dose escalation study in patients hospitalized for acute stroke. Eur. Neurol., 1998, 40(2), 78-83.
[http://dx.doi.org/10.1159/000007962] [PMID: 9693236]
[83]
Furuya, K.; Takeda, H.; Azhar, S.; McCarron, R.M.; Chen, Y.; Ruetzler, C.A.; Wolcott, K.M.; DeGraba, T.J.; Rothlein, R.; Hugli, T.E.; del Zoppo, G.J.; Hallenbeck, J.M. Examination of several potential mechanisms for the negative outcome in a clinical stroke trial of enlimomab, a murine anti-human intercellular adhesion molecule-1 antibody: a bedside-to-bench study. Stroke, 2001, 32(11), 2665-2674.
[http://dx.doi.org/10.1161/hs3211.098535] [PMID: 11692032]
[84]
Enlimomab Acute Stroke Trial Investigators Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology, 2001, 57(8), 1428-1434.
[http://dx.doi.org/10.1212/WNL.57.8.1428] [PMID: 11673584]
[85]
Zhang, L.; Zhang, Z.G.; Zhang, R.L.; Lu, M.; Krams, M.; Chopp, M. Effects of a selective CD11b/CD18 antagonist and recombinant human tissue plasminogen activator treatment alone and in combination in a rat embolic model of stroke. Stroke, 2003, 34(7), 1790-1795.
[http://dx.doi.org/10.1161/01.STR.0000077016.55891.2E] [PMID: 12805500]
[86]
Krams, M.; Lees, K.R.; Hacke, W.; Grieve, A.P.; Orgogozo, J-M.; Ford, G.A. ASTIN Study Investigators Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke. Stroke, 2003, 34(11), 2543-2548.
[http://dx.doi.org/10.1161/01.STR.0000092527.33910.89] [PMID: 14563972]
[87]
Lee, J.H.; Kam, E.H.; Kim, J.M.; Kim, S.Y.; Kim, E.J.; Cheon, S.Y.; Koo, B-N. Intranasal administration of interleukin-1 receptor antagonist in a transient focal cerebral ischemia rat model. Biomol. Ther. (Seoul), 2017, 25(2), 149-157.
[http://dx.doi.org/10.4062/biomolther.2016.050] [PMID: 27530114]
[88]
Smith, C.J.; Hulme, S.; Vail, A.; Heal, C.; Parry-Jones, A.R.; Scarth, S.; Hopkins, K.; Hoadley, M.; Allan, S.M.; Rothwell, N.J.; Hopkins, S.J.; Tyrrell, P.J. SCIL-STROKE (Subcutaneous interleukin-1 receptor antagonist in ischemic stroke): A randomized controlled phase 2 trial. Stroke, 2018, 49(5), 1210-1216.
[http://dx.doi.org/10.1161/STROKEAHA.118.020750] [PMID: 29567761]
[89]
Barone, F.C.; Irving, E.A.; Ray, A.M.; Lee, J.C.; Kassis, S.; Kumar, S.; Badger, A.M.; White, R.F.; McVey, M.J.; Legos, J.J.; Erhardt, J.A.; Nelson, A.H.; Ohlstein, E.H.; Hunter, A.J.; Ward, K.; Smith, B.R.; Adams, J.L.; Parsons, A.A. SB 239063, a second-generation p38 mitogen-activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia. J. Pharmacol. Exp. Ther., 2001, 296(2), 312-321.
[PMID: 11160612]
[90]
Legos, J.J.; Erhardt, J.A.; White, R.F.; Lenhard, S.C.; Chandra, S.; Parsons, A.A.; Tuma, R.F.; Barone, F.C. SB 239063, a novel p38 inhibitor, attenuates early neuronal injury following ischemia. Brain Res., 2001, 892(1), 70-77.
[http://dx.doi.org/10.1016/S0006-8993(00)03228-5] [PMID: 11172750]
[91]
Eckert, B.; Koch, C.; Thomalla, G.; Roether, J.; Zeumer, H. Acute basilar artery occlusion treated with combined intravenous Abciximab and intra-arterial tissue plasminogen activator: report of 3 cases. Stroke, 2002, 33(5), 1424-1427.
[http://dx.doi.org/10.1161/01.STR.0000014247.70674.7F] [PMID: 11988626]
[92]
Kleinschnitz, C.; Pozgajova, M.; Pham, M.; Bendszus, M.; Nieswandt, B.; Stoll, G. Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding. Circulation, 2007, 115(17), 2323-2330.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.107.691279] [PMID: 17438148]
[93]
Lapchak, P.A.; Araujo, D.M.; Song, D.; Zivin, J.A. The nonpeptide glycoprotein IIb/IIIa platelet receptor antagonist SM-20302 reduces tissue plasminogen activator-induced intracerebral hemorrhage after thromboembolic stroke. Stroke, 2002, 33(1), 147-152.
[http://dx.doi.org/10.1161/hs0102.100530] [PMID: 11779904]
[94]
Horisawa, S.; Kaneko, M.; Ikeda, Y.; Ueki, Y.; Sakurama, T. Antithrombotic effect of SM-20302, a nonpeptide GPIIb/IIIa antagonist, in a photochemically induced thrombosis model in guinea pigs. Thromb. Res., 1999, 94(4), 227-234.
[http://dx.doi.org/10.1016/S0049-3848(98)00215-1] [PMID: 10336238]
[95]
Abciximab Emergent Stroke Treatment Trial (AbESTT) Investigators Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of a randomized phase 2 trial. Stroke, 2005, 36(4), 880-890.
[http://dx.doi.org/10.1161/01.STR.0000157668.39374.56] [PMID: 15731473]
[96]
Adams, H.P., Jr; Effron, M.B.; Torner, J.; Dávalos, A.; Frayne, J.; Teal, P.; Leclerc, J.; Oemar, B.; Padgett, L.; Barnathan, E.S.; Hacke, W. AbESTT-II Investigators Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial: Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II). Stroke, 2008, 39(1), 87-99.
[http://dx.doi.org/10.1161/STROKEAHA.106.476648] [PMID: 18032739]
[97]
Mauler, F.; Fahrig, T.; Horváth, E.; Jork, R. Inhibition of evoked glutamate release by the neuroprotective 5-HT(1A) receptor agonist BAY x 3702 in vitro and in vivo. Brain Res., 2001, 888(1), 150-157.
[http://dx.doi.org/10.1016/S0006-8993(00)03074-2] [PMID: 11146061]
[98]
Schaper, C.; Zhu, Y.; Kouklei, M.; Culmsee, C.; Krieglstein, J. Stimulation of 5-HT(1A) receptors reduces apoptosis after transient forebrain ischemia in the rat. Brain Res., 2000, 883(1), 41-50.
[http://dx.doi.org/10.1016/S0006-8993(00)02876-6] [PMID: 11063986]
[99]
Mauler, F.; Horváth, E. Neuroprotective efficacy of repinotan HCl, a 5-HT1A receptor agonist, in animal models of stroke and traumatic brain injury. J. Cereb. Blood Flow Metab., 2005, 25(4), 451-459.
[http://dx.doi.org/10.1038/sj.jcbfm.9600038] [PMID: 15674237]
[100]
Lutsep, H.L. Repinotan, A 5-HT1A agonist, in the treatment of acute ischemic stroke. Curr. Drug Targets CNS Neurol. Disord., 2005, 4(2), 119-120.
[http://dx.doi.org/10.2174/1568007053544165] [PMID: 15857296]
[101]
Berends, A.C.; Luiten, P.G.M.; Nyakas, C. A review of the neuroprotective properties of the 5-HT1A receptor agonist repinotan HCl (BAYx3702) in ischemic stroke. CNS Drug Rev., 2005, 11(4), 379-402.
[http://dx.doi.org/10.1111/j.1527-3458.2005.tb00055.x] [PMID: 16614737]
[102]
Repinotan in Patients With Acute Ischemic Stroke - Tabular View, https://clinicaltrials.gov/ct2/show/record/NCT00044915
[103]
Goyagi, T.; Toung, T.J.K.; Kirsch, J.R.; Traystman, R.J.; Koehler, R.C.; Hurn, P.D.; Bhardwaj, A. Neuroprotective κ-opioid receptor agonist BRL 52537 attenuates ischemia-evoked nitric oxide production in vivo in rats. Stroke, 2003, 34(6), 1533-1538.
[http://dx.doi.org/10.1161/01.STR.0000072512.30658.E7] [PMID: 12738895]
[104]
Tang, A.H. Protection from cerebral ischemia by U-50,488E, a specific kappa opioid analgesic agent. Life Sci., 1985, 37(16), 1475-1482.
[http://dx.doi.org/10.1016/0024-3205(85)90178-X] [PMID: 2995747]
[105]
Gannon, R.L.; Terrian, D.M. U-50,488H inhibits dynorphin and glutamate release from guinea pig hippocampal mossy fiber terminals. Brain Res., 1991, 548(1-2), 242-247.
[http://dx.doi.org/10.1016/0006-8993(91)91127-M] [PMID: 1678297]
[106]
Olinger, C.P.; Adams, H.P., Jr; Brott, T.G.; Biller, J.; Barsan, W.G.; Toffol, G.J.; Eberle, R.W.; Marler, J.R. High-dose intravenous naloxone for the treatment of acute ischemic stroke. Stroke, 1990, 21(5), 721-725.
[http://dx.doi.org/10.1161/01.STR.21.5.721] [PMID: 2339451]
[107]
Clark, W.M.; Raps, E.C.; Tong, D.C.; Kelly, R.E. The Cervene Stroke Study Investigators Cervene (Nalmefene) in acute ischemic stroke : final results of a phase III efficacy study. Stroke, 2000, 31(6), 1234-1239.
[http://dx.doi.org/10.1161/01.STR.31.6.1234] [PMID: 10835438]
[108]
Zheng, J.; Li, H.; Guo, R.; Chen, R.; Lin, S.; Liu, M.; You, C. Neuroprotection of nalmefene for postoperative patients with spontaneous intracerebral hemorrhage. Int. J. Neurosci., 2015, 125(12), 918-923.
[http://dx.doi.org/10.3109/00207454.2014.985294] [PMID: 25375267]
[109]
Li, X-P.; Hou, W-C.; Song, L. nalmefene improves prognosis in patients with a large cerebral infarction: study protocol and preliminary results of a randomized, controlled, prospective trial. Clin. Trials Degener. Dis., 2017, 2(4), 101.
[http://dx.doi.org/10.4103/2542-3975.222182]
[110]
Sumii, T.; Lo, E.H. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke, 2002, 33(3), 831-836.
[http://dx.doi.org/10.1161/hs0302.104542] [PMID: 11872911]
[111]
Jiang, X.; Namura, S.; Nagata, I. Matrix metalloproteinase inhibitor KB-R7785 attenuates brain damage resulting from permanent focal cerebral ischemia in mice. Neurosci. Lett., 2001, 305(1), 41-44.
[http://dx.doi.org/10.1016/S0304-3940(01)01800-6] [PMID: 11356303]
[112]
Romanic, A.M.; White, R.F.; Arleth, A.J.; Ohlstein, E.H.; Barone, F.C. Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke, 1998, 29(5), 1020-1030.
[http://dx.doi.org/10.1161/01.STR.29.5.1020] [PMID: 9596253]
[113]
Alvarez-Sabín, J.; Román, G.C. The role of citicoline in neuroprotection and neurorepair in ischemic stroke. Brain Sci., 2013, 3(3), 1395-1414.
[http://dx.doi.org/10.3390/brainsci3031395] [PMID: 24961534]
[114]
Shuaib, A.; Yang, Y.; Li, Q. Evaluating the efficacy of citicoline in embolic ischemic stroke in rats: neuroprotective effects when used alone or in combination with urokinase. Exp. Neurol., 2000, 161(2), 733-739.
[http://dx.doi.org/10.1006/exnr.1999.7314] [PMID: 10686092]
[115]
Onal, M.Z.; Li, F.; Tatlisumak, T.; Locke, K.W.; Sandage, B.W., Jr; Fisher, M. Synergistic effects of citicoline and MK-801 in temporary experimental focal ischemia in rats. Stroke, 1997, 28(5), 1060-1065.
[http://dx.doi.org/10.1161/01.STR.28.5.1060] [PMID: 9158650]
[116]
Bustamante, A.; Giralt, D.; Garcia-Bonilla, L.; Campos, M.; Rosell, A.; Montaner, J. Citicoline in pre-clinical animal models of stroke: a meta-analysis shows the optimal neuroprotective profile and the missing steps for jumping into a stroke clinical trial. J. Neurochem., 2012, 123(2), 217-225.
[http://dx.doi.org/10.1111/j.1471-4159.2012.07891.x] [PMID: 22845688]
[117]
Secades, J.J.; Alvarez-Sabín, J.; Castillo, J.; Díez-Tejedor, E.; Martínez-Vila, E.; Ríos, J.; Oudovenko, N. Citicoline for acute ischemic stroke: a systematic review and formal meta-analysis of randomized, double-blind, and placebo-controlled trials. J. Stroke Cerebrovasc. Dis., 2016, 25(8), 1984-1996.
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.04.010] [PMID: 27234918]
[118]
Dávalos, A.; Alvarez-Sabín, J.; Castillo, J.; Díez-Tejedor, E.; Ferro, J.; Martínez-Vila, E.; Serena, J.; Segura, T.; Cruz, V.T.; Masjuan, J.; Cobo, E.; Secades, J.J. International Citicoline Trial on acUte Stroke (ICTUS) trial investigators Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial). Lancet, 2012, 380(9839), 349-357.
[http://dx.doi.org/10.1016/S0140-6736(12)60813-7] [PMID: 22691567]
[119]
Gandolfo, C.; Sandercock, P.; Conti, M. Lubeluzole for acute ischaemic stroke. Cochrane Database Syst. Rev.,, 2002, (1)CD001924
[PMID: 11869612 ]
[120]
Haseldonckx, M.; Van Reempts, J.; Van de Ven, M.; Wouters, L.; Borgers, M. Protection with lubeluzole against delayed ischemic brain damage in rats. A quantitative histopathologic study. Stroke, 1997, 28(2), 428-432.
[http://dx.doi.org/10.1161/01.STR.28.2.428] [PMID: 9040701]
[121]
De Ryck, M.; Keersmaekers, R.; Duytschaever, H.; Claes, C.; Clincke, G.; Janssen, M.; Van Reet, G. Lubeluzole protects sensorimotor function and reduces infarct size in a photochemical stroke model in rats. J. Pharmacol. Exp. Ther., 1996, 279(2), 748-758.
[PMID: 8930180]
[122]
Svennerholm, L. Gangliosides--a new therapeutic agent against stroke and Alzheimer’s disease. Life Sci., 1994, 55(25-26), 2125-2134.
[http://dx.doi.org/10.1016/0024-3205(94)00393-9] [PMID: 7997071]
[123]
Argentino, C.; Sacchetti, M.L.; Toni, D.; Savoini, G.; D’Arcangelo, E.; Erminio, F.; Federico, F.; Milone, F.F.; Gallai, V.; Gambi, D. GM1 ganglioside therapy in acute ischemic stroke. Italian Acute Stroke Study--Hemodilution + Drug. Stroke, 1989, 20(9), 1143-1149.
[http://dx.doi.org/10.1161/01.STR.20.9.1143] [PMID: 2672425]
[124]
Lanfranconi, S.; Locatelli, F.; Corti, S.; Candelise, L.; Comi, G.P.; Baron, P.L.; Strazzer, S.; Bresolin, N.; Bersano, A. Growth factors in ischemic stroke. J. Cell. Mol. Med., 2011, 15(8), 1645-1687.
[http://dx.doi.org/10.1111/j.1582-4934.2009.00987.x] [PMID: 20015202]
[125]
Larpthaveesarp, A.; Ferriero, D.M.; Gonzalez, F.F. Growth factors for the treatment of ischemic brain injury (growth factor treatment). Brain Sci., 2015, 5(2), 165-177.
[http://dx.doi.org/10.3390/brainsci5020165] [PMID: 25942688]
[126]
Belayev, L.; Liu, Y.; Zhao, W.; Busto, R.; Ginsberg, M.D. Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke, 2001, 32(2), 553-560.
[http://dx.doi.org/10.1161/01.STR.32.2.553] [PMID: 11157196]
[127]
Martin, R.H.; Yeatts, S.D.; Hill, M.D.; Moy, C.S.; Ginsberg, M.D.; Palesch, Y.Y. ALIAS Parts 1 and 2 and NETT Investigators ALIAS (Albumin in Acute Ischemic Stroke) Trials: Analysis of the Combined Data From Parts 1 and 2. Stroke, 2016, 47(9), 2355-2359.
[http://dx.doi.org/10.1161/STROKEAHA.116.012825] [PMID: 27462118]
[128]
Diener, H-C.; Schneider, D.; Lampl, Y.; Bornstein, N.M.; Kozak, A.; Rosenberg, G. DP-b99, a membrane-activated metal ion chelator, as neuroprotective therapy in ischemic stroke. Stroke, 2008, 39(6), 1774-1778.
[http://dx.doi.org/10.1161/STROKEAHA.107.506378] [PMID: 18403736]
[129]
Levy, D.E.; del Zoppo, G.J.; Demaerschalk, B.M.; Demchuk, A.M.; Diener, H-C.; Howard, G.; Kaste, M.; Pancioli, A.M.; Ringelstein, E.B.; Spatareanu, C.; Wasiewski, W.W. Ancrod in acute ischemic stroke: results of 500 subjects beginning treatment within 6 hours of stroke onset in the ancrod stroke program. Stroke, 2009, 40(12), 3796-3803.
[http://dx.doi.org/10.1161/STROKEAHA.109.565119] [PMID: 19875736]
[130]
Wang, Y.; Zhang, Z.G.; Rhodes, K.; Renzi, M.; Zhang, R.L.; Kapke, A.; Lu, M.; Pool, C.; Heavner, G.; Chopp, M. Post-ischemic treatment with erythropoietin or carbamylated erythropoietin reduces infarction and improves neurological outcome in a rat model of focal cerebral ischemia. Br. J. Pharmacol., 2007, 151(8), 1377-1384.
[http://dx.doi.org/10.1038/sj.bjp.0707285] [PMID: 17603558]
[131]
Safety and Pharmacokinetic Study of Carbamylated Erythropoietin (CEPO) to Treat Patients With Acute Ischemic Stroke - Full Text View https://clinicaltrials.gov/ct2/show/NCT00870844
[132]
Smith, S.E.; Lekieffre, D.; Sowinski, P.; Meldrum, B.S. Cerebroprotective effect of BW619C89 after focal or global cerebral ischaemia in the rat. Neuroreport, 1993, 4(12), 1339-1342.
[http://dx.doi.org/10.1097/00001756-199309150-00013] [PMID: 7903166]
[133]
Smith, S.E.; Hodges, H.; Sowinski, P.; Man, C.M.; Leach, M.J.; Sinden, J.D.; Gray, J.A.; Meldrum, B.S. Long-term beneficial effects of BW619C89 on neurological deficit, cognitive deficit and brain damage after middle cerebral artery occlusion in the rat. Neuroscience, 1997, 77(4), 1123-1135.
[http://dx.doi.org/10.1016/S0306-4522(96)00530-1] [PMID: 9130792]
[134]
Aronowski, J.; Strong, R.; Grotta, J.C. Treatment of experimental focal ischemia in rats with lubeluzole. Neuropharmacology, 1996, 35(6), 689-693.
[http://dx.doi.org/10.1016/0028-3908(96)84640-5] [PMID: 8887977]
[135]
Lin, B.; Dietrich, W.D.; Ginsberg, M.D.; Globus, M.Y.; Busto, R. MK-801 (dizocilpine) protects the brain from repeated normothermic global ischemic insults in the rat. J. Cereb. Blood Flow Metab., 1993, 13(6), 925-932.
[http://dx.doi.org/10.1038/jcbfm.1993.115] [PMID: 8408318]
[136]
Westermaier, T.; Stetter, C.; Kunze, E.; Willner, N.; Raslan, F.; Vince, G.H.; Ernestus, R-I. Magnesium treatment for neuroprotection in ischemic diseases of the brain. Exp. Transl. Stroke Med., 2013, 5(1), 6.
[http://dx.doi.org/10.1186/2040-7378-5-6] [PMID: 23618347]
[137]
Albers, G.W.; Goldstein, L.B.; Hall, D.; Lesko, L.M. Aptiganel Acute Stroke Investigators Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial. JAMA, 2001, 286(21), 2673-2682.
[http://dx.doi.org/10.1001/jama.286.21.2673] [PMID: 11730442]
[138]
Horn, J.; de Haan, R.J.; Vermeulen, M.; Luiten, P.G.; Limburg, M. Nimodipine in animal model experiments of focal cerebral ischemia: a systematic review. Stroke, 2001, 32(10), 2433-2438.
[http://dx.doi.org/10.1161/hs1001.096009] [PMID: 11588338]
[139]
Wiernsperger, N.; Gygax, P.; Hofmann, A. Calcium antagonist PY 108-068: demonstration of its efficacy in various types of experimental brain ischemia. Stroke, 1984, 15(4), 679-685.
[http://dx.doi.org/10.1161/01.STR.15.4.679] [PMID: 6464060]
[140]
De Ryck, M.; Van Reempts, J.; Borgers, M.; Wauquier, A.; Janssen, P.A. Photochemical stroke model: flunarizine prevents sensorimotor deficits after neocortical infarcts in rats. Stroke, 1989, 20(10), 1383-1390.
[http://dx.doi.org/10.1161/01.STR.20.10.1383] [PMID: 2799870]
[141]
Sydserff, S.G.; Cross, A.J.; Murray, T.K.; Jones, J.A.; Green, A.R. Clomethiazole is neuroprotective in models of global and focal cerebral ischemia when infused at doses producing clinically relevant plasma concentrations. Brain Res., 2000, 862(1-2), 59-62.
[http://dx.doi.org/10.1016/S0006-8993(00)02071-0] [PMID: 10799669]
[142]
Shuaib, A.; Lees, K.R.; Lyden, P.; Grotta, J.; Davalos, A.; Davis, S.M.; Diener, H-C.; Ashwood, T.; Wasiewski, W.W.; Emeribe, U. SAINT II Trial Investigators NXY-059 for the treatment of acute ischemic stroke. N. Engl. J. Med., 2007, 357(6), 562-571.
[http://dx.doi.org/10.1056/NEJMoa070240] [PMID: 17687131]
[143]
Yang, J.; Cui, X.; Li, J.; Zhang, C.; Zhang, J.; Liu, M. Edaravone for acute stroke: Meta-analyses of data from randomized controlled trials. Dev. Neurorehabil., 2015, 18(5), 330-335.
[http://dx.doi.org/10.3109/17518423.2013.830153] [PMID: 24088023]
[144]
Vemuganti, R.; Dempsey, R.J.; Bowen, K.K. Inhibition of intercellular adhesion molecule-1 protein expression by antisense oligonucleotides is neuroprotective after transient middle cerebral artery occlusion in rat. Stroke, 2004, 35(1), 179-184.
[http://dx.doi.org/10.1161/01.STR.0000106479.53235.3E] [PMID: 14657453]
[145]
Graham, S.H.; Shimizu, H.; Newman, A.; Weinstein, P.; Faden, A.I. Opioid receptor antagonist nalmefene stereospecifically inhibits glutamate release during global cerebral ischemia. Brain Res., 1993, 632(1-2), 346-350.
[http://dx.doi.org/10.1016/0006-8993(93)91175-R] [PMID: 7908601]
[146]
Anttila, J.E.; Albert, K.; Wires, E.S.; Mätlik, K.; Loram, L.C.; Watkins, L.R.; Rice, K.C.; Wang, Y.; Harvey, B.K.; Airavaara, M. Post-stroke intranasal (+)-naloxone delivery reduces microglial activation and improves behavioral recovery from ischemic injury. eNeuro, 2018, 5(2)ENEURO.0395-17. 2018.
[http://dx.doi.org/10.1523/ENEURO.0395-17.2018] [PMID: 29766045 ]
[147]
Elger, B.; Hornberger, W.; Schwarz, M.; Seega, J. MRI study on delayed ancrod therapy of focal cerebral ischaemia in rats. Eur. J. Pharmacol., 1997, 336(1), 7-14.
[http://dx.doi.org/10.1016/S0014-2999(97)01217-X] [PMID: 9384248]
[148]
Xu, S-Y.; Pan, S-Y. The failure of animal models of neuroprotection in acute ischemic stroke to translate to clinical efficacy. Med. Sci. Monit. Basic Res., 2013, 19, 37-45.
[http://dx.doi.org/10.12659/MSMBR.883750] [PMID: 23353570]
[149]
Reis, C.; Akyol, O.; Ho, W.M.; Araujo, C.; Huang, L.; Applegate, R., II; Zhang, J.H.; Phase, I.; and Phase, I.I. Therapies for acute ischemic stroke: an update on currently studied drugs in clinical research. BioMed Res. Int., 2017, 20174863079
[http://dx.doi.org/10.1155/2017/4863079] [PMID: 28286764]
[150]
Kikuchi, K.; Tanaka, E.; Murai, Y.; Tancharoen, S. Clinical trials in acute ischemic stroke. CNS Drugs, 2014, 28(10), 929-938.
[http://dx.doi.org/10.1007/s40263-014-0199-6] [PMID: 25160686]
[151]
Furlan, A.J. Challenges in acute ischemic stroke clinical trials. Curr. Cardiol. Rep., 2012, 14(6), 761-766.
[http://dx.doi.org/10.1007/s11886-012-0311-9] [PMID: 22922833]
[152]
Venketasubramanian, N.; Yoon, B.W.; Pandian, J. Stroke Epidemiology in South, East, and South-East Asia: A Review. J. Stroke Cerebrovasc. Dis., 2017, 19(3), 286-94.
[153]
Appelros, P.; Stegmayr, B.; Terént, A. Sex differences in stroke epidemiology: a systematic review. Stroke, 2009, 40(4), 1082-1090.
[http://dx.doi.org/10.1161/STROKEAHA.108.540781] [PMID: 19211488]
[154]
Liu, S.; Zhen, G.; Meloni, B.P.; Campbell, K.; Winn, H.R. Rodent stroke model guidelines for preclinical stroke trials in. J. Exp. Stroke Transl. Med., 2009, 2(2), 2-27.
[155]
Effectiveness of Butylphthalide on Dynamic Cerebral Autoregulation in Patients With Acute Ischemic Stroke. - Full Text View https://clinicaltrials.gov/ct2/show/NCT03413202
[156]
Study of rhPro-UK in Patients With Acute Ischaemic Stroke in 4.5 Hours After Stroke Onset(PROST) - Full Text View - ClinicalTrials. gov https://clinicaltrials.gov/ct2/show/NCT03541668
[157]
Clinical Trial to Evaluate the Efficacy and Safety of JPI-289 in Patients With Acute Ischemic Stroke - Full Text View - Clinical- Trials. https://clinicaltrials.gov/ct2/show/NCT03062397
[158]
Evaluation to Assess Safety and Tolerability of DM199 in Subjects With Acute Ischemic Stroke - Full Text View https://clinicaltrials.gov/ct2/show/NCT03290560
[159]
DLBS1033 for Acute Ischemic Stroke Patients - Full Text View https://clinicaltrials.gov/ct2/show/NCT02133521
[160]
Efficacy and Safety of FTY720 for Acute Stroke - Full Text View https://clinicaltrials.gov/ct2/show/NCT02002390
[161]
Zhu, Z.; Fu, Y.; Tian, D.; Sun, N.; Han, W.; Chang, G.; Dong, Y.; Xu, X.; Liu, Q.; Huang, D.; Shi, F.D. Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke: a pilot trial. Circulation, 2015, 132(12), 1104-1112.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.115.016371] [PMID: 26202811]
[162]
Cilostazol in Acute Ischemic Stroke Treatment (CAIST) - Full Text View-ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00272454
[163]
Lee, Y-S.; Bae, H-J.; Kang, D-W.; Lee, S-H.; Yu, K.; Park, J-M.; Cho, Y-J.; Hong, K-S.; Kim, D-E.; Kwon, S.U.; Lee, K.B.; Rha, J.H.; Koo, J.; Han, M.G.; Lee, S.J.; Lee, J.H.; Jung, S.W.; Lee, B.C.; Kim, J.S. Cilostazol in Acute Ischemic Stroke Treatment (CAIST Trial): a randomized double-blind non-inferiority trial. Cerebrovasc. Dis., 2011, 32(1), 65-71.
[http://dx.doi.org/10.1159/000327036] [PMID: 21613787]
[164]
Atorvastatin in Acute Stroke Treatment - Full Text View - ClinicalTrials. gov https://clinicaltrials.gov/ct2/show/NCT02225834
[165]
Tuttolomondo, A.; Di Raimondo, D.; Pecoraro, R.; Maida, C.; Arnao, V.; Della Corte, V.; Simonetta, I.; Corpora, F.; Di Bona, D.; Maugeri, R.; Iacopino, D.G.; Pinto, A. Early High-dosage atorvastatin treatment improved serum immune-inflammatory markers and functional outcome in acute ischemic strokes classified as large artery atherosclerotic stroke: A Randomized Trial. Medicine (Baltimore), 2016, 95(13)e3186
[http://dx.doi.org/10.1097/MD.0000000000003186] [PMID: 27043681]
[166]
Edaravone-Sodium Ozagrel Comparative Post-Marketing Study on Acute Ischemic Stroke - Study Results - ClinicalTrials. https://clinicaltrials.gov/ct2/show/results/NCT00200356
[167]
Shinohara, Y.; Saito, I.; Kobayashi, S.; Uchiyama, S. Edaravone (radical scavenger) versus sodium ozagrel (antiplatelet agent) in acute noncardioembolic ischemic stroke (EDO trial). Cerebrovasc. Dis., 2009, 27(5), 485-492.
[http://dx.doi.org/10.1159/000210190] [PMID: 19321945]
[168]
Histamine Glutamate Antagonism in Stroke - Full Text View https://clinicaltrials.gov/ct2/show/NCT02142712
[169]
Chamorro, Á.; Amaro, S.; Castellanos, M.; Gomis, M.; Urra, X.; Blasco, J.; Arenillas, J.F.; Román, L.S.; Muñoz, R.; Macho, J.; Cánovas, D.; Marti-Fabregas, J.; Leira, E.C.; Planas, A.M. URICO-ICTUS Investigators Uric acid therapy improves the outcomes of stroke patients treated with intravenous tissue plasminogen activator and mechanical thrombectomy. Int. J. Stroke, 2017, 12(4), 377-382.
[http://dx.doi.org/10.1177/1747493016684354] [PMID: 28345429]
[170]
Amaro, S.; Laredo, C.; Renú, A.; Llull, L.; Rudilosso, S.; Obach, V.; Urra, X.; Planas, A.M.; Chamorro, Á. URICO-ICTUS Investigators uric acid therapy prevents early ischemic stroke progression: a tertiary analysis of the urico-ictus trial (efficacy study of combined treatment with uric acid and r-tpa in acute ischemic stroke). Stroke, 2016, 47(11), 2874-2876.
[http://dx.doi.org/10.1161/STROKEAHA.116.014672] [PMID: 27758945]
[171]
Efficacy Study of Combined Treatment With Uric Acid and rtPA in Acute Ischemic Stroke - Full Text View. https://clinicaltrials.gov/ct2/show/NCT00860366
[172]
Stem Cell Therapy For Acute Ischemic Stroke Patients - Full Text View https://clinicaltrials.gov/ct2/show/NCT02425670
[173]
Prasad, K.; Sharma, A.; Garg, A.; Mohanty, S.; Bhatnagar, S.; Johri, S.; Singh, K.K.; Nair, V.; Sarkar, R.S.; Gorthi, S.P.; Hassan, K.M.; Prabhakar, S.; Marwaha, N.; Khandelwal, N.; Misra, U.K.; Kalita, J.; Nityanand, S. InveST Study Group Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. Stroke, 2014, 45(12), 3618-3624.
[http://dx.doi.org/10.1161/STROKEAHA.114.007028] [PMID: 25378424]
[174]
Ehrenreich, H.; Weissenborn, K.; Prange, H.; Schneider, D.; Weimar, C.; Wartenberg, K.; Schellinger, P.D.; Bohn, M.; Becker, H.; Wegrzyn, M.; Jähnig, P.; Herrmann, M.; Knauth, M.; Bähr, M.; Heide, W.; Wagner, A.; Schwab, S.; Reichmann, H.; Schwendemann, G.; Dengler, R.; Kastrup, A.; Bartels, C. EPO Stroke Trial Group Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke, 2009, 40(12), e647-e656.
[http://dx.doi.org/10.1161/STROKEAHA.109.564872] [PMID: 19834012]
[175]
Liu, X.; Xia, J.; Wang, L.; Song, Y.; Yang, J.; Yan, Y.; Ren, H.; Zhao, G. Efficacy and safety of ginsenoside-Rd for acute ischaemic stroke: a randomized, double-blind, placebo-controlled, phase II multicenter trial. Eur. J. Neurol., 2009, 16(5), 569-575.
[http://dx.doi.org/10.1111/j.1468-1331.2009.02534.x] [PMID: 19236467]
[176]
Clinical Trial to Assess the Efficacy and to Evaluate Safety of HT047 in Patients With Acute Ischemic Stroke - Full Text View - ClinicalTrials https://clinicaltrials.gov/ct2/show/NCT02828540
[177]
Heiss, W-D.; Brainin, M.; Bornstein, N.M.; Tuomilehto, J.; Hong, Z. Cerebrolysin Acute Stroke Treatment in Asia (CASTA) Investigators Cerebrolysin in patients with acute ischemic stroke in Asia: results of a double-blind, placebo-controlled randomized trial. Stroke, 2012, 43(3), 630-636.
[http://dx.doi.org/10.1161/STROKEAHA.111.628537] [PMID: 22282884]
[178]
Horn, C.M.; Sun, C-H.J.; Nogueira, R.G.; Patel, V.N.; Krishnan, A.; Glenn, B.A.; Belagaje, S.R.; Thomas, T.T.; Anderson, A.M.; Frankel, M.R.; Schindler, K.M.; Gupta, R. Endovascular reperfusion and cooling in cerebral acute ischemia (ReCCLAIM I). J. Neurointerv. Surg., 2014, 6(2), 91-95.
[http://dx.doi.org/10.1136/neurintsurg-2013-010656] [PMID: 23468538]
[179]
Lyden, P.; Pryor, K.E.; Coffey, C.S.; Cudkowicz, M.; Conwit, R.; Jadhav, A.; Sawyer, R.N., Jr; Claassen, J.; Adeoye, O.; Song, S.; Hannon, P.; Rost, N.S.; Hinduja, A.; Torbey, M.; Lee, J.M.; Benesch, C.; Rippee, M.; Rymer, M.; Froehler, M.T.; Clarke Haley, E.; Johnson, M.; Yankey, J.; Magee, K.; Qidwai, J.; Levy, H.; Mark Haacke, E.; Fawaz, M.; Davis, T.P.; Toga, A.W.; Griffin, J.H.; Zlokovic, B.V. NeuroNEXT Clinical Trials Network NN104 Investigators. Final results of the rhapsody trial: a multi-center, phase 2 trial using a continual reassessment method to determine the safety and tolerability of 3k3a-apc, a recombinant variant of human activated protein c, in combination with tissue plasminogen activator, mechanical thrombectomy or both in moderate to severe acute ischemic stroke. Ann. Neurol., 2019, 85(1), 125-136.
[http://dx.doi.org/10.1002/ana.25383] [PMID: 30450637]
[180]
Safety Study of Carbamylated Erythropoietin (CEPO) to Treat Patients With Acute Ischemic Stroke - Full Text View - ClinicalTrials https://clinicaltrials.gov/ct2/show/NCT00756249
[181]
Safety and Efficacy of Intravenous Natalizumab in Acute Ischemic Stroke - Full Text View. https://clinicaltrials.gov/ct2/show/NCT02730455
[182]
Effect of Natalizumab on Infarct Volume in Acute Ischemic Stroke - Full Text View https://clinicaltrials.gov/ct2/show/NCT01955707
[183]
Elkins, J.; Veltkamp, R.; Montaner, J.; Johnston, S.C.; Singhal, A.B.; Becker, K.; Lansberg, M.G.; Tang, W.; Chang, I.; Muralidharan, K.; Gheuens, S.; Mehta, L.; Elkind, M.S.V. Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol., 2017, 16(3), 217-226.
[http://dx.doi.org/10.1016/S1474-4422(16)30357-X] [PMID: 28229893]
[184]
A Safety and Dose Finding Study of Plasmin (Human) Administered Into the Middle Cerebral Artery of Stroke Patients - Full Text View. https://clinicaltrials.gov/ct2/show/NCT01014975
[185]
IVIG in Acute Ischemic Stroke: A Pilot Study - Full Text View. https://clinicaltrials.gov/ct2/show/NCT01628055


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 18
ISSUE: 7
Year: 2020
Published on: 28 July, 2020
Page: [596 - 612]
Pages: 17
DOI: 10.2174/1570159X18666200114160844
Price: $65

Article Metrics

PDF: 30
HTML: 3
EPUB: 1
PRC: 1