Cerebroprotectant

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A cerebroprotectant (formerly known as a neuroprotectant) is a drug that is intended to protect the brain after the onset of acute ischemic stroke. [1] As stroke is the second largest cause of death worldwide and a leading cause of adult disability, over 150 drugs have been tested in clinical trials to provide cerebroprotection. [2] [3] [4]

Contents

Approved drugs

Drugs in development

Approval rate

While over 150 cerebroprotectants have been tested in clinical trials, as of 2022 only the above two cerebroprotectants are approved, though several clinical trials for other drugs are ongoing. The approval rate has been less than 2%, which is low compared to the overall approval rate of all drugs brought into clinical trials in all disease areas from 2011 to 2022 which was 7.9%. [9] It is also much lower than the relatively high success rate for devices to treat acute ischemic stroke, as there have been at least 5 different clot removal devices approved since 2015. [10]

Methods to increase approval rate

There are many theories as to the causes of the low approval rate for cerebroprotectants, and many strategies have been suggested in publications to improve the chance of approval of drugs in development. The strategies that journals suggest to improve the chance of approval in clinical trials are outlined below:

Choose the right targets
Continuous research into the pathophysiology of stroke has led to improved ability to select drugs targets. [1] Acute ischemic strokes start when there is reduced blood flow, often caused by an occlusion, to part of the brain. [11] Even if an occlusion causes a complete blockage of a major artery, there is typically still some blood flow downstream of the blockage through collateral blood vessels. [12] With reduced blood flow, there is reduced oxygen supply, and to compensate the tissue goes through anaerobic metabolism which is much less efficient. [13] If anaerobic metabolism does not provide enough energy, there is energy failure, followed by ion imbalances. [14] Afterwards, the pathophysiology gets complicated and there are thought to be at least eight pathways of tissue damage. [15] By targeting processes near the top of the top of the chain of events, problems further down the chain of events can be avoided. For example, the drug tPA and mechanical thrombectomy devices all target the occlusion which is at the top of the chain of events, and have achieved FDA approval. The next step in the chain of events is hypoxia, and some oxygen delivery drugs have shown strong effects in animal studies, as shown in the table below. If processes further down the chain of events get targeted, there may be many simultaneous problems and the effect of a single therapy may be less, so there may be benefit to using multiple drugs in combination to treat multiple pathways. [1]
Choose the best candidates from pre-clinical (animal) studies
A 2006 analysis of studies for 1,026 therapies in stroke and theorized that the best drugs from pre-clinical studies were not the ones being brought into clinical trials. Many of the drugs with the strongest signals in pre-clinical models were not the ones later brought into clinical trials. [4]
Improve pre-clinical testing
Others proposed that the lack of standardization in pre-clinical models made it difficult to select the best drugs. [1] One attempt to address this comes from the National Institute of Neurological Disorders and Stroke which started the Stroke Preclinical Assessment Network to fund a testing regimen that will allow head-to-head comparisons of different drugs. [16]
Treat patients early enough
After the onset of stroke, the amount of brain tissue that dies increases over time, leading to the saying, "Time is brain." [17] Treating patients earlier can lead to a greater amount of brain tissue being saved.
Protect the brain for long enough
An element of clinical trial design that affects the probability that a truly beneficial drug will show benefit is the duration of protection. A truly effective drug that is tested in a clinical trial where it protects the brain for a longer period of time would be expected to show a greater benefit verses a placebo than the same drug in a different clinical trial where it only protects the brain for a shorter period of time. [18]
Select patients with salvageable tissue
Another element of clinical trial design is the use of imaging biomarkers to select patients that are likely to benefit from therapy. MRI and CT imaging methods that determine whether a patient is likely to have salvageable tissue have been used to great effect in clinical trials that showed the benefit of mechanical thrombectomy devices. [19] These same methods can be applied to clinical trials for cerebroprotective drugs. [18]
Restore blood flow after protection so that protected tissue can survive long term
If a drug protects the brain from reduced blood flow but then wears off before blood flow is normalized, then the long term effect of the drug may not be as great as it would be if the drug were paired with therapy to normalize blood flow. Pairing cerebroprotective drugs with approved methods to restore blood flow, such as tPA or mechanical thrombectomy, may increase their long term benefit. [11] [18]

Clinical trials

RankNameFirst TrialMechanism% Protection in Animal Studies (% Reduction in Infarct Volume)Number of Animal Studies from Which % Protection has been CalculatedCommentsFocal ischemic stroke studies with positive resultsFocal ischemic stroke studies showing no changeFocal ischemic stroke studies with negative resultsSources
1Oxygenated fluorocarbon nutrient emulsion (OFNE) or Revoxyn2001Oxygen delivery941A perfluorocarbon emulsion that required drilling a hole in the skull (called a ventricular catheter). A clinical trial in 4 patients demonstrated safety, but enrollment was slow and company folded.200 [4] [20] [21]
2 Dapsone 2007Antibacterial931Inconsistent studies in rats, one showing dramatic effect, another showing no effect. A randomized Phase II clinical trial in 30 patients showed statistically significant improvements in NIHSS and Barthel index. Development discontinued for unknown reasons.110 [22] [23] [24] [25]
3DDFPe, NanO2 or NVX-2082017Oxygen Delivery855Another perfluorocarbon emulsion injected intravenously thought to improve oxygen flow from red blood cells to tissue. A Phase Ib/II clinical trial was completed. The drug was safe at all three doses tested, and the high dose group had significantly better function independence (modified Rankin Scale).900 [26] [27] [28] [29] [30] [31]
4 Albumin 2011Antioxidant Improvement of microcirculation661Albumin therapy was associated with an increase in symptomatic intercranial hemorrhage and pulmonary edema/congestive heart failure.100 [32]
5Veripamil2016Calcium channel blocker (Phenylalkylamine calcium channel)662Veripamil was administered immediately after restoration of blood flow.201 [33] [34] [35] [36]
6 Dextromethorphan 2011NMDA ion channel blocker611Trial in 40 patients showed that it is not cerebroprotective, but does not worsen condition or neurological outcome; reduction in seizures, and increase of MI and renal failure versus placebo.100 [37] [38]
7CP101.606-271999NMDA ion channel blocker613Enrolled patients within 6 hours after stroke, but did not include patients who received tPA. The study was terminated, and the results were not reported.300 [39]
8Gavestinel (GV150526A)1999NMDA glycine antagonist6018"The cause of the neutral results with gavestinel remains to be explained. It is possible that the time window to effectively antagonize glutamate is simply less than 6 h, or that the neuroprotective benefit of infarct size reduction in animals does not translate into improved functional outcome measured in clinical trials. Just as likely, however, expectations with gavestinel were over-inflated because only positive preclinical results were published (it is common that negative results in animal studies go unreported). Mild beneficial effects were only seen in carefully standardized stroke models that do not reflect the heterogeneity of stroke patients where more robust efficacy would be needed to achieve clinical significance."860 [40] [41]
9SP-82032016antioxidant and NMDA receptor antagonist591Phase II in progress in 2018 in patients with product dosed after tPA. Pre-clinical studies showed high level of dose dependency.100 [42] [43]
10 ketamine 2014NMDA receptor antagonist571Phase I/II in progress as of 2018100 [44] [45]
11Hu23F2G (LeukArrest)1999Leukocyte adhesion inhibitor571100
12Donepezil2008selective acetylcholinesterase inhibitor561100 [46]
13Repinotan (BAY × 3072)2000Serotonin agonist562200 [4]
14Prourokinase1998Antithrombotic55121200 [4]
15 3K3A-APC 2014anti-inflammatory548A Phase II clinical trial in 110 patients published in 2019 showed the drug was safe, and there was a trend towards less hemorrhage, but there was also a trend towards less favorable outcomes. The incidence of favorable outcome (90-day mRS 0 or 1) was not statistically significantly different from placebo, (45.2% treatment vs 62.8% placebo).800 [47] [48] [49] [50] [51] [52] [53]
16Granulocytecolony stimulating factor (G-CSF)2003activator of transcription-3 (STAT3) in the periphery of the infarction531No effect - G-CSF did not improve stroke outcome in this individual patient data meta-analysis.900 [54] [55] [56]
17 Urokinase 1976Thrombolytic53121310 [4]
18 Atorvastatin 2015Statin considered to have favorable impact on blood brain barrier, oxidative stress, cerebral blood flow, and inflammation521Phase IV in progress in China as of 2019100 [57] [58]
19 Deferoxamine 2012Iron chelator; bacterial siderophore522Phase II completed but results not published, and no Phase 3 was started.200 [59] [60] [61]
20Caffeinol2002Stimulant, depressant, diuretic Adenosine receptor modulator5110820 [4]
21CNS1102 (Cerestat, aptiganel)1994NMDA ion channel blocker51111120 [4]
22 Dextrorphan 1994NMDA ion channel blocker50171360 [4]
23JPI-2892017PARP-1 Inhibitor491Jeil Pharmaceutical Co., Ltd, Phase II in progress in Korea as of 2019. Safety and dosing was demonstrated in healthy adults. [62] [63]
24 Minocycline 2007antibiotic491Phase IV terminated due to futility. Enrolled patients up to 48 hours after stroke.200 [64]
25 Remacemide 1994NMDA ion channel blocker491100 [4]
26tPA (< 3 hours)1995Thrombolytic499tPA was approved for use up to 3 hours after onset, though the initial tirals up to 6 hours after onset showed no significant improvement. Pre-clinical models showed a beneficial effect of the drug when given up to 3 hours but a detrimental effect when given beyond 3 hours.9100 [65]
27Diaspirin cross-linked hemoglobin1998Oxygen delivery Free radical scavenger485510 [4]
28Eliprodil (SL 82.0715)1994NMDA polyamine antagonist Sigma ligand484600 [4]
29CGS 19755 (selfotel)1995NMDA antagonist472411 [4]
30 Hypothermia 1998Reduce reducing cerebral oxygen demand (CMRO2), Metabolic and synaptic transmission inhibitor.469294280 [4]
31Lifarizine (RS-87476)1995Sodium/calcium channel blocker468540 [4]
32 Glibenclamide (BIIB093, BIIB-093, glibenclamide IV, formerly Cirara or RP-1127).2010selective inhibitor of SUR1-TRPM4 channels that mediate stroke related brain swelling.453As of 2022 Biogen is in Phase III in patients with large infarcts with volumes of 80 to 300 centimeters cubed. These patients tend to have poor outcomes due to the large infarcts.300 [66] [67] [68] [69] [70]
33MP-1242011PARP-1 Inhibitor442A Phase 1 drug developed by Mitsubishi Tanabe's with an unclear status as of 2019.200 [71] [72]
34NS1209/SPD 5021999Gluamate antagonist442200 [4]
35 NXY-059 2001Free radical scavenger4327AstraZeneca's drug that completed its second Phase III in 2006, leading to what some called the "nuclear winter" in stroke research. At the time, imaging biomarkers were less developed. Secondly, mechanical thrombectomy was not invented yet, and patients with large vessel occlusions in the trial likely had low reperfusion rates. Furthermore, the pathology is better known today, and the chain of events is better understood. The drug targteted processes that were far downstream in the ischemic cascade thereby giving the drug a weaker clinical signal than many drugs targeting processes further up the ischemic cascade. The first Phase III in 1700 patients saw a significant improvement in mRS (p=0.03), but missed all its secondary endpoints. A second Phase III in 3,300 patients saw no effect in any endpoint.2450 [4] [73]
36 Clomethiazole (CMZ, Zendra)1996GABA agonist427820 [4]
37 Vinpocetine (ethyl apovincaminate)1986Calcium inhibitor, Vasodilator, Sodium blocker; synthetic derivative of the vinca alkaloid vincamine, an extract from the lesser periwinkle plant.421Results of Phase III published in 2016. Off patent - first made in 1975. A clinical trial in 610 patients in China was completed, showing improved outcomes in NIHSS, and Barthel Index.100 [74] [75]
38Neu20002016NR2B-selective NMDA receptor antagonist and spin trapping molecule (=free radical scavenger or antioxidant)41.21GNT Pharma. Enrolls only patients with confirmed AIS eligible for MT up to 8 hours after onset. The drug will provide only a short duration of protection before MT restores blood flow, probably averaging an hour or less. If they paused the clock perfectly, they would need thousands of patients to show an effect, so there is risk of failing the Phase II due to having too short of a duration of protection. Therapeutic potential of Neu2000 has been well demonstrated in four animal models of stroke with better efficacy and therapeutic time windows than either NMDA receptor antagonist or anti-oxidant advanced to clinical trials. In human phase I studies of 165 healthy subjects conducted in the United States and China, Neu2000KWL showed promising safety profiles without any serious adverse events.4 [76] [77]
39Sipatrigine (BW619C89)1995Sodium channel antagonist Glutamate release inhibitor41374040 [4]
40NA-1 (TatNR2B9c)2008Postsynaptic density-95 protein inhibitor406NoNO Inc is using an ion channel inhibitor called NA-1 (nerenetide). They recently completed a Phase III clinical trial in Large Vessel Occlusion (LVO) patients undergoing mechanical thrombectomy, but the trial showed neutral results in the overall population. The subset of patients that did not get tPA showed benefit, therefore they are seeking to run another Phase III clinical in LVO patients who are ineligible for tPA and hope to initiate this trial in 2021. They are enrolling in another Phase III trial that enrolls a broad population of stroke patients in the field, and results are expected in 2022.620 [78] [79] [80] [81] [82] [83] [84] [85]
41AER-2712018inhibitor of Aquaporin-4 (AQP4) water channels391Initiated Phase 1 trial in June 2018. The osmotic imbalance and subsequent influx of water via AQP4 occurs as a result of a lack of oxygen and leads to edema, midline shift, increased intracranial pressure and brain herniation resulting in permanent disability or mortality. Targets the same physiology as Biogen's BIIB-093 (glyburide for incjection or CIRARA), but via a different pathway. Edema is further down the ischemic cascade than hypoxia.000 [86]
42 Erythropoietin (EPO)2002Controls red blood cell production399Tested again in 2009. Clnical trial showed no significant difference in neurological recovery. Significantly increased mortality rate and safety concerns1120 [4]
43ARL 15896 (AR-A15896AR)1999NMDA antagonist39151080 [4]
44 Piracetam 1988AMPA (NA+) modulator395410 [4]
45Nafronyl oxalate (naftidrofuryl)1978Serotonin antagonist385620 [4]
46ACEA 1021 (licostinel)1997NMDA glycine site antagonist37251960 [4]
47Propentofylline (HWA 285)1992Phosphodiesterase inhibitor377920 [4]
48S-0139 (SB-737004)1999Endothelin antagonist364310 [4]
49PG2 (Polysaccharides of Astragalus membranaceus)2015Chinese Herb, Antiinflammatory361Phase IV clinical trial status unclear.100 [87] [88]
50 Trans sodium crocetinate 2018increases diffusion of oxygen3533 [89] [90] [91]
51TNK (tenecteplase)2000Thrombolytic agent352200 [4]
52 Magnesium Sulfate 1993NMDA ion channel blocker. Calcium antagonist3510The first drug tested that had a significant amount of patients dosed in the first 2 hours in the FAST-MAG trial. Phase III results published in 2015 showed no therapeutic benefit.1100 [4] [92]
53propanolol1988β-adrenergic blockade, Membrane stabilization344Studied most recently in 2013. Phase II/III completed, but results not published.380 [4]
54Mannitol1978Hyperosmotic agent. Reduces edema and ICP341910151 [4]
55Dextran1969Hemodilution347451 [4]
56 N-acetyl-cysteine (NAC)2015Free radical scavenger331100 [93]
57PS519/MLN5192000Proteasome inhibitor32141130 [4]
58 Heparin 1979Anticoagulant321710103 [4]
59FK506 (pacrolimus)2004Immunosuppressant3172Stopped in Phase II, adverse side effects52270 [4]
60Neutrophil inhibitory factor (rNIF, UK-279.276)2000Neutrophil inhibitor3112840 [4]
61YM90K1997AMPA antagonist31231960 [4]
62 Aspirin 1995Antiplatelet31199130 [4]
63 Lovastatin (aka simvastatin)2001HMGCoA reductase inhibitor3020Finished recruitment in Phase II trial in 2017, results not published as of 2019.1110 [4] [94] [95]
64Normobaric oxygen treatment2009Oxygen Delivery306Several human studies evaluating normobaric oxygen therapy for stroke treatment have been performed. However, there is not much room to increase oxygen delivery by increasing the concentration of oxygen breathed does not increase the blood oxygen level much. The normal oxygen saturation of red blood cells is 95-99%, and plasma only dissolves a small amount of oxygen. Human studies showed no significant difference in neurological recovery. No trials have shown any evidence that the therapy is detrimental.501 [96] [97] [98] [99] [100] [101]
65Basic fibroblast growth factor (trafermin. Fiblast)1998Growth factor293522190 [4]
66 Naloxone 1981Opioid antagonist297870 [4]
67 Ebselen 2009Free radical scavenger; synthetic organo-selenium antiinflammatory, anti-oxidant and cytoprotective activity; mimic glutathione peroxidase279Tested in Phase III but never reached market, and now out of patent.1060 [4]
68BIII-890-CL2001Sodium Channel Blocker276Still in trial in 2014600 [4]
69YM8721999AMPA antagonist27322280 [4]
70Ebselen (Harmokisane)1998Free radical scavenger2791060 [4]
71Abciximab (reopro, c7E3 Fab)1998Antiplatelet: glycoprotein inhibitor272110 [4]
72Tirilazad (U74006F)1994Free radical scavenger26161180 [4]
73nimodipine1984antihypertensive drug2637May be in clinical trials in China in 2016, but status is unknown. Failed earlier clinical trials.24280 [102] [103]
74Enoxaparin2003Antithrombotic252512130 [4]
75ONO-25062003Astrocyte modulating agent Anenuates extracellular monamine258530 [4]
76 EGB-761 (Ginkgo biloba extract)1995MAO inhibitor Antiplatelet.25151330 [4]
77Citicoline (CDP choline)1987Membrane precursor, antioxidant2513490 [4]
78 Edaravone (MCI-186)2001Free radical scavenger nootropic and neuroprotective agent248Approved in Japan.750 [104] [105]
79Hyperbaric oxygen treatment1966Oxygen delivery24171352 [4]
80Indomethacin2001Cyclooxygenase inhibitor232320 [4]
81Lubeluzole1994Sodium/calcium channel blocker NOS inhibitor23191380 [4]
82Hydroxyethyl starch pentastarch1980Hemodilution233431 [4]
83Cyclosporin A2014Immunosuppressant221Not effective in reducing infarct size. However, a smaller infarct size was observed in patients with proximal cerebral arteryocclusion and efficient recanalization.920 [106]
84 natalizumab 2016prevents leukocytes from moving across the blood-brain barrier223Discontinued by Biogen after a Phase II trial showed that natalizumab administered ≤24 hours after acute ischemic stroke did not improve patient outcomes.420 [107]
85Anerod1983Fibrinogen depleting214410 [4]
86ZK200775 (MPQX)1997AMPA antagonist19211290 [4]
87 Dexamethasone 1971Glucocorticoid, antiinflammatory1911Continued in 2011. Clinical trials showed improvement of level of consciousness was statistically significant in Dexamethasone treated group, but did not reduce volume of hypodense area.781 [4]
88Nicaraven (N,N′-propylenedinicotinamide)2001Free radical scavenger174220 [4]
89Insulin1993Lowers glucose165412 [4]
90ABL-101 (Oxycyte)2018Oxygen Delivery151Developed by Aurum Biosciences, formerly developed by Oxycyte. A perfluorocarbon emulsion that works like a blood substitute.100 [108]
91BMS-2043521998Potassium channel opener149710 [4]
92Enlimomab (anti–ICAM-1 antibody)1996Leukocyte migration and adhesion inhibitor149671 [4]
93 Nicardipine 1988Calcium antagonist1168100 [4]
94 Argatroban 1986Anticoagulant114330 [4]
95TAK-2182001Dopamine suppressor101010 [4]
96 Paracetemol (Acetaminophen)2009Analgesic/antipyretic COX inhibitor81010 [4]
97n-PA/tPA (alteplase)1988Antithrombotic486523811 [4]
98Ganglioside GM11984Metabolism, growth41640 [4]
99GSK2493202013Antagonises or neutralises myelin associated glycoprotein (MAG) - mediated inhibition01GlaxoSmithKline, discontinued in 2017 after showing no effect at interim analysis.010 [109]
100 Simvastatin 2008HMGCoA reductase inhibitor Antioxidant01No differences were found between treatment arms regarding the primary outcome.010 [94] [110]
101 Baclofen 2001GABA-B Antagonist00110 [4]
102Amphetamines2003Stimulant-31120 [4]
103Papaverine1976Calcium channel blocker-31010 [4]
104 Flunarizine 1990Calcium channel blocker-63411 [4]
105Prosatacyclin1984Antiplatelet: eicosanoid Vasodilator-61110 [4]
106tPA (>3 hours)1995Thrombolytic-392The data in animals showed benefit below 3 hours after stroke onset and a detrimental effect after three hours (an increase in infarct volume). The data is calculated from the caterpillar plot in figure 1.072 [65]
107Streptokinase1963Thrombolytic-5256145 [4]
108LT30012019Thrombolytic and antioxidant00Lumosa Therapeutics was running a Phase II clinical trial in 2022000 [111]
109 TMS-007 2014Thrombolytic00Biogen acquired TMS-007 in 2021 after a positive Phase IIa trial.000 [112] [113]
110GM6022016anti-inflammatory—-Phase II completed, but no Phase III has appeared to have been started. Run by Genervon. No pre-clinical data published.--- [114] [115]
111Vitamin B22015Causes a Reduction of Glutamate-mediated Excitotoxicity—0Phase II complete, but no results published.000 [116]
112Irbesartan2012AT1 receptor antagonist Antihypertensive—-Agent did not appear to substantially modify infarct growth.1-- [117] [118]
113Lu AA24493 (carbamylated erythropoietin CEPO)2011Controls red blood cell production—-Unknown toxicity claims halted development. Trial run by H. Lundbeck AS---
114NTx-2652009Regeneration; Human Chorionic Gonadotropin (hCG) and Epoetin Alfa (EPO)—-No significant difference in neurological recovery.--- [119]
115ILS-9202009Calcium channel blocker—-Now owned by Pfizer, but no longer on Pfizer's pipeline.--- [120]
116Eptifibatide (cromafiban; Integrilin)2003Antiplatelet: glycoprotein inhibitor—0000 [4]
117Desmoteplase (DSPA)2002Antithrombotic—0000 [4]
118S-17462001NMDA glycine/AMPA antagonist—0000 [4]
119Tirofiban (MK-383, aggrastat)2001Antiplatelet: glycoprotein inhibitor—0000 [4]
120Triflusal (2-acetoxy-4-trifluoromethylbenzonic acid)2001Arachidonic acid metabolism inhibitor (antiplatelet)—0120 [4]
121Cerebrolysin2001Nootropic—0A total of 1070 patients were enrolled in this study. Five hundred twenty-nine patients were assigned to Cerebrolysin and 541 to placebo. The confirmatory end point showed no significant difference between the treatment groups. When the predefined stratification by severity was repeated with the criterion NIHSS, however, a small superiority for Cerebrolysin in the sub-group with baseline NIHSS>12 (OR, 1.27; CI-LB, 0.97; P=0.04) could be shown . Also, when applying the mRS, a small superiority in the sub-group with baseline NIHSS>12 (OR, 1.27; CI-LB, 0.90; P=0.09) was found. The following analysis also focused on the subgroup baseline NIHSS>12 points only and provided a global test result for all 3 criteria combined. This global test results in MW=0.53 (CI-LB, 0.47; P=0.16), which showed a beneficial trend for Cerebrolysin in the study patients.110 [4] [121]
122DP-b99 (DPBAPA)2000Calcium chelator—0Interim futility analysis showed no evidence of efficacy, published in 2008.000 [122]
123Diazepam (valium)2000Benzodiazepine—0010 [4]
124Certoparin2000Anticoagulant—0000 [4]
125Dalteparin2000Anticoagulant—0000 [4]
126Radix salviae miltiorrhizae2000Antioxidant Partial endothelin-1 inhibitor—0110 [4]
127glyceril trinitrate1999NO donor—-Phase III results published in 2015. ENOS enrolled 4011 participants with acute stroke (within 48 h of onset). Overall, there was no significant shift in functional outcome measured using the modified Rankin Scale at day 90, or of any secondary outcomes. Off patent. $7 per patch.100 [123] [124] [125]
128Candesartan cilexetil (TCV-116, Blopress, CV-11974)1999AT1 receptor antagonist Antihypertensive—-Results published in 2012: no significant difference in neurological recovery; harmful effect suggested--- [126]
129Fludrocortisone1999Mineralocorticoid—0000 [4]
130LDP-01 (Anti–β-2-integrin antibody)1999Leukocyte adhesion and migration inhibitor—0000 [4]
131Nalmefene1998Opioid antagonist—0000 [4]
132NPS 15061998NMDA ion channel blocker—0620 [4]
133RPR 1098911998Antiplatelet glycoprotein inhibitor—0000 [4]
134Tinzaparin1998Anticoagulant—0000 [4]
135Org 10172 (danaparoid, Orgaran)1997Antithrombotic—0000 [4]
136Semax1997Derivative of ACTH-4-10—0000 [4]
137Glycine1996NMDA antagonist—0000 [4]
138Fosphentoyn1995Sodium Channel Blocker, Glutemate Release Inhibitor—0Phase III terminated early due to futility.000 [127]
139Batroxobin (defibrase, DF-521)1995Fibrinogen depleting—0400 [4]
140Nadroparin1995Antithrombotic—0000 [4]
141Defibrotide (polydeoxyribonucleotide)1989Antiplatelet: glycoprotein inhibitor—0000 [4]
142Atenol (Tenormin)1988Beta blocker—0000 [4]
143Corticotrophin1987GABA receptor modulator Pituitary hormone—0000 [4]
144PY 108-0681986Calcium antagonist—0200 [4]
145Trazodone (Desyrel)1986Serotonin reuptake inhibitor—0000 [4]
146Nicergoline1985α2 adrenoceptor agonist—0100 [4]
147Nicergoline1985Alpha2 adrenoceptor agonist—0100 [4]
148Pentoxifylline1981Improve capillary flow—0010 [4]
149Hydergine1978Nootropic, antioxidant.—0000 [4]
150Tinofedrine (D 8955, Novocebrin)1978Blood flow, increased metabolism—0000 [4]
151Xanthinol nicotinate (Sadamin)1977Vitamin B(3): metabolic enhancer—0000 [4]
152Aminophylline1976Phosphodiesterase inhibitor—0000 [4]
153Glycerol1972Hyperosmolar agent—0020 [4]
154Cyclandelate1966Vasodilator (calcium modulator)—0000 [4]

References

  1. 1 2 3 4 Lyden P, Buchan A, Boltze J, Fisher M (August 2021). "Top Priorities for Cerebroprotective Studies-A Paradigm Shift: Report From STAIR XI". Stroke. 52 (9): 3063–3071. doi:10.1161/STROKEAHA.121.034947. PMC   8384700 . PMID   34289707.
  2. ↑ World Health Organization. "The top 10 causes of death" . Retrieved 11 May 2022.
  3. ↑ Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. (American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee) (March 2020). "Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association". Circulation. 141 (9): e139 –e596. doi: 10.1161/CIR.0000000000000757 . PMID   31992061. S2CID   210949245.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW (March 2006). "1,026 experimental treatments in acute stroke". Annals of Neurology. 59 (3): 467–477. doi:10.1002/ana.20741. PMID   16453316. S2CID   42939489.
  5. ↑ Genentech, Inc. "ACTIVASE (alteplase) for injection" (PDF). FDA. Archived from the original (PDF) on June 15, 2016. Retrieved 11 May 2022.
  6. ↑ F. Hoffman-La Roche Ltd. "Finance Report 2021" (PDF). Retrieved 11 May 2022.
  7. ↑ Boehringher Ingelheim. "2019 Annual Report" (PDF). Retrieved 11 May 2022.
  8. ↑ Lapchak PA (1 July 2010). "A critical assessment of edaravone acute ischemic stroke efficacy trials: is edaravone an effective neuroprotective therapy?". Expert Opinion on Pharmacotherapy. 11 (10): 1753–1763. doi:10.1517/14656566.2010.493558. PMC   2891515 . PMID   20491547.
  9. ↑ Biotechnology Industry Association. "Clinical Development Success Rates and Contributing Factors 2011-2020" (PDF). Retrieved 11 May 2022.
  10. ↑ Munich SA, Vakharia K, Levy EI (July 2019). "Overview of Mechanical Thrombectomy Techniques". Neurosurgery. 85 (suppl_1): S60 –S67. doi: 10.1093/neuros/nyz071 . PMID   31197338.
  11. 1 2 Matei N, Camara J, Zhang JH (2021). "The Next Step in the Treatment of Stroke". Frontiers in Neurology. 11 582605. doi: 10.3389/fneur.2020.582605 . PMC   7862333 . PMID   33551950.
  12. ↑ Vagal A, Aviv R, Sucharew H, Reddy M, Hou Q, Michel P, et al. (September 2018). "Collateral Clock Is More Important Than Time Clock for Tissue Fate". Stroke. 49 (9): 2102–2107. doi:10.1161/STROKEAHA.118.021484. PMC   6206882 . PMID   30354992.
  13. ↑ Krnjević K (September 1999). "Early effects of hypoxia on brain cell function". Croatian Medical Journal. 40 (3): 375–380. PMID   10411965.
  14. ↑ Kaur H, Prakash A, Medhi B (2013). "Drug therapy in stroke: from preclinical to clinical studies". Pharmacology. 92 (5–6): 324–334. doi: 10.1159/000356320 . PMID   24356194. S2CID   2317118.
  15. ↑ Kalogeris T, Baines CP, Krenz M, Korthuis RJ (December 2016). "Ischemia/Reperfusion". Comprehensive Physiology. 7 (1): 113–170. doi:10.1002/cphy.c160006. ISBN   978-0-470-65071-4. PMC   5648017 . PMID   28135002.
  16. ↑ "Stroke Preclinical Assessment Network (SPAN) FAQs". NINDS. Retrieved 30 May 2022.[ dead link ]
  17. ↑ Saver JL (January 2006). "Time is brain--quantified". Stroke. 37 (1): 263–266. doi: 10.1161/01.STR.0000196957.55928.ab . PMID   16339467. S2CID   24552241.
  18. 1 2 3 Fisher M, Savitz SI (April 2022). "Pharmacological brain cytoprotection in acute ischaemic stroke - renewed hope in the reperfusion era". Nature Reviews. Neurology. 18 (4): 193–202. doi:10.1038/s41582-021-00605-6. PMC   8788909 . PMID   35079135.
  19. ↑ Albers GW (September 2018). "Use of Imaging to Select Patients for Late Window Endovascular Therapy". Stroke. 49 (9): 2256–2260. doi: 10.1161/STROKEAHA.118.021011 . PMID   30355004. S2CID   53022574.
  20. ↑ Bell RD, Powers BL, Brock D, Provencio JJ, Flanders A, Benetiz R, et al. (2006). "Ventriculo-lumbar perfusion in acute ischemic stroke". Neurocritical Care. 5 (1): 21–29. doi:10.1385/NCC:5:1:21. PMID   16960290. S2CID   12607331.
  21. ↑ D'Arville C (December 2004). "Partnering: key to early-stage biotech survival, but at what cost?". Biotechnology Healthcare. 1 (6): 26–34. PMC   3570991 . PMID   23424295.
  22. ↑ Nader-Kawachi J, Góngora-Rivera F, Santos-Zambrano J, Calzada P, Ríos C (April 2007). "Neuroprotective effect of dapsone in patients with acute ischemic stroke: a pilot study". Neurological Research. 29 (3): 331–334. doi:10.1179/016164107X159234. PMID   17509235. S2CID   23075441.
  23. ↑ Ríos C, Nader-Kawachi J, Rodriguez-Payán AJ, Nava-Ruiz C (March 2004). "Neuroprotective effect of dapsone in an occlusive model of focal ischemia in rats". Brain Research. 999 (2): 212–215. doi:10.1016/j.brainres.2003.11.040. PMID   14759500. S2CID   6110585.
  24. ↑ Wozel G, Blasum C (March 2014). "Dapsone in dermatology and beyond". Archives of Dermatological Research. 306 (2): 103–124. doi:10.1007/s00403-013-1409-7. PMC   3927068 . PMID   24310318.
  25. ↑ Diaz-Ruiz A, Roldan-Valadez E, Ortiz-Plata A, Mondragón-Lozano R, Heras-Romero Y, Mendez-Armenta M, et al. (September 2016). "Dapsone improves functional deficit and diminishes brain damage evaluated by 3-Tesla magnetic resonance image after transient cerebral ischemia and reperfusion in rats". Brain Research. 1646: 384–392. doi:10.1016/j.brainres.2016.06.023. PMID   27321157. S2CID   25685864.
  26. ↑ Culp WC, Woods SD, Skinner RD, Brown AT, Lowery JD, Johnson JL, et al. (January 2012). "Dodecafluoropentane emulsion decreases infarct volume in a rabbit ischemic stroke model". Journal of Vascular and Interventional Radiology. 23 (1): 116–121. doi:10.1016/j.jvir.2011.10.001. PMC   3253225 . PMID   22079515.
  27. ↑ Woods SD, Skinner RD, Ricca AM, Brown AT, Lowery JD, Borrelli MJ, et al. (October 2013). "Progress in dodecafluoropentane emulsion as a neuroprotective agent in a rabbit stroke model". Molecular Neurobiology. 48 (2): 363–367. doi:10.1007/s12035-013-8495-6. PMC   3787698 . PMID   23813100.
  28. ↑ Brown AT, Arthur MC, Nix JS, Montgomery JA, Skinner RD, Roberson PK, et al. (2014-12-30). "Dodecafluoropentane Emulsion (DDFPe) Decreases Stroke Size and Improves Neurological Scores in a Permanent Occlusion Rat Stroke Model". The Open Neurology Journal. 8: 27–33. doi: 10.2174/1874205X01408010027 . PMC   4321204 . PMID   25674164.
  29. ↑ Culp WC, Brown AT, Lowery JD, Arthur MC, Roberson PK, Skinner RD (October 2015). "Dodecafluoropentane Emulsion Extends Window for tPA Therapy in a Rabbit Stroke Model". Molecular Neurobiology. 52 (2): 979–984. doi:10.1007/s12035-015-9243-x. PMC   4998836 . PMID   26055229.
  30. ↑ Arthur MC, Brown A, Carlson K, Lowery J, Skinner RD, Culp WC (August 2017). "Dodecafluoropentane Improves Neurological Function Following Anterior Ischemic Stroke". Molecular Neurobiology. 54 (6): 4764–4770. doi:10.1007/s12035-016-0019-8. PMC   5299093 . PMID   27501802.
  31. ↑ Culp WC, Onteddu SS, Brown A, Nalleballe K, Sharma R, Skinner RD, et al. (August 2019). "Dodecafluoropentane Emulsion in Acute Ischemic Stroke: A Phase Ib/II Randomized and Controlled Dose-Escalation Trial". Journal of Vascular and Interventional Radiology. 30 (8): 1244–1250.e1. doi:10.1016/j.jvir.2019.04.020. PMID   31349978. S2CID   198933339.
  32. ↑ Belayev L, Zhao W, Pattany PM, Weaver RG, Huh PW, Lin B, et al. (December 1998). "Diffusion-weighted magnetic resonance imaging confirms marked neuroprotective efficacy of albumin therapy in focal cerebral ischemia". Stroke. 29 (12): 2587–2599. doi: 10.1161/01.str.29.12.2587 . PMID   9836772. S2CID   10997469.
  33. ↑ Hosaka T, Yamamoto YL, Diksic M (December 1991). "Efficacy of retrograde perfusion of the cerebral vein with verapamil after focal ischemia in rat brain". Stroke. 22 (12): 1562–1566. doi: 10.1161/01.STR.22.12.1562 . PMID   1962332. S2CID   8924213.
  34. ↑ Roy MW, Dempsey RJ, Meyer KL, Donaldson DL, Tibbs PA, Young AB (December 1985). "Effects of verapamil and diltiazem on acute stroke in cats". Journal of Neurosurgery. 63 (6): 929–936. doi: 10.3171/jns.1985.63.6.0929 . PMID   4056906.
  35. ↑ Maniskas ME, Roberts JM, Aron I, Fraser JF, Bix GJ (April 2016). "Stroke neuroprotection revisited: Intra-arterial verapamil is profoundly neuroprotective in experimental acute ischemic stroke". Journal of Cerebral Blood Flow and Metabolism. 36 (4): 721–730. doi:10.1177/0271678X15608395. PMC   4821022 . PMID   26661189.
  36. ↑ Clinical trial number NCT02235558 for "Super-Selective Intra-Arterial Administration of Verapamil for Neuroprotection After Intra-Arterial Thrombolysis for Acute Ischemic Stroke Phase I Study" at ClinicalTrials.gov
  37. ↑ Britton P, Lu XC, Laskosky MS, Tortella FC (1997). "Dextromethorphan protects against cerebral injury following transient, but not permanent, focal ischemia in rats". Life Sciences. 60 (20): 1729–1740. doi:10.1016/s0024-3205(97)00132-x. PMID   9150412.
  38. ↑ Mousavi SA, Saadatnia M, Khorvash F, Hoseini T, Sariaslani P (June 2011). "Evaluation of the neuroprotective effect of dextromethorphan in the acute phase of ischaemic stroke". Archives of Medical Science. 7 (3): 465–469. doi:10.5114/aoms.2011.23413. PMC   3258743 . PMID   22295030.
  39. ↑ Clinical trial number Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy and Safety of a 72-Hour Infusion of CP-101,606 in Subjects With Acute Ischemic Stroke. NCT00073476A Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy and Safety of a 72-Hour Infusion of CP-101,606 in Subjects With Acute Ischemic Stroke. at ClinicalTrials.gov
  40. ↑ Sacco RL, DeRosa JT, Haley EC, Levin B, Ordronneau P, Phillips SJ, et al. (April 2001). "Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial". JAMA. 285 (13): 1719–1728. doi: 10.1001/jama.285.13.1719 . PMID   11277826.
  41. ↑ Labiche LA, Grotta JC (January 2004). "Clinical trials for cytoprotection in stroke". NeuroRx. 1 (1): 46–70. doi:10.1602/neurorx.1.1.46. PMC   534912 . PMID   15717007.
  42. ↑ Noh SJ, Lee SH, Shin KY, Lee CK, Cho IH, Kim HS, et al. (March 2011). "SP-8203 reduces oxidative stress via SOD activity and behavioral deficit in cerebral ischemia". Pharmacology, Biochemistry, and Behavior. 98 (1): 150–154. doi:10.1016/j.pbb.2010.12.014. PMID   21172384. S2CID   37640897.
  43. ↑ Clinical trial number NCT02787278 for "A Prospective, Randomized, Double-blinded Phase IIa Clinical Trial to Investigate the Safety and Efficacy of Two Doses of SP-8203 in Patients With Ischemic Stroke Requiring rtPA Standard of Care" at ClinicalTrials.gov
  44. ↑ Gakuba C, Gauberti M, Mazighi M, Defer G, Hanouz JL, Vivien D (October 2011). "Preclinical evidence toward the use of ketamine for recombinant tissue-type plasminogen activator-mediated thrombolysis under anesthesia or sedation". Stroke. 42 (10): 2947–2949. doi: 10.1161/STROKEAHA.111.620468 . PMID   21817137. S2CID   2847553.
  45. ↑ Clinical trial number NCT02258204 for "Effets de la kétamine en Association Avec le Rt-PA au Cours de l'Infarctus cérébral Aigu: étude Pilote contrôlée randomisée en Double Aveugle Avec critère de Jugement Radiologique" at ClinicalTrials.gov
  46. ↑ Fujiki M, Kobayashi H, Uchida S, Inoue R, Ishii K (May 2005). "Neuroprotective effect of donepezil, a nicotinic acetylcholine-receptor activator, on cerebral infarction in rats". Brain Research. 1043 (1–2): 236–241. doi:10.1016/j.brainres.2005.02.063. PMID   15862539. S2CID   27373206.
  47. ↑ Wang Y, Zhao Z, Chow N, Rajput PS, Griffin JH, Lyden PD, et al. (December 2013). "Activated protein C analog protects from ischemic stroke and extends the therapeutic window of tissue-type plasminogen activator in aged female mice and hypertensive rats". Stroke. 44 (12): 3529–3536. doi:10.1161/STROKEAHA.113.003350. PMC   3912991 . PMID   24159062.
  48. ↑ Shibata M, Kumar SR, Amar A, Fernandez JA, Hofman F, Griffin JH, et al. (April 2001). "Anti-inflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke". Circulation. 103 (13): 1799–1805. doi: 10.1161/01.CIR.103.13.1799 . PMID   11282913. S2CID   15027502.
  49. ↑ Cheng T, Liu D, Griffin JH, Fernández JA, Castellino F, Rosen ED, et al. (March 2003). "Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective". Nature Medicine. 9 (3): 338–342. doi:10.1038/nm826. PMID   12563316. S2CID   306232.
  50. ↑ Wang Y, Sinha RK, Mosnier LO, Griffin JH, Zlokovic BV (August 2013). "Neurotoxicity of the anticoagulant-selective E149A-activated protein C variant after focal ischemic stroke in mice". Blood Cells, Molecules & Diseases. 51 (2): 104–108. doi:10.1016/j.bcmd.2013.02.009. PMC   3812054 . PMID   23541526.
  51. ↑ Wang Y, Zhao Z, Chow N, Ali T, Griffin JH, Zlokovic BV (April 2013). "Activated protein C analog promotes neurogenesis and improves neurological outcome after focal ischemic stroke in mice via protease activated receptor 1". Brain Research. 1507: 97–104. doi:10.1016/j.brainres.2013.02.023. PMC   3739836 . PMID   23438513.
  52. ↑ Wang Y, Zhang Z, Chow N, Davis TP, Griffin JH, Chopp M, et al. (September 2012). "An activated protein C analog with reduced anticoagulant activity extends the therapeutic window of tissue plasminogen activator for ischemic stroke in rodents". Stroke. 43 (9): 2444–2449. doi:10.1161/STROKEAHA.112.658997. PMC   3429704 . PMID   22811462.
  53. ↑ Wang Y, Thiyagarajan M, Chow N, Singh I, Guo H, Davis TP, et al. (May 2009). "Differential neuroprotection and risk for bleeding from activated protein C with varying degrees of anticoagulant activity". Stroke. 40 (5): 1864–1869. doi:10.1161/STROKEAHA.108.536680. PMC   2691176 . PMID   19057019.
  54. ↑ Schäbitz WR, Kollmar R, Schwaninger M, Juettler E, Bardutzky J, Schölzke MN, et al. (March 2003). "Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia". Stroke. 34 (3): 745–751. doi: 10.1161/01.STR.0000057814.70180.17 . PMID   12624302. S2CID   9993275.
  55. ↑ Minnerup J, Sevimli S, Schäbitz WR (October 2009). "Granulocyte-colony stimulating factor for stroke treatment: mechanisms of action and efficacy in preclinical studies". Experimental & Translational Stroke Medicine. 1 (1) 2. doi: 10.1186/2040-7378-1-2 . PMC   2816868 . PMID   20142989.
  56. ↑ England TJ, Sprigg N, Alasheev AM, Belkin AA, Kumar A, Prasad K, et al. (November 2016). "Granulocyte-Colony Stimulating Factor (G-CSF) for stroke: an individual patient data meta-analysis". Scientific Reports. 6 36567. Bibcode:2016NatSR...636567E. doi:10.1038/srep36567. PMC   5109224 . PMID   27845349.
  57. ↑ Hong H, Zeng JS, Kreulen DL, Kaufman DI, Chen AF (November 2006). "Atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in ischemic stroke". American Journal of Physiology. Heart and Circulatory Physiology. 291 (5): H2210 –H2215. doi:10.1152/ajpheart.01270.2005. PMID   16766636. S2CID   11908429.
  58. ↑ Clinical trial number NCT02452502 for "The Safety and Efficacy Study of High Dose Atorvastatin After Thrombolytic Treatment in Acute Ischemic Stroke" at ClinicalTrials.gov
  59. ↑ Xing Y, Hua Y, Keep RF, Xi G (September 2009). "Effects of deferoxamine on brain injury after transient focal cerebral ischemia in rats with hyperglycemia". Brain Research. 1291: 113–121. doi:10.1016/j.brainres.2009.07.032. PMC   2737516 . PMID   19631616.
  60. ↑ Hanson LR, Roeytenberg A, Martinez PM, Coppes VG, Sweet DC, Rao RJ, et al. (September 2009). "Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke". The Journal of Pharmacology and Experimental Therapeutics. 330 (3): 679–686. doi:10.1124/jpet.108.149807. PMC   2729791 . PMID   19509317.
  61. ↑ Clinical trial number NCT00777140 for "Double-blind, Randomized, Placebo Controlled, Dose-finding Phase 2 Clinical Trial of Intravenous Deferoxamine in Patients With Acute Ischemic Stroke Treated With Tissue Plasminogen Activator" at ClinicalTrials.gov
  62. ↑ Kim Y, Kim YS, Noh MY, Lee H, Joe B, Kim HY, et al. (June 2017). "Neuroprotective effects of a novel poly (ADP-ribose) polymerase-1 inhibitor, JPI-289, in hypoxic rat cortical neurons". Clinical and Experimental Pharmacology & Physiology. 44 (6): 671–679. doi:10.1111/1440-1681.12757. PMID   28370165. S2CID   32162935.
  63. ↑ Clinical trial number NCT03062397 for "A Multi-center, Randomized, Double-blind, Placebo-controlled, Phase IIa Clinical Trial to Evaluate the Efficacy and Safety of JPI-289 in Patients With Acute Ischemic Stroke" at ClinicalTrials.gov
  64. ↑ Xu L, Fagan SC, Waller JL, Edwards D, Borlongan CV, Zheng J, et al. (April 2004). "Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats". BMC Neurology. 4 7. doi: 10.1186/1471-2377-4-7 . PMC   415551 . PMID   15109399.
  65. 1 2 Orset C, Haelewyn B, Allan SM, Ansar S, Campos F, Cho TH, et al. (May 2016). "Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke: A Retrospective Pooled Analysis". Stroke. 47 (5): 1312–1318. doi:10.1161/STROKEAHA.116.012238. PMC   4846545 . PMID   27032444.
  66. ↑ Simard JM, Chen M, Tarasov KV, Bhatta S, Ivanova S, Melnitchenko L, et al. (April 2006). "Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke". Nature Medicine. 12 (4): 433–440. doi:10.1038/nm1390. PMC   2740734 . PMID   16550187.
  67. ↑ Simard JM, Sheth KN, Kimberly WT, Stern BJ, del Zoppo GJ, Jacobson S, et al. (April 2014). "Glibenclamide in cerebral ischemia and stroke". Neurocritical Care. 20 (2): 319–333. doi:10.1007/s12028-013-9923-1. PMC   3954940 . PMID   24132564.
  68. ↑ Wali B, Ishrat T, Atif F, Hua F, Stein DG, Sayeed I (2012). "Glibenclamide Administration Attenuates Infarct Volume, Hemispheric Swelling, and Functional Impairments following Permanent Focal Cerebral Ischemia in Rats". Stroke Research and Treatment. 2012 460909. doi: 10.1155/2012/460909 . PMC   3440943 . PMID   22988544.
  69. ↑ Ortega FJ, Gimeno-Bayon J, Espinosa-Parrilla JF, Carrasco JL, Batlle M, Pugliese M, et al. (May 2012). "ATP-dependent potassium channel blockade strengthens microglial neuroprotection after hypoxia-ischemia in rats". Experimental Neurology. 235 (1): 282–296. doi:10.1016/j.expneurol.2012.02.010. hdl: 2445/34278 . PMID   22387180. S2CID   4828181.
  70. ↑ Clinical trial number NCT02864953 for "Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Phase 3 Study to Evaluate the Efficacy and Safety of Intravenous BIIB093 (Glibenclamide) for Severe Cerebral Edema Following Large Hemispheric Infarction" at ClinicalTrials.gov
  71. ↑ Matsuura S, Egi Y, Yuki S, Horikawa T, Satoh H, Akira T (September 2011). "MP-124, a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor, ameliorates ischemic brain damage in a non-human primate model". Brain Research. 1410: 122–131. doi:10.1016/j.brainres.2011.05.069. PMID   21741620. S2CID   22390945.
  72. ↑ Egi Y, Matsuura S, Maruyama T, Fujio M, Yuki S, Akira T (May 2011). "Neuroprotective effects of a novel water-soluble poly(ADP-ribose) polymerase-1 inhibitor, MP-124, in in vitro and in vivo models of cerebral ischemia". Brain Research. 1389: 169–176. doi:10.1016/j.brainres.2011.03.031. PMID   21420942. S2CID   20524045.
  73. ↑ Dirnagl U, Macleod MR (August 2009). "Stroke research at a road block: the streets from adversity should be paved with meta-analysis and good laboratory practice". British Journal of Pharmacology. 157 (7): 1154–1156. doi:10.1111/j.1476-5381.2009.00211.x. PMC   2743833 . PMID   19664136.
  74. ↑ Clinical trial number NCT01400035 for "The Investigation of Vinpocetine (Cavinton) for Treatment of Acute Cerebral Infarction, an Open, Multicenter, Randomized, Control Study" at ClinicalTrials.gov
  75. ↑ Zhang W, Huang Y, Li Y, Tan L, Nao J, Hu H, et al. (September 2016). "Efficacy and Safety of Vinpocetine as Part of Treatment for Acute Cerebral Infarction: A Randomized, Open-Label, Controlled, Multicenter CAVIN (Chinese Assessment for Vinpocetine in Neurology) Trial". Clinical Drug Investigation. 36 (9): 697–704. doi:10.1007/s40261-016-0415-x. PMID   27283947. S2CID   207484127.
  76. ↑ Clinical trial number NCT02831088 for "A Phase II, Double-blind, Randomized, Placebo-controlled, Multi-center Study to Assess Efficacy and Safety of Neu2000KWL in Patients With Acute Ischemic Stroke Receiving Endovascular Therapy" at ClinicalTrials.gov
  77. ↑ Springer JE, Rao RR, Lim HR, Cho SI, Moon GJ, Lee HY, et al. (January 2010). "The functional and neuroprotective actions of Neu2000, a dual-acting pharmacological agent, in the treatment of acute spinal cord injury". Journal of Neurotrauma. 27 (1): 139–149. doi:10.1089/neu.2009.0952. PMC   3525902 . PMID   19772458.
  78. ↑ Milani D, Cross JL, Anderton RS, Blacker DJ, Knuckey NW, Meloni BP (January 2017). "Neuroprotective efficacy of poly-arginine R18 and NA-1 (TAT-NR2B9c) peptides following transient middle cerebral artery occlusion in the rat". Neuroscience Research. 114: 9–15. doi: 10.1016/j.neures.2016.09.002 . PMID   27639457. S2CID   23400287.
  79. ↑ Sun HS, Doucette TA, Liu Y, Fang Y, Teves L, Aarts M, et al. (September 2008). "Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat". Stroke. 39 (9): 2544–2553. doi: 10.1161/STROKEAHA.107.506048 . PMID   18617669. S2CID   6500196.
  80. ↑ Soriano FX, Martel MA, Papadia S, Vaslin A, Baxter P, Rickman C, et al. (October 2008). "Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand". The Journal of Neuroscience. 28 (42): 10696–10710. doi:10.1523/JNEUROSCI.1207-08.2008. PMC   2602846 . PMID   18923045.
  81. ↑ Teves LM, Cui H, Tymianski M (March 2016). "Efficacy of the PSD95 inhibitor Tat-NR2B9c in mice requires dose translation between species". Journal of Cerebral Blood Flow and Metabolism. 36 (3): 555–561. doi:10.1177/0271678X15612099. PMC   4794097 . PMID   26661213.
  82. ↑ Hill MD, Martin RH, Mikulis D, Wong JH, Silver FL, terBrugge KG, et al. (2012-11-01). "Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial" . The Lancet Neurology. 11 (11): 942–950. doi:10.1016/S1474-4422(12)70225-9. ISSN   1474-4422. PMID   23051991. S2CID   19169136.
  83. ↑ Cook DJ, Teves L, Tymianski M (February 2012). "Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain". Nature. 483 (7388): 213–217. Bibcode:2012Natur.483..213C. doi:10.1038/nature10841. PMID   22388811. S2CID   4334868.
  84. ↑ Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, et al. (October 2002). "Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions". Science. 298 (5594): 846–850. Bibcode:2002Sci...298..846A. doi:10.1126/science.1072873. PMID   12399596. S2CID   35409678.
  85. ↑ Bråtane BT, Cui H, Cook DJ, Bouley J, Tymianski M, Fisher M (November 2011). "Neuroprotection by freezing ischemic penumbra evolution without cerebral blood flow augmentation with a postsynaptic density-95 protein inhibitor". Stroke. 42 (11): 3265–3270. doi: 10.1161/STROKEAHA.111.618801 . PMID   21903963. S2CID   1799582.
  86. ↑ Yao X, Derugin N, Manley GT, Verkman AS (January 2015). "Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia". Neuroscience Letters. 584: 368–372. doi:10.1016/j.neulet.2014.10.040. PMC   4737527 . PMID   25449874.
  87. ↑ Liu G, Song J, Guo Y, Wang T, Zhou Z (October 2013). "Astragalus injection protects cerebral ischemic injury by inhibiting neuronal apoptosis and the expression of JNK3 after cerebral ischemia reperfusion in rats". Behavioral and Brain Functions. 9 36. doi: 10.1186/1744-9081-9-36 . PMC   3850702 . PMID   24083559.
  88. ↑ Clinical trial number NCT01554787 for "Randomized, Double Blind, Placebo Control Trial to Evaluate the Efficacy of Astragalus Membranaceus in the Patients After Stroke With Fatigue" at ClinicalTrials.gov
  89. ↑ Wang Y, Yoshimura R, Manabe H, Schretter C, Clarke R, Cai Y, et al. (October 2014). "Trans-sodium crocetinate improves outcomes in rodent models of occlusive and hemorrhagic stroke". Brain Research. 1583: 245–254. doi:10.1016/j.brainres.2014.08.013. PMC   4170841 . PMID   25128603.
  90. ↑ Manabe H, Okonkwo DO, Gainer JL, Clarke RH, Lee KS (October 2010). "Protection against focal ischemic injury to the brain by trans-sodium crocetinate. Laboratory investigation". Journal of Neurosurgery. 113 (4): 802–809. doi:10.3171/2009.10.JNS09562. PMC   3380430 . PMID   19961314.
  91. ↑ Deng J, Xiong L, Zuo Z (April 2015). "Trans-sodium crocetinate provides neuroprotection against cerebral ischemia and reperfusion in obese mice". Journal of Neuroscience Research. 93 (4): 615–622. doi:10.1002/jnr.23522. PMC   4329099 . PMID   25491171.
  92. ↑ Saver JL, Starkman S, Eckstein M, Stratton SJ, Pratt FD, Hamilton S, et al. (February 2015). "Prehospital use of magnesium sulfate as neuroprotection in acute stroke". The New England Journal of Medicine. 372 (6): 528–536. doi:10.1056/NEJMoa1408827. PMC   4920545 . PMID   25651247.
  93. ↑ Khan M, Sekhon B, Jatana M, Giri S, Gilg AG, Sekhon C, et al. (May 2004). "Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke". Journal of Neuroscience Research. 76 (4): 519–527. doi:10.1002/jnr.20087. PMID   15114624. S2CID   38505912.
  94. 1 2 Shehadah A, Chen J, Cui X, Roberts C, Lu M, Chopp M (July 2010). "Combination treatment of experimental stroke with Niaspan and Simvastatin, reduces axonal damage and improves functional outcome". Journal of the Neurological Sciences. 294 (1–2): 107–111. doi:10.1016/j.jns.2010.03.020. PMC   2885546 . PMID   20451219.
  95. ↑ Clinical trial number NCT01976936 for "A Phase 2 Safety Study in Which Ischemic Stroke Patients Will be Randomized Within 24 Hours of Symptom Onset to Placebo or Oral Lovastatin 640 mg Per Day for 3 Days. " at ClinicalTrials.gov
  96. ↑ Henninger N, Bouley J, Nelligan JM, Sicard KM, Fisher M (September 2007). "Normobaric hyperoxia delays perfusion/diffusion mismatch evolution, reduces infarct volume, and differentially affects neuronal cell death pathways after suture middle cerebral artery occlusion in rats". Journal of Cerebral Blood Flow and Metabolism. 27 (9): 1632–1642. doi:10.1038/sj.jcbfm.9600463. PMID   17311078. S2CID   34948648.
  97. ↑ Chen C, Cui H, Li Z, Wang R, Zhou C (November 2013). "Normobaric oxygen for cerebral ischemic injury". Neural Regeneration Research. 8 (31): 2885–2894. doi:10.3969/j.issn.1673-5374.2013.31.001. PMC   4146175 . PMID   25206609.
  98. ↑ Singhal AB, Wang X, Sumii T, Mori T, Lo EH (July 2002). "Effects of normobaric hyperoxia in a rat model of focal cerebral ischemia-reperfusion". Journal of Cerebral Blood Flow and Metabolism. 22 (7): 861–868. doi: 10.1097/00004647-200207000-00011 . PMID   12142571. S2CID   43081106.
  99. ↑ Pasban E, Panahpour H, Vahdati A (June 2017). "Early oxygen therapy does not protect the brain from vasogenic edema following acute ischemic stroke in adult male rats". Scientific Reports. 7 (1) 3221. Bibcode:2017NatSR...7.3221P. doi:10.1038/s41598-017-02748-3. PMC   5468255 . PMID   28607351.
  100. ↑ Shin HK, Dunn AK, Jones PB, Boas DA, Lo EH, Moskowitz MA, et al. (June 2007). "Normobaric hyperoxia improves cerebral blood flow and oxygenation, and inhibits peri-infarct depolarizations in experimental focal ischaemia". Brain. 130 (Pt 6): 1631–1642. doi:10.1093/brain/awm071. PMC   3023418 . PMID   17468117.
  101. ↑ Roffe C, Nevatte T, Sim J, Bishop J, Ives N, Ferdinand P, et al. (September 2017). "Effect of Routine Low-Dose Oxygen Supplementation on Death and Disability in Adults With Acute Stroke: The Stroke Oxygen Study Randomized Clinical Trial". JAMA. 318 (12): 1125–1135. doi:10.1001/jama.2017.11463. PMC   5818819 . PMID   28973619.
  102. ↑ Clinical trial number NCT02248233 for "Nimodipine for Treating Acute Massive Cerebral Infarction: a Randomized, Double-blind, Controlled Clinical Study" at ClinicalTrials.gov
  103. ↑ Clinical trial number NCT01220622 for "Nimodipine Preventing Cognitive Impairment in Ischemic Cerebrovascular Events: A Randomized, Placebo-Controlled, Double-Blind Trial (NICE)" at ClinicalTrials.gov
  104. ↑ Clinical trial number NCT02430350 for "Compound Edaravone Injection for Acute Ischemic Stroke, a Multi-center, Randomized, Double-blind, Parallel, and Active-controlled Phase III Trial" at ClinicalTrials.gov
  105. ↑ Xu J, Wang A, Meng X, Yalkun G, Xu A, Gao Z, et al. (March 2021). "Edaravone Dexborneol Versus Edaravone Alone for the Treatment of Acute Ischemic Stroke: A Phase III, Randomized, Double-Blind, Comparative Trial". Stroke. 52 (3): 772–780. doi: 10.1161/STROKEAHA.120.031197 . PMID   33588596. S2CID   231937405.
  106. ↑ Nighoghossian N, Ovize M, Mewton N, Ong E, Cho TH (2016). "Cyclosporine A, a Potential Therapy of Ischemic Reperfusion Injury. A Common History for Heart and Brain". Cerebrovascular Diseases. 42 (5–6): 309–318. doi: 10.1159/000446850 . PMID   27245840. S2CID   25272164.
  107. ↑ "Biogen Reports Top-Line Results from Phase 2b Study of Natalizumab in Acute Ischemic Stroke | Biogen". media.biogen.com. Retrieved 2022-06-02.
  108. ↑ Woitzik J, Weinzierl N, Schilling L (July 2005). "Early administration of a second-generation perfluorochemical decreases ischemic brain damage in a model of permanent middle cerebral artery occlusion in the rat". Neurological Research. 27 (5): 509–515. doi:10.1179/016164105X15677. PMID   15978177. S2CID   21813111.
  109. ↑ Barbay S, Plautz EJ, Zoubina E, Frost SB, Cramer SC, Nudo RJ (June 2015). "Effects of postinfarct myelin-associated glycoprotein antibody treatment on motor recovery and motor map plasticity in squirrel monkeys". Stroke. 46 (6): 1620–1625. doi:10.1161/STROKEAHA.114.008088. PMID   25931462. S2CID   9317407.
  110. ↑ Montaner J, Bustamante A, García-Matas S, Martínez-Zabaleta M, Jiménez C, de la Torre J, et al. (November 2016). "Combination of Thrombolysis and Statins in Acute Stroke Is Safe: Results of the STARS Randomized Trial (Stroke Treatment With Acute Reperfusion and Simvastatin)". Stroke. 47 (11): 2870–2873. doi: 10.1161/STROKEAHA.116.014600 . hdl: 10668/10546 . PMID   27758944. S2CID   3704362.
  111. ↑ Clinical trial number NCT04091945 for "A Phase IIa, Double-Blind, Single Dose, Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Potential Efficacy of LT3001 Drug Product in Subjects With Acute Ischemic Stroke (AIS) " at ClinicalTrials.gov
  112. ↑ "臨床試験情報詳細画面 | 一般財団法人日本医薬情報センター 臨床試験情報". www.clinicaltrials.jp. Retrieved 2022-06-02.
  113. ↑ Fierce Biotech (12 May 2021). "Biogen buys midphase drug to challenge Roche for stroke market".
  114. ↑ "Genervon Pipeline".
  115. ↑ Clinical trial number NCT01221246 for "A Phase 2 Double Blinded, Randomized, Placebo Controlled Dose Escalation Study to Evaluate the Efficacy and the Safety of GM602 in Patients With Acute Middle Cerebral Artery Ischemic Stroke Within an 18-hour Treatment Window" at ClinicalTrials.gov
  116. ↑ Clinical trial number NCT02446977 for "Randomized Clinical Trial to Investigate Whether Administration of CBG000592 (Riboflavin/Vitamin B2) in Patients With Acute Ischemic Stroke Causes a Reduction of Glutamate-mediated Excitotoxicity " at ClinicalTrials.gov
  117. ↑ Beer C, Blacker D, Bynevelt M, Hankey GJ, Puddey IB (February 2012). "A randomized placebo controlled trial of early treatment of acute ischemic stroke with atorvastatin and irbesartan". International Journal of Stroke. 7 (2): 104–111. doi:10.1111/j.1747-4949.2011.00653.x. PMID   22044557. S2CID   21245997.
  118. ↑ Pratap R, Pillai KK, Khanam R, Islam F, Ahmad SJ, Akhtar M (May 2011). "Protective effect of irbesartan, an angiotensin II receptor antagonist, alone and in combination with aspirin on middle cerebral artery occlusion model of focal cerebral ischemia in rats". Human & Experimental Toxicology. 30 (5): 354–362. Bibcode:2011HETox..30..354P. doi: 10.1177/0960327110371257 . PMID   20488839. S2CID   1651465.
  119. ↑ "Stem Cell Therapeutics Stroke Drug, NTx-265 Fails Phase 2 Trial". BioSpace. Retrieved 2022-06-03.
  120. ↑ Clinical trial number NCT00827190 for "Ascending Single Dose Study Of The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of ILS-920 Administered Intravenously To Healthy Adult Subjects" at ClinicalTrials.gov
  121. ↑ "Clinical efficacy in stroke". www.cerebrolysin.com. Retrieved 2022-06-03.
  122. ↑ Diener HC, Schneider D, Lampl Y, Bornstein NM, Kozak A, Rosenberg G (June 2008). "DP-b99, a membrane-activated metal ion chelator, as neuroprotective therapy in ischemic stroke". Stroke. 39 (6): 1774–1778. doi: 10.1161/STROKEAHA.107.506378 . PMID   18403736. S2CID   19228032.
  123. ↑ Clinical trial number NCT01811693 for "The Field Administration of Stroke Therapy-Blood Pressure Lowering Pilot Trial" at ClinicalTrials.gov
  124. ↑ Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA (September 1994). "Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase". Science. 265 (5180): 1883–1885. Bibcode:1994Sci...265.1883H. doi:10.1126/science.7522345. PMID   7522345.
  125. ↑ Bath P, Woodhouse L, Scutt P, Krishnan K, Wardlaw J, Bereczki D, et al. (ENOS Trial Investigators) (February 2015). "Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial". Lancet. 385 (9968): 617–628. doi:10.1016/S0140-6736(14)61121-1. PMC   4343308 . PMID   25465108.
  126. ↑ Lapchak PA, Zhang JH (2017-01-12). Neuroprotective Therapy for Stroke and Ischemic Disease. Springer. ISBN   978-3-319-45345-3.
  127. ↑ Cheng YD, Al-Khoury L, Zivin JA (January 2004). "Neuroprotection for ischemic stroke: two decades of success and failure". NeuroRx. 1 (1): 36–45. doi:10.1602/neurorx.1.1.36. PMC   534911 . PMID   15717006.
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