Medicine: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 tested in clinical trials to provide cerebroprotection.[2][3][4]

Approved drugs

  • Tissue plasminogen activator (also known as tPA, t-PA, rtPA, Activase, or Alteplase or Actilyse)[5] is a drug that breaks down blood clots. It was first approved in 1996, yet this drug has no generic competition. US sales of the drug under the brand name Activase and a similar drug were approximately US$1.3 billion in 2021, while European sales under the brand name Actilyse were an additional 448 million Euro in 2019.[6][7]
  • Edaravone (radicut) was approved in Japan in 2001.[8] It has an unknown mechanism of action, but is hypothesized to act through its antioxidant properties.

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

Rank Name First Trial Mechanism % Protection in Animal Studies (% Reduction in Infarct Volume) Number of Animal Studies from Which % Protection has been Calculated Comments Focal ischemic stroke studies with positive results Focal ischemic stroke studies showing no change Focal ischemic stroke studies with negative results Sources
1 Oxygenated fluorocarbon nutrient emulsion (OFNE) or Revoxyn 2001 Oxygen delivery 94 1 A perfluorocarbon emulsion that was equired drilling hole in skull (called a ventricular catheter), inserting a lumbar catheter, mixing with artificial CSF and oxygen, and using special machine to administer drug through skull while draining CSF. A clinical trial in 4 patients demonstrated safety, but enrollment was slow and company folded. 2 0 0 [4][20][21]
2 Dapsone 2007 Antibacterial 93 1 Two studies in rats measured infarct volume. A study done in 2003 showed dramatic effect, and a study done in 2016 showed no change, raising questions about repeatability. A randomized Phase II clinical trial in 30 patients showed statistically significant improvements in NIHSS and Barthel index. A Phase II/III clinical trial was allowed to start in Mexico in 2010, but appears to never have started for an unknown reasons. A 2014 paper on potential uses of Dapsone mentions no development plans for it. 1 1 0 [22][23][24][25]
3 DDFPe, NanO2 or NVX-208 2017 Oxygen Delivery 85 5 Another perfluorocarbon emulsion injected intravenously thought to improve oxygen flrow 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) 9 0 0 [26][27][28][29][30][31]
4 Albumin 2011 Antioxidant Improvement of microcirculation 66 1 Albumin therapy was associated with an increase in symptomatic intercranial hemorrhage and pulmonary edema/congestive heart failure. 1 0 0 [32]
5 Veripamil 2016 Calcium channel blocker (Phenylalkylamine calcium channel) 66 2 Veripamil was administered immediately after restoration of blood flow. 2 0 1 [33][34][35][36]
6 Dextromethorphan 2011 NMDA ion channel blocker 61 1 Trial 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. 1 0 0 [37][38]
7 CP101.606-27 1999 NMDA ion channel blocker 61 3 Enrolled patients within 6 hours after stroke, but did not include patients who received tPA. The study was terminated, and the results were not reported. 3 0 0 [39]
8 Gavestinel (GV150526A) 1999 NMDA glycine antagonist 60 18 "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." NuvOx's hypothesis is that this trial took all comers, did not use imaging to sratify, tPA is not used in most patients and mechanical thrombectomy was not available so most patients did not reperfuse and therefore did not have a strong response at 90 days. 8 6 0 [40][41]
9 SP-8203 2016 antioxidant and NMDA receptor antagonist 59 1 Phase II in progress in 2018 in patients with product dosed after tPA. Pre-clinical studies showed high level of dose dependency. 1 0 0 [42][43]
10 ketamine 2014 NMDA receptor antagonist 57 1 Phase I/II in progress as of 2018 1 0 0 [44][45]
11 Hu23F2G (LeukArrest) 1999 Leukocyte adhesion inhibitor 57 1 1 0 0
12 Donepezil 2008 selective acetylcholinesterase inhibitor 56 1 1 0 0 [46]
13 Repinotan (BAY × 3072) 2000 Serotonin agonist 56 2 2 0 0 [4]
14 Prourokinase 1998 Antithrombotic 55 12 12 0 0 [4]
15 3K3A-APC 2014 anti-inflammatory 54 8 ZZ Biotech published a Phase II clinical trial in 110 patients given standard of care in 2019. The drug was given intravenously as a 15-minute infusion every 12 hours for up to five treatments, and four dose levels were evaluated. Functional outcomes were measured up to 90 days. The drug was safe, and there was a trend towards less hemorrhage, but there was also a trend towards worse functional independence. 3K3A-APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p = 0.046) and total hemorrhage volume from an average of 2.1 ± 5.8 ml in placebo to 0.8 ± 2.1 ml in the combined treatment arms (p = 0.066). 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). 8 0 0 [47][48][49][50][51][52][53]
16 Granulocytecolony stimulating factor (G-CSF) 2003 activator of transcription-3 (STAT3) in the periphery of the infarction 53 1 No effect - G-CSF did not improve stroke outcome in this individual patient data meta-analysis. 9 0 0 [54][55][56]
17 Urokinase 1976 Thrombolytic 53 12 13 1 0 [4]
18 Atorvastatin 2015 Statin considered to have favorable impact on blood brain barrier, oxidative stress, cerebral blood flow, and inflammation 52 1 Phase IV in progress in China as of 2019 1 0 0 [57][58]
19 Deferoxamine 2012 Iron chelator; bacterial siderophore 52 2 Phase II completed but results not published, and no Phase 3 was started. 2 0 0 [59][60][61]
20 Caffeinol 2002 Stimulant, depressant, diuretic Adenosine receptor modulator 51 10 8 2 0 [4]
21 CNS1102 (Cerestat, aptiganel) 1994 NMDA ion channel blocker 51 11 11 2 0 [4]
22 Dextrorphan 1994 NMDA ion channel blocker 50 17 13 6 0 [4]
23 JPI-289 2017 PARP-1 Inhibitor 49 1 Jeil Pharmaceutical Co., Ltd, Phase II in progress in Korea as of 2019. Safety and dosing was demonstrated in healthy adults. [62][63]
24 Minocycline 2007 antibiotic 49 1 Phase IV terminated due to futility. Enrolled patients up to 48 hours after stroke. 2 0 0 [64]
25 Remacemide 1994 NMDA ion channel blocker 49 1 1 0 0 [4]
26 tPA (< 3 hours) 1995 Thrombolytic 49 9 tPA 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. 9 10 0 [65]
27 Diaspirin cross-linked hemoglobin 1998 Oxygen delivery Free radical scavenger 48 5 5 1 0 [4]
28 Eliprodil (SL 82.0715) 1994 NMDA polyamine antagonist Sigma ligand 48 4 6 0 0 [4]
29 CGS 19755 (selfotel) 1995 NMDA antagonist 47 2 4 1 1 [4]
30 Hypothermia 1998 Reduce reducing cerebral oxygen demand (CMRO2), Metabolic and synaptic transmission inhibitor. 46 92 94 28 0 [4]
31 Lifarizine (RS-87476) 1995 Sodium/calcium channel blocker 46 8 5 4 0 [4]
32 Glibenclamide (BIIB093, BIIB-093, glibenclamide IV, formerly Cirara or RP-1127). 2010 selective inhibitor of SUR1-TRPM4 channels that mediate stroke related brain swelling. 45 3 As 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. 3 0 0 [66][67][68][69][70]
33 MP-124 2011 PARP-1 Inhibitor 44 2 A Phase 1 drug developed by Mitsubishi Tanabe's with an unclear status as of 2019. 2 0 0 [71][72]
34 NS1209/SPD 502 1999 Gluamate antagonist 44 2 2 0 0 [4]
35 NXY-059 2001 Free radical scavenger 43 27 AstraZeneca'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. 24 5 0 [4][73]
36 Clomethiazole (CMZ, Zendra) 1996 GABA agonist 42 7 8 2 0 [4]
37 Vinpocetine (ethyl apovincaminate) 1986 Calcium inhibitor, Vasodilator, Sodium blocker; synthetic derivative of the vinca alkaloid vincamine, an extract from the lesser periwinkle plant. 42 1 Results 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. 1 0 0 [74][75]
38 Neu2000 2016 NR2B-selective NMDA receptor antagonist and spin trapping molecule (=free radical scavenger or antioxidant) 41.2 1 GNT 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]
39 Sipatrigine (BW619C89) 1995 Sodium channel antagonist Glutamate release inhibitor 41 37 40 4 0 [4]
40 NA-1 (TatNR2B9c) 2008 Postsynaptic density-95 protein inhibitor 40 6 NoNO 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. 6 2 0 [78][79][80][81][82][83][84][85]
41 AER-271 2018 inhibitor of Aquaporin-4 (AQP4) water channels 39 1 Initiated 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. 0 0 0 [86]
42 Erythropoietin (EPO) 2002 Controls red blood cell production 39 9 Tested again in 2009. Clnical trial showed no significant difference in neurological recovery. Significantly increased mortality rate and safety concerns 11 2 0 [4]
43 ARL 15896 (AR-A15896AR) 1999 NMDA antagonist 39 15 10 8 0 [4]
44 Piracetam 1988 AMPA (NA+) modulator 39 5 4 1 0 [4]
45 Nafronyl oxalate (naftidrofuryl) 1978 Serotonin antagonist 38 5 6 2 0 [4]
46 ACEA 1021 (licostinel) 1997 NMDA glycine site antagonist 37 25 19 6 0 [4]
47 Propentofylline (HWA 285) 1992 Phosphodiesterase inhibitor 37 7 9 2 0 [4]
48 S-0139 (SB-737004) 1999 Endothelin antagonist 36 4 3 1 0 [4]
49 PG2 (Polysaccharides of Astragalus membranaceus) 2015 Chinese Herb, Antiinflammatory 36 1 Phase IV clinical trial status unclear. 1 0 0 [87][88]
50 Trans sodium crocetinate 2018 increases diffusion of oxygen 35 3 3 [89][90][91]
51 TNK (tenecteplase) 2000 Thrombolytic agent 35 2 2 0 0 [4]
52 Magnesium Sulfate 1993 NMDA ion channel blocker. Calcium antagonist 35 10 The 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. 11 0 0 [4][92]
53 propanolol 1988 β-adrenergic blockade, Membrane stabilization 34 4 Studied most recently in 2013. Phase II/III completed, but results not published. 3 8 0 [4]
54 Mannitol 1978 Hyperosmotic agent. Reduces edema and ICP 34 19 10 15 1 [4]
55 Dextran 1969 Hemodilution 34 7 4 5 1 [4]
56 N-acetyl-cysteine (NAC) 2015 Free radical scavenger 33 1 1 0 0 [93]
57 PS519/MLN519 2000 Proteasome inhibitor 32 14 11 3 0 [4]
58 Heparin 1979 Anticoagulant 32 17 10 10 3 [4]
59 FK506 (pacrolimus) 2004 Immunosuppressant 31 72 Stopped in Phase II, adverse side effects 52 27 0 [4]
60 Neutrophil inhibitory factor (rNIF, UK-279.276) 2000 Neutrophil inhibitor 31 12 8 4 0 [4]
61 YM90K 1997 AMPA antagonist 31 23 19 6 0 [4]
62 Aspirin 1995 Antiplatelet 31 19 9 13 0 [4]
63 Lovastatin (aka simvastatin) 2001 HMGCoA reductase inhibitor 30 20 Finished recruitment in Phase II trial in 2017, results not published as of 2019. 11 1 0 [4][94][95]
64 Normobaric oxygen treatment 2009 Oxygen Delivery 30 6 Several 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. 5 0 1 [96][97][98][99][100][101]
65 Basic fibroblast growth factor (trafermin. Fiblast) 1998 Growth factor 29 35 22 19 0 [4]
66 Naloxone 1981 Opioid antagonist 29 7 8 7 0 [4]
67 Ebselen 2009 Free radical scavenger; synthetic organo-selenium antiinflammatory, anti-oxidant and cytoprotective activity; mimic glutathione peroxidase 27 9 Tested in Phase III but never reached market, and now out of patent. 10 6 0 [4]
68 BIII-890-CL 2001 Sodium Channel Blocker 27 6 Still in trial in 2014 6 0 0 [4]
69 YM872 1999 AMPA antagonist 27 32 22 8 0 [4]
70 Ebselen (Harmokisane) 1998 Free radical scavenger 27 9 10 6 0 [4]
71 Abciximab (reopro, c7E3 Fab) 1998 Antiplatelet: glycoprotein inhibitor 27 2 1 1 0 [4]
72 Tirilazad (U74006F) 1994 Free radical scavenger 26 16 11 8 0 [4]
73 nimodipine 1984 antihypertensive drug 26 37 May be in clinical trials in China in 2016, but status is unknown. Failed earlier clinical trials. 24 28 0 [102][103]
74 Enoxaparin 2003 Antithrombotic 25 25 12 13 0 [4]
75 ONO-2506 2003 Astrocyte modulating agent Anenuates extracellular monamine 25 8 5 3 0 [4]
76 EGB-761 (Gingko biloba extract) 1995 MAO inhibitor Antiplatelet. 25 15 13 3 0 [4]
77 Citicoline (CDP choline) 1987 Membrane precursor, antioxidant 25 13 4 9 0 [4]
78 Edaravone (MCI-186) 2001 Free radical scavenger nootropic and neuroprotective agent 24 8 Approved in Japan. 7 5 0 [104][105]
79 Hyperbaric oxygen treatment 1966 Oxygen delivery 24 17 13 5 2 [4]
80 Indomethacin 2001 Cyclooxygenase inhibitor 23 2 3 2 0 [4]
81 Lubeluzole 1994 Sodium/calcium channel blocker NOS inhibitor 23 19 13 8 0 [4]
82 Hydroxyethyl starch pentastarch 1980 Hemodilution 23 3 4 3 1 [4]
83 Cyclosporin A 2014 Immunosuppressant 22 1 Not effective in reducing infarct size. However, a smaller infarct size was observed in patients with proximal cerebral arteryocclusion and efficient recanalization. 9 2 0 [106]
84 natalizumab 2016 prevents leukocytes from moving across the blood-brain barrier 22 3 Discontinued by Biogen after a Phase II trial showed that natalizumab administered ≤24 hours after acute ischemic stroke did not improve patient outcomes. 4 2 0 [107]
85 Anerod 1983 Fibrinogen depleting 21 4 4 1 0 [4]
86 ZK200775 (MPQX) 1997 AMPA antagonist 19 21 12 9 0 [4]
87 Dexamethasone 1971 Glucocorticoid, antiinflammatory 19 11 Continued 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. 7 8 1 [4]
88 Nicaraven (N,N′-propylenedinicotinamide) 2001 Free radical scavenger 17 4 2 2 0 [4]
89 Insulin 1993 Lowers glucose 16 5 4 1 2 [4]
90 ABL-101 (Oxycyte) 2018 Oxygen Delivery 15 1 Developed by Aurum Biosciences, formerly developed by Oxycyte. A perfluorocarbon emulsion that works like a blood substitute. 1 0 0 [108]
91 BMS-204352 1998 Potassium channel opener 14 9 7 1 0 [4]
92 Enlimomab (anti–ICAM-1 antibody) 1996 Leukocyte migration and adhesion inhibitor 14 9 6 7 1 [4]
93 Nicardipine 1988 Calcium antagonist 11 6 8 10 0 [4]
94 Argatroban 1986 Anticoagulant 11 4 3 3 0 [4]
95 TAK-218 2001 Dopamine suppressor 10 1 0 1 0 [4]
96 Paracetemol (Acetaminophen) 2009 Analgesic/antipyretic COX inhibitor 8 1 0 1 0 [4]
97 n-PA/tPA (alteplase) 1988 Antithrombotic 4 86 52 38 11 [4]
98 Ganglioside GM1 1984 Metabolism, growth 4 1 6 4 0 [4]
99 GSK249320 2013 Antagonises or neutralises myelin associated glycoprotein (MAG) - mediated inhibition 0 1 GlaxoSmithKline, discontinued in 2017 after showing no effect at interim analysis. 0 1 0 [109]
100 Simvastatin 2008 HMGCoA reductase inhibitor Antioxidant 0 1 No differences were found between treatment arms regarding the primary outcome. 0 1 0 [94][110]
101 Baclofen 2001 GABA-B Antagonist 0 0 1 1 0 [4]
102 Amphetamines 2003 Stimulant -3 1 1 2 0 [4]
103 Papaverine 1976 Calcium channel blocker -3 1 0 1 0 [4]
104 Flunarizine 1990 Calcium channel blocker -6 3 4 1 1 [4]
105 Prosatacyclin 1984 Antiplatelet: eicosanoid Vasodilator -6 1 1 1 0 [4]
106 tPA (>3 hours) 1995 Thrombolytic -39 2 The 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. 0 7 2 [65]
107 Streptokinase 1963 Thrombolytic -525 6 1 4 5 [4]
108 LT3001 2019 Thrombolytic and antioxidant 0 0 Lumosa Therapeutics was running a Phase II clinical trial in 2022 0 0 0 [111]
109 TMS-007 2014 Thrombolytic 0 0 Biogen acquired TMS-007 in 2021 after a positive Phase IIa trial. 0 0 0 [112][113]
110 GM602 2016 anti-inflammatory — - Phase II completed, but no Phase III has appeared to have been started. Run by Genervon. No pre-clinical data published. - - - [114][115]
111 Vitamin B2 2015 Causes a Reduction of Glutamate-mediated Excitotoxicity — 0 Phase II complete, but no results published. 0 0 0 [116]
112 Irbesartan 2012 AT1 receptor antagonist Antihypertensive — - Agent did not appear to substantially modify infarct growth. 1 - - [117][118]
113 Lu AA24493 (carbamylated erythropoietin CEPO) 2011 Controls red blood cell production — - Unknown toxicity claims halted development. Trial run by H. Lundbeck AS - - -
114 NTx-265 2009 Regeneration; Human Chorionic Gonadotropin (hCG) and Epoetin Alfa (EPO) — - No significant difference in neurological recovery. - - - [119]
115 ILS-920 2009 Calicum channel blocker — - Now owned by Pfizer, but no longer on Pfizer's pipeline. - - - [120]
116 Eptifibatide (cromafiban; Integrilin) 2003 Antiplatelet: glycoprotein inhibitor — 0 0 0 0 [4]
117 Desmoteplase (DSPA) 2002 Antithrombotic — 0 0 0 0 [4]
118 S-1746 2001 NMDA glycine/AMPA antagonist — 0 0 0 0 [4]
119 Tirofiban (MK-383, aggrastat) 2001 Antiplatelet: glycoprotein inhibitor — 0 0 0 0 [4]
120 Triflusal (2-acetoxy-4-trifluoromethylbenzonic acid) 2001 Arachidonic acid metabolism inhibitor (antiplatelet) — 0 1 2 0 [4]
121 Cerebrolysin 2001 Nootropic — 0 A 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. 1 1 0 [4][121]
122 DP-b99 (DPBAPA) 2000 Calcium chelator — 0 Interim futility analysis showed no evidence of efficacy, published in 2008. 0 0 0 [122]
123 Diazepam (valium) 2000 Benzodiazepine — 0 0 1 0 [4]
124 Certoparin 2000 Anticoagulant — 0 0 0 0 [4]
125 Dalteparin 2000 Anticoagulant — 0 0 0 0 [4]
126 Radix salviae miltiorrhizae 2000 Antioxidant Partial endothelin-1 inhibitor — 0 1 1 0 [4]
127 glyceril trinitrate 1999 NO 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. 1 0 0 [123][124][125]
128 Candesartan cilexetil (TCV-116, Blopress, CV-11974) 1999 AT1 receptor antagonist Antihypertensive — - Results published in 2012: no significant difference in neurological recovery; harmful effect suggested - - - [126]
129 Fludrocortisone 1999 Mineralocorticoid — 0 0 0 0 [4]
130 LDP-01 (Anti–β-2-integrin antibody) 1999 Leukocyte adhesion and migration inhibitor — 0 0 0 0 [4]
131 Nalmefene 1998 Opioid antagonist — 0 0 0 0 [4]
132 NPS 1506 1998 NMDA ion channel blocker — 0 6 2 0 [4]
133 RPR 109891 1998 Antiplatelet glycoprotein inhibitor — 0 0 0 0 [4]
134 Tinzaparin 1998 Anticoagulant — 0 0 0 0 [4]
135 Org 10172 (danaparoid, Orgaran) 1997 Antithrombotic — 0 0 0 0 [4]
136 Semax 1997 Derivative of ACTH-4-10 — 0 0 0 0 [4]
137 Glycine 1996 NMDA antagonist — 0 0 0 0 [4]
138 Fosphentoyn 1995 Sodium Channel Blocker, Glutemate Release Inhibitor — 0 Phase III terminated early due to futility. 0 0 0 [127]
139 Batroxobin (defibrase, DF-521) 1995 Fibrinogen depleting — 0 4 0 0 [4]
140 Nadroparin 1995 Antithrombotic — 0 0 0 0 [4]
141 Defibrotide (polydeoxyribonucleotide) 1989 Antiplatelet: glycoprotein inhibitor — 0 0 0 0 [4]
142 Atenol (Tenormin) 1988 Beta blocker — 0 0 0 0 [4]
143 Corticotrophin 1987 GABA receptor modulator Pituitary hormone — 0 0 0 0 [4]
144 PY 108-068 1986 Calcium antagonist — 0 2 0 0 [4]
145 Trazodone (Desyrel) 1986 Serotonin reuptake inhibitor — 0 0 0 0 [4]
146 Nicergoline 1985 α2 adrenoceptor agonist — 0 1 0 0 [4]
147 Nicergoline 1985 Alpha2 adrenoceptor agonist — 0 1 0 0 [4]
148 Pentoxifylline 1981 Improve capillary flow — 0 0 1 0 [4]
149 Hydergine 1978 Nootropic, antioxidant. — 0 0 0 0 [4]
150 Tinofedrine (D 8955, Novocebrin) 1978 Blood flow, increased metabolism — 0 0 0 0 [4]
151 Xanthinol nicotinate (Sadamin) 1977 Vitamin B(3): metabolic enhancer — 0 0 0 0 [4]
152 Aminophylline 1976 Phosphodiesterase inhibitor — 0 0 0 0 [4]
153 Glycerol 1972 Hyperosmolar agent — 0 0 2 0 [4]
154 Cyclandelate 1966 Vasodilator (calcium modulator) — 0 0 0 0 [4]

References

  1. ↑ 1.0 1.1 1.2 1.3 "Top Priorities for Cerebroprotective Studies-A Paradigm Shift: Report From STAIR XI". Stroke 52 (9): 3063–3071. August 2021. doi:10.1161/STROKEAHA.121.034947. PMID 34289707. 
  2. ↑ World Health Organization. "The top 10 causes of death". https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death. 
  3. ↑ "Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association". Circulation 141 (9): e139–e596. March 2020. doi:10.1161/CIR.0000000000000757. PMID 31992061. 
  4. ↑ 4.000 4.001 4.002 4.003 4.004 4.005 4.006 4.007 4.008 4.009 4.010 4.011 4.012 4.013 4.014 4.015 4.016 4.017 4.018 4.019 4.020 4.021 4.022 4.023 4.024 4.025 4.026 4.027 4.028 4.029 4.030 4.031 4.032 4.033 4.034 4.035 4.036 4.037 4.038 4.039 4.040 4.041 4.042 4.043 4.044 4.045 4.046 4.047 4.048 4.049 4.050 4.051 4.052 4.053 4.054 4.055 4.056 4.057 4.058 4.059 4.060 4.061 4.062 4.063 4.064 4.065 4.066 4.067 4.068 4.069 4.070 4.071 4.072 4.073 4.074 4.075 4.076 4.077 4.078 4.079 4.080 4.081 4.082 4.083 4.084 4.085 4.086 4.087 4.088 4.089 4.090 4.091 4.092 4.093 4.094 4.095 4.096 4.097 4.098 4.099 4.100 4.101 4.102 4.103 4.104 4.105 4.106 4.107 "1,026 experimental treatments in acute stroke". Annals of Neurology 59 (3): 467–477. March 2006. doi:10.1002/ana.20741. PMID 16453316. 
  5. ↑ Genentech, Inc.. "ACTIVASE (alteplase) for injection". FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103172s5203lbl.pdf. 
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  8. ↑ Lapchak, Paul A (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. PMID 20491547. 
  9. ↑ Biotechnology Industry Association. "Clinical Development Success Rates and Contributing Factors 2011-2020". https://go.bio.org/rs/490-EHZ-999/images/ClinicalDevelopmentSuccessRates2011_2020.pdf. 
  10. ↑ "Overview of Mechanical Thrombectomy Techniques". Neurosurgery 85 (suppl_1): S60–S67. July 2019. doi:10.1093/neuros/nyz071. PMID 31197338. 
  11. ↑ 11.0 11.1 "The Next Step in the Treatment of Stroke". Frontiers in Neurology 11: 582605. 2021. doi:10.3389/fneur.2020.582605. PMID 33551950. 
  12. ↑ "Collateral Clock Is More Important Than Time Clock for Tissue Fate". Stroke 49 (9): 2102–2107. September 2018. doi:10.1161/STROKEAHA.118.021484. PMID 30354992. 
  13. ↑ "Early effects of hypoxia on brain cell function". Croatian Medical Journal 40 (3): 375–380. September 1999. PMID 10411965. https://pubmed.ncbi.nlm.nih.gov/10411965/. 
  14. ↑ "Drug therapy in stroke: from preclinical to clinical studies" (in english). Pharmacology 92 (5–6): 324–334. 2013. doi:10.1159/000356320. PMID 24356194. 
  15. ↑ "Ischemia/Reperfusion". Comprehensive Physiology 7 (1): 113–170. December 2016. doi:10.1002/cphy.c160006. ISBN 9780470650714. PMID 28135002. 
  16. ↑ "Stroke Preclinical Assessment Network (SPAN) FAQs". NINDS. https://www.ninds.nih.gov/stroke-preclinical-assessment-network-span-faqs. 
  17. ↑ "Time is brain--quantified". Stroke 37 (1): 263–266. January 2006. doi:10.1161/01.STR.0000196957.55928.ab. PMID 16339467. 
  18. ↑ 18.0 18.1 18.2 "Pharmacological brain cytoprotection in acute ischaemic stroke - renewed hope in the reperfusion era". Nature Reviews. Neurology 18 (4): 193–202. April 2022. doi:10.1038/s41582-021-00605-6. PMID 35079135. 
  19. ↑ "Use of Imaging to Select Patients for Late Window Endovascular Therapy". Stroke 49 (9): 2256–2260. September 2018. doi:10.1161/STROKEAHA.118.021011. PMID 30355004. 
  20. ↑ "Ventriculo-lumbar perfusion in acute ischemic stroke". Neurocritical Care 5 (1): 21–29. 2006. doi:10.1385/NCC:5:1:21. PMID 16960290. 
  21. ↑ "Partnering: key to early-stage biotech survival, but at what cost?". Biotechnology Healthcare 1 (6): 26–34. December 2004. PMID 23424295. 
  22. ↑ "Neuroprotective effect of dapsone in patients with acute ischemic stroke: a pilot study". Neurological Research 29 (3): 331–334. April 2007. doi:10.1179/016164107X159234. PMID 17509235. 
  23. ↑ "Neuroprotective effect of dapsone in an occlusive model of focal ischemia in rats". Brain Research 999 (2): 212–215. March 2004. doi:10.1016/j.brainres.2003.11.040. PMID 14759500. 
  24. ↑ "Dapsone in dermatology and beyond". Archives of Dermatological Research 306 (2): 103–124. March 2014. doi:10.1007/s00403-013-1409-7. PMID 24310318. 
  25. ↑ "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. September 2016. doi:10.1016/j.brainres.2016.06.023. PMID 27321157. 
  26. ↑ "Dodecafluoropentane emulsion decreases infarct volume in a rabbit ischemic stroke model". Journal of Vascular and Interventional Radiology 23 (1): 116–121. January 2012. doi:10.1016/j.jvir.2011.10.001. PMID 22079515. 
  27. ↑ "Progress in dodecafluoropentane emulsion as a neuroprotective agent in a rabbit stroke model". Molecular Neurobiology 48 (2): 363–367. October 2013. doi:10.1007/s12035-013-8495-6. PMID 23813100. 
  28. ↑ "Dodecafluoropentane Emulsion (DDFPe) Decreases Stroke Size and Improves Neurological Scores in a Permanent Occlusion Rat Stroke Model". The Open Neurology Journal 8: 27–33. 2014-12-30. doi:10.2174/1874205X01408010027. PMID 25674164. 
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  30. ↑ "Dodecafluoropentane Improves Neurological Function Following Anterior Ischemic Stroke". Molecular Neurobiology 54 (6): 4764–4770. August 2017. doi:10.1007/s12035-016-0019-8. PMID 27501802. 
  31. ↑ "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. August 2019. doi:10.1016/j.jvir.2019.04.020. PMID 31349978. 
  32. ↑ "Diffusion-weighted magnetic resonance imaging confirms marked neuroprotective efficacy of albumin therapy in focal cerebral ischemia". Stroke 29 (12): 2587–2599. December 1998. doi:10.1161/01.str.29.12.2587. PMID 9836772. 
  33. ↑ "Efficacy of retrograde perfusion of the cerebral vein with verapamil after focal ischemia in rat brain". Stroke 22 (12): 1562–1566. December 1991. doi:10.1161/01.STR.22.12.1562. PMID 1962332. 
  34. ↑ "Effects of verapamil and diltiazem on acute stroke in cats". Journal of Neurosurgery 63 (6): 929–936. December 1985. doi:10.3171/jns.1985.63.6.0929. PMID 4056906. 
  35. ↑ "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. April 2016. doi:10.1177/0271678X15608395. 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. ↑ "Dextromethorphan protects against cerebral injury following transient, but not permanent, focal ischemia in rats". Life Sciences 60 (20): 1729–1740. 1997. doi:10.1016/s0024-3205(97)00132-x. PMID 9150412. 
  38. ↑ "Evaluation of the neuroprotective effect of dextromethorphan in the acute phase of ischaemic stroke". Archives of Medical Science 7 (3): 465–469. June 2011. doi:10.5114/aoms.2011.23413. 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
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  42. ↑ "SP-8203 reduces oxidative stress via SOD activity and behavioral deficit in cerebral ischemia". Pharmacology, Biochemistry, and Behavior 98 (1): 150–154. March 2011. doi:10.1016/j.pbb.2010.12.014. PMID 21172384. 
  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
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  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
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  47. ↑ "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. December 2013. doi:10.1161/STROKEAHA.113.003350. PMID 24159062. 
  48. ↑ "Anti-inflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke". Circulation 103 (13): 1799–1805. April 2001. doi:10.1161/01.CIR.103.13.1799. PMID 11282913. 
  49. ↑ "Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective". Nature Medicine 9 (3): 338–342. March 2003. doi:10.1038/nm826. PMID 12563316. 
  50. ↑ "Neurotoxicity of the anticoagulant-selective E149A-activated protein C variant after focal ischemic stroke in mice". Blood Cells, Molecules & Diseases 51 (2): 104–108. August 2013. doi:10.1016/j.bcmd.2013.02.009. PMID 23541526. 
  51. ↑ "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. April 2013. doi:10.1016/j.brainres.2013.02.023. PMID 23438513. 
  52. ↑ "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. September 2012. doi:10.1161/STROKEAHA.112.658997. PMID 22811462. 
  53. ↑ "Differential neuroprotection and risk for bleeding from activated protein C with varying degrees of anticoagulant activity". Stroke 40 (5): 1864–1869. May 2009. doi:10.1161/STROKEAHA.108.536680. PMID 19057019. 
  54. ↑ "Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia". Stroke 34 (3): 745–751. March 2003. doi:10.1161/01.STR.0000057814.70180.17. PMID 12624302. 
  55. ↑ "Granulocyte-colony stimulating factor for stroke treatment: mechanisms of action and efficacy in preclinical studies". Experimental & Translational Stroke Medicine 1 (1): 2. October 2009. doi:10.1186/2040-7378-1-2. PMID 20142989. 
  56. ↑ "Granulocyte-Colony Stimulating Factor (G-CSF) for stroke: an individual patient data meta-analysis". Scientific Reports 6: 36567. November 2016. doi:10.1038/srep36567. PMID 27845349. Bibcode: 2016NatSR...636567E. 
  57. ↑ "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. November 2006. doi:10.1152/ajpheart.01270.2005. PMID 16766636. 
  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. ↑ "Effects of deferoxamine on brain injury after transient focal cerebral ischemia in rats with hyperglycemia". Brain Research 1291: 113–121. September 2009. doi:10.1016/j.brainres.2009.07.032. PMID 19631616. 
  60. ↑ "Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke". The Journal of Pharmacology and Experimental Therapeutics 330 (3): 679–686. September 2009. doi:10.1124/jpet.108.149807. 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
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  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
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  66. ↑ "Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke". Nature Medicine 12 (4): 433–440. April 2006. doi:10.1038/nm1390. PMID 16550187. 
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  68. ↑ "Glibenclamide Administration Attenuates Infarct Volume, Hemispheric Swelling, and Functional Impairments following Permanent Focal Cerebral Ischemia in Rats". Stroke Research and Treatment 2012: 460909. 2012. doi:10.1155/2012/460909. PMID 22988544. 
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  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
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  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
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  80. ↑ "Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand". The Journal of Neuroscience 28 (42): 10696–10710. October 2008. doi:10.1523/JNEUROSCI.1207-08.2008. PMID 18923045. 
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  86. ↑ "Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia". Neuroscience Letters 584: 368–372. January 2015. doi:10.1016/j.neulet.2014.10.040. PMID 25449874. 
  87. ↑ "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. October 2013. doi:10.1186/1744-9081-9-36. 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. ↑ "Trans-sodium crocetinate improves outcomes in rodent models of occlusive and hemorrhagic stroke". Brain Research 1583: 245–254. October 2014. doi:10.1016/j.brainres.2014.08.013. PMID 25128603. 
  90. ↑ "Protection against focal ischemic injury to the brain by trans-sodium crocetinate. Laboratory investigation". Journal of Neurosurgery 113 (4): 802–809. October 2010. doi:10.3171/2009.10.JNS09562. PMID 19961314. 
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  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". https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-142654. 
  113. ↑ Fierce Biotech (12 May 2021). "Biogen buys midphase drug to challenge Roche for stroke market". https://www.fiercebiotech.com/biotech/biogen-buys-midphase-drug-to-challenge-roche-for-stroke-market. 
  114. ↑ "Genervon Pipeline". http://www.genervon.com/genervon/medicines_pipeline.php. 
  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. ↑ "A randomized placebo controlled trial of early treatment of acute ischemic stroke with atorvastatin and irbesartan". International Journal of Stroke 7 (2): 104–111. February 2012. doi:10.1111/j.1747-4949.2011.00653.x. PMID 22044557. 
  118. ↑ "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. May 2011. doi:10.1177/0960327110371257. PMID 20488839. 
  119. ↑ "Stem Cell Therapeutics Stroke Drug, NTx-265 Fails Phase 2 Trial" (in en-US). https://www.biospace.com/article/stem-cell-therapeutics-stroke-drug-ntx-265-fails-phase-2-trial-/. 
  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". https://www.cerebrolysin.com/stroke/clinical-efficacy.html. 
  122. ↑ "DP-b99, a membrane-activated metal ion chelator, as neuroprotective therapy in ischemic stroke". Stroke 39 (6): 1774–1778. June 2008. doi:10.1161/STROKEAHA.107.506378. PMID 18403736. 
  123. ↑ Clinical trial number NCT01811693 for "The Field Administration of Stroke Therapy-Blood Pressure Lowering Pilot Trial" at ClinicalTrials.gov
  124. ↑ "Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase". Science 265 (5180): 1883–1885. September 1994. doi:10.1126/science.7522345. PMID 7522345. Bibcode: 1994Sci...265.1883H. 
  125. ↑ "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. February 2015. doi:10.1016/S0140-6736(14)61121-1. PMID 25465108. 
  126. ↑ (in en) Neuroprotective Therapy for Stroke and Ischemic Disease. Springer. 2017-01-12. ISBN 978-3-319-45345-3. https://books.google.com/books?id=J5flDQAAQBAJ. 
  127. ↑ "Neuroprotection for ischemic stroke: two decades of success and failure". NeuroRx 1 (1): 36–45. January 2004. doi:10.1602/neurorx.1.1.36. PMID 15717006. 




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