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Cerebroprotectants

From EverybodyWiki Bios & Wiki


Cerebroprotectants (formerly known as neuroprotectants) for acute ischemic stroke are drugs that are 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 cerebroprotectants have been tested in clinical trials.[2][3][4]

Approved cerebroprotectants

  • Tissue plasminogen activator (also known as tPA, t-PA, rtPA, Activase, or Alteplase or Actilyse)[5] 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]

Approval rate for drugs in development

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 the 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 metabolim does not provide enough energy, there is energy failure, followed by ion imbalances.[14] Afterwards, the pathophysilogy 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. However, these approved therapies all take time to work, leaving room for faster acting cerebroprotectants.[16][17] 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 processses 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.[18]

Start treatment earlier: After the onset of stroke, the amount of brain tissue that dies increases over time, leading to the saying, "Time is brain."[19] Treating patients earlier can lead to a greater amount of brain tissue being saved.

Protect the brain for longer: An element of clinical trial design that affects the propability that a truly beneficial drug will show benfenit in a clinical trial 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.[20]

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.[21] These same methods can be applied to clinical trials for cerebroprotective drugs.[20]

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][20]

List of cerebroprotectants tested in 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][22][23]
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 [24][25][26][27]
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 [28][29][30][31][32][33]
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 [34]
5 Veripamil 2016 Calcium channel blocker (Phenylalkylamine calcium channel) 66 2 Veripamil was administered immediately after restoration of blood flow. 2 0 1 [35][36][37][38]
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 [39][40]
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 [41]
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 [42][43]
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-clincal studies showed high level of dose dependency. 1 0 0 [44][45]
10 ketamine 2014 NMDA receptor antagonist 57 1 Phase I/II in progress as of 2018 1 0 0 [46][47]
11 Hu23F2G (LeukArrest) 1999 Leukocyte adhesion inhibitor 57 1 1 0 0
12 Donepezil 2008 selective acetylcholinesterase inhibitor 56 1 1 0 0 [48]
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 hemorrage, 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 [49][50][51][52][53][54][55][56]
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 [57][58][59]
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 [60][61]
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 [62][63][64]
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. [65][66]
24 Minocycline 2007 antibiotic 49 1 Phase IV terminated due to futility. Enrolled patients up to 48 hours after stroke. 2 0 0 [67]
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 [68]
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 [69][70][71][72][73]
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 [74][75]
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 singificant improvement in mRS (p=0.03), but missed all its seconardy endpoints. A second Phase III in 3,300 patients saw no effect in any endpoint. 24 5 0 [4][76]
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 [77][78]
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 [79][80]
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 [81][82][83][84][85][86][87][88]
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 [89]
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 [90][91]
50 Trans sodium crocetinate 2018 increases diffusion of oxygen 35 3 3 [92][93][94]
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][95]
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 [96]
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][97][98]
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 desolves 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 [99][100][101][102][103][104]
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 [105][106][107]
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 [108][109]
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 [110]
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 [111]
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 [112]
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 [113]
100 Simvastatin 2008 HMGCoA reductase inhibitor Antioxidant 0 1 No differences were found between treatment arms regarding the primary outcome. 0 1 0 [114][115]
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 [116]
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 [117]
109 TMS-007 2014 Thrombolytic 0 0 Biogen acquired TMS-007 in 2021 after a positive Phase IIa trial. 0 0 0 [118][119]
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. - - - [120][121]
111 Vitamin B2 2015 Causes a Reduction of Glutamate-mediated Excitotoxicity — 0 Phase II complete, but no results published. 0 0 0 [122]
112 Irbesartan 2012 AT1 receptor antagonist Antihypertensive — - Agent did not appear to substantially modify infarct growth. 1 - - [123][124]
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. - - - [125]
115 ILS-920 2009 Calicum channel blocker — - Now owned by Pfizer, but no longer on Pfizer's pipeline. - - - [126]
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][127]
122 DP-b99 (DPBAPA) 2000 Calcium chelator — 0 Interim futility analysis showed no evidence of efficacy, published in 2008. 0 0 0 [128]
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 [129][130][131]
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 - - - [132]
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 [133]
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 Lyden, Patrick; Buchan, Alastair; Boltze, Johannes; Fisher, Marc (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. ISSN 1524-4628. PMC 8384700 Check |pmc= value (help). PMID 34289707 Check |pmid= value (help).
  2. ↑ World Health Organization. "The top 10 causes of death". Retrieved 11 May 2022.
  3. ↑ Tsao, CW; Aday, AW; Almarzooq, ZI; Alonso, A; Beaton, AZ; Bittencourt, MS (2022). "Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association". Circulation. 145 (8): e153–e639. doi:10.1161/CIR.0000000000001052. PMID 35078371 Check |pmid= value (help). Unknown parameter |s2cid= ignored (help)
  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 O'Collins, Victoria E.; Macleod, Malcolm R.; Donnan, Geoffrey A.; Horky, Laura L.; van der Worp, Bart H.; Howells, David W. (March 2006). "1,026 experimental treatments in acute stroke". Annals of Neurology. 59 (3): 467–477. doi:10.1002/ana.20741. ISSN 0364-5134. PMID 16453316. Unknown parameter |s2cid= ignored (help)
  5. ↑ Genentech, Inc. "ACTIVASE (alteplase) for injection" (PDF). FDA. Retrieved 11 May 2022.
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  12. ↑ Vagal, Achala; Aviv, Richard; Sucharew, Heidi; Reddy, Mahati; Hou, Qinghua; Michel, Patrik; Jovin, Tudor; Tomsick, Thomas; Wintermark, Max; Khatri, Pooja (1 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. ISSN 0353-9504. PMID 10411965.
  14. ↑ Kaur, Harjeet; Prakash, Ajay; Medhi, Bikash (2013). "Drug Therapy in Stroke: From Preclinical to Clinical Studies". Pharmacology. 92 (5–6): 324–334. doi:10.1159/000356320. ISSN 0031-7012. PMID 24356194. Unknown parameter |s2cid= ignored (help)
  15. ↑ Kalogeris, Theodore; Baines, Christopher P.; Krenz, Maike; Korthuis, Ronald J. (6 December 2016). "Ischemia/Reperfusion". Comprehensive Physiology. 7 (1): 113–170. doi:10.1002/cphy.c160006. ISSN 2040-4603. PMC 5648017. PMID 28135002.
  16. ↑ Menon, Bijoy K; Najm, Mohamed; Al-Ajlan, Fahad; Puig Alcantara, Josep; Dowlatshahi, Dar; Calleja, Ana; Sohn, Sung-Il; Ahn, Seong H; Poppe, Alexandre; Mikulik, Robert; Asdaghi, Negar; Field, Thalia S; Jin, Albert; Asil, Talip; Boulanger, Jean-Martin; Smith, Eric E; Coutts, Shelagh B; Barber, Phil A; Bal, Simer; Mishra, Sachin; Trivedi, Anurag; Dey, Sadanand; Goyal, Mayank; Hill, Michael D; Demchuk, Andrew M; null, null (1 February 2017). "Abstract 186: IV tPA Recanalization Rates by Site of Occlusion and Time After tPA Bolus- Main Results Of The Interrsect Multinational Multicenter Prospective Cohort Study". Stroke. 48 (suppl_1): A186. doi:10.1161/str.48.suppl_1.186.
  17. ↑ Froehler, Michael T.; Saver, Jeffrey L.; Zaidat, Osama O.; Jahan, Reza; Aziz-Sultan, Mohammad Ali; Klucznik, Richard P.; Haussen, Diogo C.; Hellinger, Frank R.; Yavagal, Dileep R.; Yao, Tom L.; Liebeskind, David S.; Jadhav, Ashutosh P.; Gupta, Rishi; Hassan, Ameer E.; Martin, Coleman O.; Bozorgchami, Hormozd; Kaushal, Ritesh; Nogueira, Raul G.; Gandhi, Ravi H.; Peterson, Eric C.; Dashti, Shervin R.; Given, Curtis A.; Mehta, Brijesh P.; Deshmukh, Vivek; Starkman, Sidney; Linfante, Italo; McPherson, Scott H.; Kvamme, Peter; Grobelny, Thomas J.; Hussain, Muhammad S.; Thacker, Ike; Vora, Nirav; Chen, Peng Roc; Monteith, Stephen J.; Ecker, Robert D.; Schirmer, Clemens M.; Sauvageau, Eric; Abou-Chebl, Alex; Derdeyn, Colin P.; Maidan, Lucian; Badruddin, Aamir; Siddiqui, Adnan H.; Dumont, Travis M.; Alhajeri, Abdulnasser; Taqi, M. Asif; Asi, Khaled; Carpenter, Jeffrey; Boulos, Alan; Jindal, Gaurav; Puri, Ajit S.; Chitale, Rohan; Deshaies, Eric M.; Robinson, David H.; Kallmes, David F.; Baxter, Blaise W.; Jumaa, Mouhammad A.; Sunenshine, Peter; Majjhoo, Aniel; English, Joey D.; Suzuki, Shuichi; Fessler, Richard D.; Delgado Almandoz, Josser E.; Martin, Jerry C.; Mueller-Kronast, Nils H. (12 December 2017). "Interhospital Transfer Before Thrombectomy Is Associated With Delayed Treatment and Worse Outcome in the STRATIS Registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke)". Circulation. 136 (24): 2311–2321. doi:10.1161/CIRCULATIONAHA.117.028920. ISSN 1524-4539. PMC 5732640. PMID 28943516.
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  19. ↑ Saver, Jeffrey L. (1 January 2006). "Time Is Brain—Quantified". Stroke. 37 (1): 263–266. doi:10.1161/01.STR.0000196957.55928.ab. PMID 16339467. Unknown parameter |s2cid= ignored (help)
  20. ↑ 20.0 20.1 20.2 Fisher, Marc; Savitz, Sean I. (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. ISSN 1759-4766. PMC 8788909 Check |pmc= value (help). PMID 35079135 Check |pmid= value (help).
  21. ↑ Albers, Gregory W. (1 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. Unknown parameter |s2cid= ignored (help)
  22. ↑ Bell, Rodney D.; Powers, Barbara L.; Brock, David; Provencio, J. Javier; Flanders, Adam; Benetiz, Ronald; Rosenwasser, Robert; Strause, Jamie; Frazer, Glenn; Kramer, Michael S.; Hesson, David (2006). "Ventriculo-lumbar perfusion in acute ischemic stroke". Neurocritical Care. 5 (1): 21–29. doi:10.1385/NCC:5:1:21. ISSN 1541-6933. PMID 16960290. Unknown parameter |s2cid= ignored (help)
  23. ↑ D'ARVILLE, CAROLYN (December 2004). "Partnering: Key to Early-Stage Biotech Survival, But at What Cost?". Biotechnology Healthcare. 1 (6): 26–34. ISSN 1554-169X. PMC 3570991. PMID 23424295.
  24. ↑ Nader-Kawachi, Juan; Góngora-Rivera, Fernando; Santos-Zambrano, José; Calzada, Paloma; Ríos, Camilo (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. ISSN 0161-6412. PMID 17509235. Unknown parameter |s2cid= ignored (help)
  25. ↑ Rıos, Camilo; Nader-Kawachi, Juan; Rodriguez-Payán, Ana Julia; Nava-Ruiz, Concepción (2004-03-05). "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. ISSN 0006-8993. PMID 14759500. Unknown parameter |s2cid= ignored (help)
  26. ↑ Wozel, Gottfried; Blasum, Christian (2014). "Dapsone in dermatology and beyond". Archives of Dermatological Research. 306 (2): 103–124. doi:10.1007/s00403-013-1409-7. ISSN 0340-3696. PMC 3927068. PMID 24310318.
  27. ↑ Diaz-Ruiz, Araceli; Roldan-Valadez, Ernesto; Ortiz-Plata, Alma; Mondragón-Lozano, Rodrigo; Heras-Romero, Yessica; Mendez-Armenta, Marisela; Osorio-Rico, Laura; Nava-Ruiz, Concepción; Ríos, Camilo (2016-09-01). "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. ISSN 0006-8993. PMID 27321157. Unknown parameter |s2cid= ignored (help)
  28. ↑ Culp, William C.; Woods, Sean D.; Skinner, Robert D.; Brown, Aliza T.; Lowery, John D.; Johnson, Jennifer L. H.; Unger, Evan C.; Hennings, Leah J.; Borrelli, Michael J.; Roberson, Paula K. (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. ISSN 1051-0443. PMC 3253225. PMID 22079515.
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  32. ↑ Arthur, M. Christine; Brown, Aliza; Carlson, Kristen; Lowery, John; Skinner, Robert D.; Culp, William C. (August 2017). "Dodecafluoropentane Improves Neurological Function Following Anterior Ischemic Stroke". Molecular Neurobiology. 54 (6): 4764–4770. doi:10.1007/s12035-016-0019-8. ISSN 0893-7648. PMC 5299093. PMID 27501802.
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