Cerebroprotectant
Type of drug intended to protect the brain after stroke onset
From Wikipedia, the free encyclopedia
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]
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 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. | 2 | 0 | 0 | [4][20][21] |
| 2 | Dapsone | 2007 | Antibacterial | 93 | 1 | Inconsistent 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. | 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 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). | 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." | 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 | A 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). | 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 (Ginkgo 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 | Calcium 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] |