Cerebroprotectant

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 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. 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.[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 benfenit is the duration of protection. A truly effective drug that is tested in a clinical trial where it protects the brain for a longer period of time would be expected to show a greater benefit verses a placebo than the same drug in a different clinical trial where it only protects the brain for a shorter period of time.[18]
Select patients with salvageable tissue
Another element of clinical trial design is the use of imaging biomarkers to select patients that are likely to benefit from therapy. MRI and CT imaging methods that determine whether a patient is likely to have salvageable tissue have been used to great effect in clinical trials that showed the benefit of mechanical thrombectomy devices.[19] These same methods can be applied to clinical trials for cerebroprotective drugs.[18]
Restore blood flow after protection so that protected tissue can survive long term
If a drug protects the brain from reduced blood flow but then wears off before blood flow is normalized, then the long term effect of the drug may not be as great as it would be if the drug were paired with therapy to normalize blood flow. Pairing cerebroprotective drugs with approved methods to restore blood flow, such as tPA or mechanical thrombectomy, may increase their long term benefit.[11][18]

Clinical trials
RankNameFirst TrialMechanism % Protection in Animal Studies (% Reduction in Infarct Volume)Number of Animal Studies from Which % Protection has been CalculatedCommentsFocal ischemic stroke studies with positive resultsFocal ischemic stroke studies showing no changeFocal ischemic stroke studies with negative resultsSources
1Oxygenated fluorocarbon nutrient emulsion (OFNE) or Revoxyn2001Oxygen delivery941A perfluorocarbon emulsion that 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.200[4][20][21]
2Dapsone2007Antibacterial931Two 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.110[22][23][24][25]
3DDFPe, NanO2 or NVX-2082017Oxygen Delivery855Another 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)900[26][27][28][29][30][31]
4Albumin2011Antioxidant Improvement of microcirculation661Albumin therapy was associated with an increase in symptomatic intercranial hemorrhage and pulmonary edema/congestive heart failure.100[32]
5Veripamil2016Calcium channel blocker (Phenylalkylamine calcium channel)662Veripamil was administered immediately after restoration of blood flow.201[33][34][35][36]
6Dextromethorphan2011NMDA ion channel blocker611Trial in 40 patients showed that it is not cerebroprotective, but does not worsen condition or neurological outcome; reduction in seizures, and increase of MI and renal failure versus placebo.100[37][38]
7CP101.606-271999NMDA ion channel blocker613Enrolled patients within 6 hours after stroke, but did not include patients who received tPA. The study was terminated, and the results were not reported.300[39]
8Gavestinel (GV150526A)1999NMDA glycine antagonist6018"The cause of the neutral results with gavestinel remains to be explained. It is possible that the time window to effectively antagonize glutamate is simply less than 6 h, or that the neuroprotective benefit of infarct size reduction in animals does not translate into improved functional outcome measured in clinical trials. Just as likely, however, expectations with gavestinel were over-inflated because only positive preclinical results were published (it is common that negative results in animal studies go unreported). Mild beneficial effects were only seen in carefully standardized stroke models that do not reflect the heterogeneity of stroke patients where more robust efficacy would be needed to achieve clinical significance." 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.860[40][41]
9SP-82032016antioxidant and NMDA receptor antagonist591Phase II in progress in 2018 in patients with product dosed after tPA. Pre-clinical studies showed high level of dose dependency.100[42][43]
10ketamine2014NMDA receptor antagonist571Phase I/II in progress as of 2018100[44][45]
11Hu23F2G (LeukArrest)1999Leukocyte adhesion inhibitor571100
12Donepezil2008selective acetylcholinesterase inhibitor561100[46]
13Repinotan (BAY × 3072)2000Serotonin agonist562200[4]
14Prourokinase1998Antithrombotic55121200[4]
153K3A-APC2014anti-inflammatory548ZZ 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).800[47][48][49][50][51][52][53]
16Granulocytecolony stimulating factor (G-CSF)2003activator of transcription-3 (STAT3) in the periphery of the infarction531No effect - G-CSF did not improve stroke outcome in this individual patient data meta-analysis.900[54][55][56]
17Urokinase1976Thrombolytic53121310[4]
18Atorvastatin2015Statin considered to have favorable impact on blood brain barrier, oxidative stress, cerebral blood flow, and inflammation521Phase IV in progress in China as of 2019100[57][58]
19Deferoxamine2012Iron chelator; bacterial siderophore522Phase II completed but results not published, and no Phase 3 was started.200[59][60][61]
20Caffeinol2002Stimulant, depressant, diuretic Adenosine receptor modulator5110820[4]
21CNS1102 (Cerestat, aptiganel)1994NMDA ion channel blocker51111120[4]
22Dextrorphan1994NMDA ion channel blocker50171360[4]
23JPI-2892017PARP-1 Inhibitor491Jeil Pharmaceutical Co., Ltd, Phase II in progress in Korea as of 2019. Safety and dosing was demonstrated in healthy adults.[62][63]
24Minocycline2007antibiotic491Phase IV terminated due to futility. Enrolled patients up to 48 hours after stroke.200[64]
25Remacemide1994NMDA ion channel blocker491100[4]
26tPA (< 3 hours)1995Thrombolytic499tPA was approved for use up to 3 hours after onset, though the initial tirals up to 6 hours after onset showed no significant improvement. Pre-clinical models showed a beneficial effect of the drug when given up to 3 hours but a detrimental effect when given beyond 3 hours.9100[65]
27Diaspirin cross-linked hemoglobin1998Oxygen delivery Free radical scavenger485510[4]
28Eliprodil (SL 82.0715)1994NMDA polyamine antagonist Sigma ligand484600[4]
29CGS 19755 (selfotel)1995NMDA antagonist472411[4]
30Hypothermia1998Reduce reducing cerebral oxygen demand (CMRO2), Metabolic and synaptic transmission inhibitor.469294280[4]
31Lifarizine (RS-87476)1995Sodium/calcium channel blocker468540[4]
32Glibenclamide (BIIB093, BIIB-093, glibenclamide IV, formerly Cirara or RP-1127).2010selective inhibitor of SUR1-TRPM4 channels that mediate stroke related brain swelling.453As of 2022 Biogen is in Phase III in patients with large infarcts with volumes of 80 to 300 centimeters cubed. These patients tend to have poor outcomes due to the large infarcts.300[66][67][68][69][70]
33MP-1242011PARP-1 Inhibitor442A Phase 1 drug developed by Mitsubishi Tanabe's with an unclear status as of 2019.200[71][72]
34NS1209/SPD 5021999Gluamate antagonist442200[4]
35NXY-0592001Free radical scavenger4327AstraZeneca's drug that completed its second Phase III in 2006, leading to what some called the "nuclear winter" in stroke research. At the time, imaging biomarkers were less developed. Secondly, mechanical thrombectomy was not invented yet, and patients with large vessel occlusions in the trial likely had low reperfusion rates. Furthermore, the pathology is better known today, and the chain of events is better understood. The drug targteted processes that were far downstream in the ischemic cascade thereby giving the drug a weaker clinical signal than many drugs targeting processes further up the ischemic cascade. The first Phase III in 1700 patients saw a significant improvement in mRS (p=0.03), but missed all its secondary endpoints. A second Phase III in 3,300 patients saw no effect in any endpoint.2450[4][73]
36Clomethiazole (CMZ, Zendra)1996GABA agonist427820[4]
37Vinpocetine (ethyl apovincaminate)1986Calcium inhibitor, Vasodilator, Sodium blocker; synthetic derivative of the vinca alkaloid vincamine, an extract from the lesser periwinkle plant.421Results of Phase III published in 2016. Off patent - first made in 1975. A clinical trial in 610 patients in China was completed, showing improved outcomes in NIHSS, and Barthel Index.100[74][75]
38Neu20002016NR2B-selective NMDA receptor antagonist and spin trapping molecule (=free radical scavenger or antioxidant)41.21GNT Pharma. Enrolls only patients with confirmed AIS eligible for MT up to 8 hours after onset. The drug will provide only a short duration of protection before MT restores blood flow, probably averaging an hour or less. If they paused the clock perfectly, they would need thousands of patients to show an effect, so there is risk of failing the Phase II due to having too short of a duration of protection. Therapeutic potential of Neu2000 has been well demonstrated in four animal models of stroke with better efficacy and therapeutic time windows than either NMDA receptor antagonist or anti-oxidant advanced to clinical trials. In human phase I studies of 165 healthy subjects conducted in the United States and China, Neu2000KWL showed promising safety profiles without any serious adverse events.4[76][77]
39Sipatrigine (BW619C89)1995Sodium channel antagonist Glutamate release inhibitor41374040[4]
40NA-1 (TatNR2B9c)2008Postsynaptic density-95 protein inhibitor406NoNO Inc is using an ion channel inhibitor called NA-1 (nerenetide). They recently completed a Phase III clinical trial in Large Vessel Occlusion (LVO) patients undergoing mechanical thrombectomy, but the trial showed neutral results in the overall population. The subset of patients that did not get tPA showed benefit, therefore they are seeking to run another Phase III clinical in LVO patients who are ineligible for tPA and hope to initiate this trial in 2021. They are enrolling in another Phase III trial that enrolls a broad population of stroke patients in the field, and results are expected in 2022.620[78][79][80][81][82][83][84][85]
41AER-2712018inhibitor of Aquaporin-4 (AQP4) water channels391Initiated Phase 1 trial in June 2018. The osmotic imbalance and subsequent influx of water via AQP4 occurs as a result of a lack of oxygen and leads to edema, midline shift, increased intracranial pressure and brain herniation resulting in permanent disability or mortality. Targets the same physiology as Biogen's BIIB-093 (glyburide for incjection or CIRARA), but via a different pathway. Edema is further down the ischemic cascade than hypoxia.000[86]
42Erythropoietin (EPO)2002Controls red blood cell production399Tested again in 2009. Clnical trial showed no significant difference in neurological recovery. Significantly increased mortality rate and safety concerns1120[4]
43ARL 15896 (AR-A15896AR)1999NMDA antagonist39151080[4]
44Piracetam1988AMPA (NA+) modulator395410[4]
45Nafronyl oxalate (naftidrofuryl)1978Serotonin antagonist385620[4]
46ACEA 1021 (licostinel)1997NMDA glycine site antagonist37251960[4]
47Propentofylline (HWA 285)1992Phosphodiesterase inhibitor377920[4]
48S-0139 (SB-737004)1999Endothelin antagonist364310[4]
49PG2 (Polysaccharides of Astragalus membranaceus)2015Chinese Herb, Antiinflammatory361Phase IV clinical trial status unclear.100[87][88]
50Trans sodium crocetinate2018increases diffusion of oxygen3533[89][90][91]
51TNK (tenecteplase)2000Thrombolytic agent352200[4]
52Magnesium Sulfate1993NMDA ion channel blocker. Calcium antagonist3510The first drug tested that had a significant amount of patients dosed in the first 2 hours in the FAST-MAG trial. Phase III results published in 2015 showed no therapeutic benefit.1100[4][92]
53propanolol1988β-adrenergic blockade, Membrane stabilization344Studied most recently in 2013. Phase II/III completed, but results not published.380[4]
54Mannitol1978Hyperosmotic agent. Reduces edema and ICP341910151[4]
55Dextran1969Hemodilution347451[4]
56N-acetyl-cysteine (NAC)2015Free radical scavenger331100[93]
57PS519/MLN5192000Proteasome inhibitor32141130[4]
58Heparin1979Anticoagulant321710103[4]
59FK506 (pacrolimus)2004Immunosuppressant3172Stopped in Phase II, adverse side effects52270[4]
60Neutrophil inhibitory factor (rNIF, UK-279.276)2000Neutrophil inhibitor3112840[4]
61YM90K1997AMPA antagonist31231960[4]
62Aspirin1995Antiplatelet31199130[4]
63Lovastatin (aka simvastatin)2001HMGCoA reductase inhibitor3020Finished recruitment in Phase II trial in 2017, results not published as of 2019.1110[4][94][95]
64Normobaric oxygen treatment2009Oxygen Delivery306Several human studies evaluating normobaric oxygen therapy for stroke treatment have been performed. However, there is not much room to increase oxygen delivery by increasing the concentration of oxygen breathed does not increase the blood oxygen level much. The normal oxygen saturation of red blood cells is 95-99%, and plasma only 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.501[96][97][98][99][100][101]
65Basic fibroblast growth factor (trafermin. Fiblast)1998Growth factor293522190[4]
66Naloxone1981Opioid antagonist297870[4]
67Ebselen2009Free radical scavenger; synthetic organo-selenium antiinflammatory, anti-oxidant and cytoprotective activity; mimic glutathione peroxidase279Tested in Phase III but never reached market, and now out of patent.1060[4]
68BIII-890-CL2001Sodium Channel Blocker276Still in trial in 2014600[4]
69YM8721999AMPA antagonist27322280[4]
70Ebselen (Harmokisane)1998Free radical scavenger2791060[4]
71Abciximab (reopro, c7E3 Fab)1998Antiplatelet: glycoprotein inhibitor272110[4]
72Tirilazad (U74006F)1994Free radical scavenger26161180[4]
73nimodipine1984antihypertensive drug2637May be in clinical trials in China in 2016, but status is unknown. Failed earlier clinical trials.24280[102][103]
74Enoxaparin2003Antithrombotic252512130[4]
75ONO-25062003Astrocyte modulating agent Anenuates extracellular monamine258530[4]
76EGB-761 (Gingko biloba extract)1995MAO inhibitor Antiplatelet.25151330[4]
77Citicoline (CDP choline)1987Membrane precursor, antioxidant2513490[4]
78Edaravone (MCI-186)2001Free radical scavenger nootropic and neuroprotective agent248Approved in Japan.750[104][105]
79Hyperbaric oxygen treatment1966Oxygen delivery24171352[4]
80Indomethacin2001Cyclooxygenase inhibitor232320[4]
81Lubeluzole1994Sodium/calcium channel blocker NOS inhibitor23191380[4]
82Hydroxyethyl starch pentastarch1980Hemodilution233431[4]
83Cyclosporin A2014Immunosuppressant221Not effective in reducing infarct size. However, a smaller infarct size was observed in patients with proximal cerebral arteryocclusion and efficient recanalization.920[106]
84natalizumab2016prevents leukocytes from moving across the blood-brain barrier223Discontinued by Biogen after a Phase II trial showed that natalizumab administered ≤24 hours after acute ischemic stroke did not improve patient outcomes.420[107]
85Anerod1983Fibrinogen depleting214410[4]
86ZK200775 (MPQX)1997AMPA antagonist19211290[4]
87Dexamethasone1971Glucocorticoid, antiinflammatory1911Continued in 2011. Clinical trials showed improvement of level of consciousness was statistically significant in Dexamethasone treated group, but did not reduce volume of hypodense area.781[4]
88Nicaraven (N,N′-propylenedinicotinamide)2001Free radical scavenger174220[4]
89Insulin1993Lowers glucose165412[4]
90ABL-101 (Oxycyte)2018Oxygen Delivery151Developed by Aurum Biosciences, formerly developed by Oxycyte. A perfluorocarbon emulsion that works like a blood substitute.100[108]
91BMS-2043521998Potassium channel opener149710[4]
92Enlimomab (anti–ICAM-1 antibody)1996Leukocyte migration and adhesion inhibitor149671[4]
93Nicardipine1988Calcium antagonist1168100[4]
94Argatroban1986Anticoagulant114330[4]
95TAK-2182001Dopamine suppressor101010[4]
96Paracetemol (Acetaminophen)2009Analgesic/antipyretic COX inhibitor81010[4]
97n-PA/tPA (alteplase)1988Antithrombotic486523811[4]
98Ganglioside GM11984Metabolism, growth41640[4]
99GSK2493202013Antagonises or neutralises myelin associated glycoprotein (MAG) - mediated inhibition01GlaxoSmithKline, discontinued in 2017 after showing no effect at interim analysis.010[109]
100Simvastatin2008HMGCoA reductase inhibitor Antioxidant01No differences were found between treatment arms regarding the primary outcome.010[94][110]
101Baclofen2001GABA-B Antagonist00110[4]
102Amphetamines2003Stimulant-31120[4]
103Papaverine1976Calcium channel blocker-31010[4]
104Flunarizine1990Calcium channel blocker-63411[4]
105Prosatacyclin1984Antiplatelet: eicosanoid Vasodilator-61110[4]
106tPA (>3 hours)1995Thrombolytic-392The data in animals showed benefit below 3 hours after stroke onset and a detrimental effect after three hours (an increase in infarct volume). The data is calculated from the caterpillar plot in figure 1.072[65]
107Streptokinase1963Thrombolytic-5256145[4]
108LT30012019Thrombolytic and antioxidant00Lumosa Therapeutics was running a Phase II clinical trial in 2022000[111]
109TMS-0072014Thrombolytic00Biogen acquired TMS-007 in 2021 after a positive Phase IIa trial.000[112][113]
110GM6022016anti-inflammatory—-Phase II completed, but no Phase III has appeared to have been started. Run by Genervon. No pre-clinical data published.---[114][115]
111Vitamin B22015Causes a Reduction of Glutamate-mediated Excitotoxicity—0Phase II complete, but no results published.000[116]
112Irbesartan2012AT1 receptor antagonist Antihypertensive—-Agent did not appear to substantially modify infarct growth.1--[117][118]
113Lu AA24493 (carbamylated erythropoietin CEPO)2011Controls red blood cell production—-Unknown toxicity claims halted development. Trial run by H. Lundbeck AS---
114NTx-2652009Regeneration; Human Chorionic Gonadotropin (hCG) and Epoetin Alfa (EPO)—-No significant difference in neurological recovery.---[119]
115ILS-9202009Calicum channel blocker—-Now owned by Pfizer, but no longer on Pfizer's pipeline.---[120]
116Eptifibatide (cromafiban; Integrilin)2003Antiplatelet: glycoprotein inhibitor—0000[4]
117Desmoteplase (DSPA)2002Antithrombotic—0000[4]
118S-17462001NMDA glycine/AMPA antagonist—0000[4]
119Tirofiban (MK-383, aggrastat)2001Antiplatelet: glycoprotein inhibitor—0000[4]
120Triflusal (2-acetoxy-4-trifluoromethylbenzonic acid)2001Arachidonic acid metabolism inhibitor (antiplatelet)—0120[4]
121Cerebrolysin2001Nootropic—0A total of 1070 patients were enrolled in this study. Five hundred twenty-nine patients were assigned to Cerebrolysin and 541 to placebo. The confirmatory end point showed no significant difference between the treatment groups. When the predefined stratification by severity was repeated with the criterion NIHSS, however, a small superiority for Cerebrolysin in the sub-group with baseline NIHSS>12 (OR, 1.27; CI-LB, 0.97; P=0.04) could be shown . Also, when applying the mRS, a small superiority in the sub-group with baseline NIHSS>12 (OR, 1.27; CI-LB, 0.90; P=0.09) was found. The following analysis also focused on the subgroup baseline NIHSS>12 points only and provided a global test result for all 3 criteria combined. This global test results in MW=0.53 (CI-LB, 0.47; P=0.16), which showed a beneficial trend for Cerebrolysin in the study patients.110[4][121]
122DP-b99 (DPBAPA)2000Calcium chelator—0Interim futility analysis showed no evidence of efficacy, published in 2008.000[122]
123Diazepam (valium)2000Benzodiazepine—0010[4]
124Certoparin2000Anticoagulant—0000[4]
125Dalteparin2000Anticoagulant—0000[4]
126Radix salviae miltiorrhizae2000Antioxidant Partial endothelin-1 inhibitor—0110[4]
127glyceril trinitrate1999NO donor—-Phase III results published in 2015. ENOS enrolled 4011 participants with acute stroke (within 48 h of onset). Overall, there was no significant shift in functional outcome measured using the modified Rankin Scale at day 90, or of any secondary outcomes. Off patent. $7 per patch.100[123][124][125]
128Candesartan cilexetil (TCV-116, Blopress, CV-11974)1999AT1 receptor antagonist Antihypertensive—-Results published in 2012: no significant difference in neurological recovery; harmful effect suggested---[126]
129Fludrocortisone1999Mineralocorticoid—0000[4]
130LDP-01 (Anti–β-2-integrin antibody)1999Leukocyte adhesion and migration inhibitor—0000[4]
131Nalmefene1998Opioid antagonist—0000[4]
132NPS 15061998NMDA ion channel blocker—0620[4]
133RPR 1098911998Antiplatelet glycoprotein inhibitor—0000[4]
134Tinzaparin1998Anticoagulant—0000[4]
135Org 10172 (danaparoid, Orgaran)1997Antithrombotic—0000[4]
136Semax1997Derivative of ACTH-4-10—0000[4]
137Glycine1996NMDA antagonist—0000[4]
138Fosphentoyn1995Sodium Channel Blocker, Glutemate Release Inhibitor—0Phase III terminated early due to futility.000[127]
139Batroxobin (defibrase, DF-521)1995Fibrinogen depleting—0400[4]
140Nadroparin1995Antithrombotic—0000[4]
141Defibrotide (polydeoxyribonucleotide)1989Antiplatelet: glycoprotein inhibitor—0000[4]
142Atenol (Tenormin)1988Beta blocker—0000[4]
143Corticotrophin1987GABA receptor modulator Pituitary hormone—0000[4]
144PY 108-0681986Calcium antagonist—0200[4]
145Trazodone (Desyrel)1986Serotonin reuptake inhibitor—0000[4]
146Nicergoline1985α2 adrenoceptor agonist—0100[4]
147Nicergoline1985Alpha2 adrenoceptor agonist—0100[4]
148Pentoxifylline1981Improve capillary flow—0010[4]
149Hydergine1978Nootropic, antioxidant.—0000[4]
150Tinofedrine (D 8955, Novocebrin)1978Blood flow, increased metabolism—0000[4]
151Xanthinol nicotinate (Sadamin)1977Vitamin B(3): metabolic enhancer—0000[4]
152Aminophylline1976Phosphodiesterase inhibitor—0000[4]
153Glycerol1972Hyperosmolar agent—0020[4]
154Cyclandelate1966Vasodilator (calcium modulator)—0000[4]

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