stringtranslate.com

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 have been tested in clinical trials to provide cerebroprotection.[2][3][4]

Approved drugs

Drugs in development

Approval rate

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

Methods to increase approval rate

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

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

Clinical trials

References

  1. ^ a b c d Lyden P, Buchan A, Boltze J, Fisher M (August 2021). "Top Priorities for Cerebroprotective Studies-A Paradigm Shift: Report From STAIR XI". Stroke. 52 (9): 3063–3071. doi:10.1161/STROKEAHA.121.034947. PMC 8384700. PMID 34289707.
  2. ^ World Health Organization. "The top 10 causes of death". Retrieved 11 May 2022.
  3. ^ Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. (American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee) (March 2020). "Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association". Circulation. 141 (9): e139–e596. doi:10.1161/CIR.0000000000000757. PMID 31992061. S2CID 210949245.
  4. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn bo bp bq br bs bt bu bv bw bx by bz ca cb cc cd ce cf cg ch ci cj ck cl cm cn co cp cq cr cs ct cu cv cw cx cy cz da db dc dd O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW (March 2006). "1,026 experimental treatments in acute stroke". Annals of Neurology. 59 (3): 467–477. doi:10.1002/ana.20741. PMID 16453316. S2CID 42939489.
  5. ^ Genentech, Inc. "ACTIVASE (alteplase) for injection" (PDF). FDA. Retrieved 11 May 2022.
  6. ^ F. Hoffman-La Roche Ltd. "Finance Report 2021" (PDF). Retrieved 11 May 2022.
  7. ^ Boehringher Ingelheim. "2019 Annual Report" (PDF). Retrieved 11 May 2022.
  8. ^ Lapchak PA (1 July 2010). "A critical assessment of edaravone acute ischemic stroke efficacy trials: is edaravone an effective neuroprotective therapy?". Expert Opinion on Pharmacotherapy. 11 (10): 1753–1763. doi:10.1517/14656566.2010.493558. PMC 2891515. PMID 20491547.
  9. ^ Biotechnology Industry Association. "Clinical Development Success Rates and Contributing Factors 2011-2020" (PDF). Retrieved 11 May 2022.
  10. ^ Munich SA, Vakharia K, Levy EI (July 2019). "Overview of Mechanical Thrombectomy Techniques". Neurosurgery. 85 (suppl_1): S60–S67. doi:10.1093/neuros/nyz071. PMID 31197338.
  11. ^ a b Matei N, Camara J, Zhang JH (2021). "The Next Step in the Treatment of Stroke". Frontiers in Neurology. 11: 582605. doi:10.3389/fneur.2020.582605. PMC 7862333. PMID 33551950.
  12. ^ Vagal A, Aviv R, Sucharew H, Reddy M, Hou Q, Michel P, et al. (September 2018). "Collateral Clock Is More Important Than Time Clock for Tissue Fate". Stroke. 49 (9): 2102–2107. doi:10.1161/STROKEAHA.118.021484. PMC 6206882. PMID 30354992.
  13. ^ Krnjević K (September 1999). "Early effects of hypoxia on brain cell function". Croatian Medical Journal. 40 (3): 375–380. PMID 10411965.
  14. ^ Kaur H, Prakash A, Medhi B (2013). "Drug therapy in stroke: from preclinical to clinical studies". Pharmacology. 92 (5–6): 324–334. doi:10.1159/000356320. PMID 24356194. S2CID 2317118.
  15. ^ Kalogeris T, Baines CP, Krenz M, Korthuis RJ (December 2016). "Ischemia/Reperfusion". Comprehensive Physiology. 7 (1): 113–170. doi:10.1002/cphy.c160006. ISBN 978-0-470-65071-4. PMC 5648017. PMID 28135002.
  16. ^ "Stroke Preclinical Assessment Network (SPAN) FAQs". NINDS. Retrieved 30 May 2022.
  17. ^ Saver JL (January 2006). "Time is brain--quantified". Stroke. 37 (1): 263–266. doi:10.1161/01.STR.0000196957.55928.ab. PMID 16339467. S2CID 24552241.
  18. ^ a b c Fisher M, Savitz SI (April 2022). "Pharmacological brain cytoprotection in acute ischaemic stroke - renewed hope in the reperfusion era". Nature Reviews. Neurology. 18 (4): 193–202. doi:10.1038/s41582-021-00605-6. PMC 8788909. PMID 35079135.
  19. ^ Albers GW (September 2018). "Use of Imaging to Select Patients for Late Window Endovascular Therapy". Stroke. 49 (9): 2256–2260. doi:10.1161/STROKEAHA.118.021011. PMID 30355004. S2CID 53022574.
  20. ^ Bell RD, Powers BL, Brock D, Provencio JJ, Flanders A, Benetiz R, et al. (2006). "Ventriculo-lumbar perfusion in acute ischemic stroke". Neurocritical Care. 5 (1): 21–29. doi:10.1385/NCC:5:1:21. PMID 16960290. S2CID 12607331.
  21. ^ D'Arville C (December 2004). "Partnering: key to early-stage biotech survival, but at what cost?". Biotechnology Healthcare. 1 (6): 26–34. PMC 3570991. PMID 23424295.
  22. ^ Nader-Kawachi J, Góngora-Rivera F, Santos-Zambrano J, Calzada P, Ríos C (April 2007). "Neuroprotective effect of dapsone in patients with acute ischemic stroke: a pilot study". Neurological Research. 29 (3): 331–334. doi:10.1179/016164107X159234. PMID 17509235. S2CID 23075441.
  23. ^ Ríos C, Nader-Kawachi J, Rodriguez-Payán AJ, Nava-Ruiz C (March 2004). "Neuroprotective effect of dapsone in an occlusive model of focal ischemia in rats". Brain Research. 999 (2): 212–215. doi:10.1016/j.brainres.2003.11.040. PMID 14759500. S2CID 6110585.
  24. ^ Wozel G, Blasum C (March 2014). "Dapsone in dermatology and beyond". Archives of Dermatological Research. 306 (2): 103–124. doi:10.1007/s00403-013-1409-7. PMC 3927068. PMID 24310318.
  25. ^ Diaz-Ruiz A, Roldan-Valadez E, Ortiz-Plata A, Mondragón-Lozano R, Heras-Romero Y, Mendez-Armenta M, et al. (September 2016). "Dapsone improves functional deficit and diminishes brain damage evaluated by 3-Tesla magnetic resonance image after transient cerebral ischemia and reperfusion in rats". Brain Research. 1646: 384–392. doi:10.1016/j.brainres.2016.06.023. PMID 27321157. S2CID 25685864.
  26. ^ Culp WC, Woods SD, Skinner RD, Brown AT, Lowery JD, Johnson JL, et al. (January 2012). "Dodecafluoropentane emulsion decreases infarct volume in a rabbit ischemic stroke model". Journal of Vascular and Interventional Radiology. 23 (1): 116–121. doi:10.1016/j.jvir.2011.10.001. PMC 3253225. PMID 22079515.
  27. ^ Woods SD, Skinner RD, Ricca AM, Brown AT, Lowery JD, Borrelli MJ, et al. (October 2013). "Progress in dodecafluoropentane emulsion as a neuroprotective agent in a rabbit stroke model". Molecular Neurobiology. 48 (2): 363–367. doi:10.1007/s12035-013-8495-6. PMC 3787698. PMID 23813100.
  28. ^ Brown AT, Arthur MC, Nix JS, Montgomery JA, Skinner RD, Roberson PK, et al. (2014-12-30). "Dodecafluoropentane Emulsion (DDFPe) Decreases Stroke Size and Improves Neurological Scores in a Permanent Occlusion Rat Stroke Model". The Open Neurology Journal. 8: 27–33. doi:10.2174/1874205X01408010027. PMC 4321204. PMID 25674164.
  29. ^ Culp WC, Brown AT, Lowery JD, Arthur MC, Roberson PK, Skinner RD (October 2015). "Dodecafluoropentane Emulsion Extends Window for tPA Therapy in a Rabbit Stroke Model". Molecular Neurobiology. 52 (2): 979–984. doi:10.1007/s12035-015-9243-x. PMC 4998836. PMID 26055229.
  30. ^ Arthur MC, Brown A, Carlson K, Lowery J, Skinner RD, Culp WC (August 2017). "Dodecafluoropentane Improves Neurological Function Following Anterior Ischemic Stroke". Molecular Neurobiology. 54 (6): 4764–4770. doi:10.1007/s12035-016-0019-8. PMC 5299093. PMID 27501802.
  31. ^ Culp WC, Onteddu SS, Brown A, Nalleballe K, Sharma R, Skinner RD, et al. (August 2019). "Dodecafluoropentane Emulsion in Acute Ischemic Stroke: A Phase Ib/II Randomized and Controlled Dose-Escalation Trial". Journal of Vascular and Interventional Radiology. 30 (8): 1244–1250.e1. doi:10.1016/j.jvir.2019.04.020. PMID 31349978. S2CID 198933339.
  32. ^ Belayev L, Zhao W, Pattany PM, Weaver RG, Huh PW, Lin B, et al. (December 1998). "Diffusion-weighted magnetic resonance imaging confirms marked neuroprotective efficacy of albumin therapy in focal cerebral ischemia". Stroke. 29 (12): 2587–2599. doi:10.1161/01.str.29.12.2587. PMID 9836772. S2CID 10997469.
  33. ^ Hosaka T, Yamamoto YL, Diksic M (December 1991). "Efficacy of retrograde perfusion of the cerebral vein with verapamil after focal ischemia in rat brain". Stroke. 22 (12): 1562–1566. doi:10.1161/01.STR.22.12.1562. PMID 1962332. S2CID 8924213.
  34. ^ Roy MW, Dempsey RJ, Meyer KL, Donaldson DL, Tibbs PA, Young AB (December 1985). "Effects of verapamil and diltiazem on acute stroke in cats". Journal of Neurosurgery. 63 (6): 929–936. doi:10.3171/jns.1985.63.6.0929. PMID 4056906.
  35. ^ Maniskas ME, Roberts JM, Aron I, Fraser JF, Bix GJ (April 2016). "Stroke neuroprotection revisited: Intra-arterial verapamil is profoundly neuroprotective in experimental acute ischemic stroke". Journal of Cerebral Blood Flow and Metabolism. 36 (4): 721–730. doi:10.1177/0271678X15608395. PMC 4821022. PMID 26661189.
  36. ^ Clinical trial number NCT02235558 for "Super-Selective Intra-Arterial Administration of Verapamil for Neuroprotection After Intra-Arterial Thrombolysis for Acute Ischemic Stroke Phase I Study" at ClinicalTrials.gov
  37. ^ Britton P, Lu XC, Laskosky MS, Tortella FC (1997). "Dextromethorphan protects against cerebral injury following transient, but not permanent, focal ischemia in rats". Life Sciences. 60 (20): 1729–1740. doi:10.1016/s0024-3205(97)00132-x. PMID 9150412.
  38. ^ Mousavi SA, Saadatnia M, Khorvash F, Hoseini T, Sariaslani P (June 2011). "Evaluation of the neuroprotective effect of dextromethorphan in the acute phase of ischaemic stroke". Archives of Medical Science. 7 (3): 465–469. doi:10.5114/aoms.2011.23413. PMC 3258743. PMID 22295030.
  39. ^ Clinical trial number Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy and Safety of a 72-Hour Infusion of CP-101,606 in Subjects With Acute Ischemic Stroke. NCT00073476A Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy and Safety of a 72-Hour Infusion of CP-101,606 in Subjects With Acute Ischemic Stroke. at ClinicalTrials.gov
  40. ^ Sacco RL, DeRosa JT, Haley EC, Levin B, Ordronneau P, Phillips SJ, et al. (April 2001). "Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial". JAMA. 285 (13): 1719–1728. doi:10.1001/jama.285.13.1719. PMID 11277826.
  41. ^ Labiche LA, Grotta JC (January 2004). "Clinical trials for cytoprotection in stroke". NeuroRx. 1 (1): 46–70. doi:10.1602/neurorx.1.1.46. PMC 534912. PMID 15717007.
  42. ^ Noh SJ, Lee SH, Shin KY, Lee CK, Cho IH, Kim HS, et al. (March 2011). "SP-8203 reduces oxidative stress via SOD activity and behavioral deficit in cerebral ischemia". Pharmacology, Biochemistry, and Behavior. 98 (1): 150–154. doi:10.1016/j.pbb.2010.12.014. PMID 21172384. S2CID 37640897.
  43. ^ Clinical trial number NCT02787278 for "A Prospective, Randomized, Double-blinded Phase IIa Clinical Trial to Investigate the Safety and Efficacy of Two Doses of SP-8203 in Patients With Ischemic Stroke Requiring rtPA Standard of Care" at ClinicalTrials.gov
  44. ^ Gakuba C, Gauberti M, Mazighi M, Defer G, Hanouz JL, Vivien D (October 2011). "Preclinical evidence toward the use of ketamine for recombinant tissue-type plasminogen activator-mediated thrombolysis under anesthesia or sedation". Stroke. 42 (10): 2947–2949. doi:10.1161/STROKEAHA.111.620468. PMID 21817137. S2CID 2847553.
  45. ^ Clinical trial number NCT02258204 for "Effets de la kétamine en Association Avec le Rt-PA au Cours de l'Infarctus cérébral Aigu: étude Pilote contrôlée randomisée en Double Aveugle Avec critère de Jugement Radiologique" at ClinicalTrials.gov
  46. ^ Fujiki M, Kobayashi H, Uchida S, Inoue R, Ishii K (May 2005). "Neuroprotective effect of donepezil, a nicotinic acetylcholine-receptor activator, on cerebral infarction in rats". Brain Research. 1043 (1–2): 236–241. doi:10.1016/j.brainres.2005.02.063. PMID 15862539. S2CID 27373206.
  47. ^ Wang Y, Zhao Z, Chow N, Rajput PS, Griffin JH, Lyden PD, et al. (December 2013). "Activated protein C analog protects from ischemic stroke and extends the therapeutic window of tissue-type plasminogen activator in aged female mice and hypertensive rats". Stroke. 44 (12): 3529–3536. doi:10.1161/STROKEAHA.113.003350. PMC 3912991. PMID 24159062.
  48. ^ Shibata M, Kumar SR, Amar A, Fernandez JA, Hofman F, Griffin JH, et al. (April 2001). "Anti-inflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke". Circulation. 103 (13): 1799–1805. doi:10.1161/01.CIR.103.13.1799. PMID 11282913. S2CID 15027502.
  49. ^ Cheng T, Liu D, Griffin JH, Fernández JA, Castellino F, Rosen ED, et al. (March 2003). "Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective". Nature Medicine. 9 (3): 338–342. doi:10.1038/nm826. PMID 12563316. S2CID 306232.
  50. ^ Wang Y, Sinha RK, Mosnier LO, Griffin JH, Zlokovic BV (August 2013). "Neurotoxicity of the anticoagulant-selective E149A-activated protein C variant after focal ischemic stroke in mice". Blood Cells, Molecules & Diseases. 51 (2): 104–108. doi:10.1016/j.bcmd.2013.02.009. PMC 3812054. PMID 23541526.
  51. ^ Wang Y, Zhao Z, Chow N, Ali T, Griffin JH, Zlokovic BV (April 2013). "Activated protein C analog promotes neurogenesis and improves neurological outcome after focal ischemic stroke in mice via protease activated receptor 1". Brain Research. 1507: 97–104. doi:10.1016/j.brainres.2013.02.023. PMC 3739836. PMID 23438513.
  52. ^ Wang Y, Zhang Z, Chow N, Davis TP, Griffin JH, Chopp M, et al. (September 2012). "An activated protein C analog with reduced anticoagulant activity extends the therapeutic window of tissue plasminogen activator for ischemic stroke in rodents". Stroke. 43 (9): 2444–2449. doi:10.1161/STROKEAHA.112.658997. PMC 3429704. PMID 22811462.
  53. ^ Wang Y, Thiyagarajan M, Chow N, Singh I, Guo H, Davis TP, et al. (May 2009). "Differential neuroprotection and risk for bleeding from activated protein C with varying degrees of anticoagulant activity". Stroke. 40 (5): 1864–1869. doi:10.1161/STROKEAHA.108.536680. PMC 2691176. PMID 19057019.
  54. ^ Schäbitz WR, Kollmar R, Schwaninger M, Juettler E, Bardutzky J, Schölzke MN, et al. (March 2003). "Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia". Stroke. 34 (3): 745–751. doi:10.1161/01.STR.0000057814.70180.17. PMID 12624302. S2CID 9993275.
  55. ^ Minnerup J, Sevimli S, Schäbitz WR (October 2009). "Granulocyte-colony stimulating factor for stroke treatment: mechanisms of action and efficacy in preclinical studies". Experimental & Translational Stroke Medicine. 1 (1): 2. doi:10.1186/2040-7378-1-2. PMC 2816868. PMID 20142989.
  56. ^ England TJ, Sprigg N, Alasheev AM, Belkin AA, Kumar A, Prasad K, et al. (November 2016). "Granulocyte-Colony Stimulating Factor (G-CSF) for stroke: an individual patient data meta-analysis". Scientific Reports. 6: 36567. Bibcode:2016NatSR...636567E. doi:10.1038/srep36567. PMC 5109224. PMID 27845349.
  57. ^ Hong H, Zeng JS, Kreulen DL, Kaufman DI, Chen AF (November 2006). "Atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in ischemic stroke". American Journal of Physiology. Heart and Circulatory Physiology. 291 (5): H2210–H2215. doi:10.1152/ajpheart.01270.2005. PMID 16766636. S2CID 11908429.
  58. ^ Clinical trial number NCT02452502 for "The Safety and Efficacy Study of High Dose Atorvastatin After Thrombolytic Treatment in Acute Ischemic Stroke" at ClinicalTrials.gov
  59. ^ Xing Y, Hua Y, Keep RF, Xi G (September 2009). "Effects of deferoxamine on brain injury after transient focal cerebral ischemia in rats with hyperglycemia". Brain Research. 1291: 113–121. doi:10.1016/j.brainres.2009.07.032. PMC 2737516. PMID 19631616.
  60. ^ Hanson LR, Roeytenberg A, Martinez PM, Coppes VG, Sweet DC, Rao RJ, et al. (September 2009). "Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke". The Journal of Pharmacology and Experimental Therapeutics. 330 (3): 679–686. doi:10.1124/jpet.108.149807. PMC 2729791. PMID 19509317.
  61. ^ Clinical trial number NCT00777140 for "Double-blind, Randomized, Placebo Controlled, Dose-finding Phase 2 Clinical Trial of Intravenous Deferoxamine in Patients With Acute Ischemic Stroke Treated With Tissue Plasminogen Activator" at ClinicalTrials.gov
  62. ^ Kim Y, Kim YS, Noh MY, Lee H, Joe B, Kim HY, et al. (June 2017). "Neuroprotective effects of a novel poly (ADP-ribose) polymerase-1 inhibitor, JPI-289, in hypoxic rat cortical neurons". Clinical and Experimental Pharmacology & Physiology. 44 (6): 671–679. doi:10.1111/1440-1681.12757. PMID 28370165. S2CID 32162935.
  63. ^ Clinical trial number NCT03062397 for "A Multi-center, Randomized, Double-blind, Placebo-controlled, Phase IIa Clinical Trial to Evaluate the Efficacy and Safety of JPI-289 in Patients With Acute Ischemic Stroke" at ClinicalTrials.gov
  64. ^ Xu L, Fagan SC, Waller JL, Edwards D, Borlongan CV, Zheng J, et al. (April 2004). "Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats". BMC Neurology. 4: 7. doi:10.1186/1471-2377-4-7. PMC 415551. PMID 15109399.
  65. ^ a b Orset C, Haelewyn B, Allan SM, Ansar S, Campos F, Cho TH, et al. (May 2016). "Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke: A Retrospective Pooled Analysis". Stroke. 47 (5): 1312–1318. doi:10.1161/STROKEAHA.116.012238. PMC 4846545. PMID 27032444.
  66. ^ Simard JM, Chen M, Tarasov KV, Bhatta S, Ivanova S, Melnitchenko L, et al. (April 2006). "Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke". Nature Medicine. 12 (4): 433–440. doi:10.1038/nm1390. PMC 2740734. PMID 16550187.
  67. ^ Simard JM, Sheth KN, Kimberly WT, Stern BJ, del Zoppo GJ, Jacobson S, et al. (April 2014). "Glibenclamide in cerebral ischemia and stroke". Neurocritical Care. 20 (2): 319–333. doi:10.1007/s12028-013-9923-1. PMC 3954940. PMID 24132564.
  68. ^ Wali B, Ishrat T, Atif F, Hua F, Stein DG, Sayeed I (2012). "Glibenclamide Administration Attenuates Infarct Volume, Hemispheric Swelling, and Functional Impairments following Permanent Focal Cerebral Ischemia in Rats". Stroke Research and Treatment. 2012: 460909. doi:10.1155/2012/460909. PMC 3440943. PMID 22988544.
  69. ^ Ortega FJ, Gimeno-Bayon J, Espinosa-Parrilla JF, Carrasco JL, Batlle M, Pugliese M, et al. (May 2012). "ATP-dependent potassium channel blockade strengthens microglial neuroprotection after hypoxia-ischemia in rats". Experimental Neurology. 235 (1): 282–296. doi:10.1016/j.expneurol.2012.02.010. hdl:2445/34278. PMID 22387180. S2CID 4828181.
  70. ^ Clinical trial number NCT02864953 for "Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Phase 3 Study to Evaluate the Efficacy and Safety of Intravenous BIIB093 (Glibenclamide) for Severe Cerebral Edema Following Large Hemispheric Infarction" at ClinicalTrials.gov
  71. ^ Matsuura S, Egi Y, Yuki S, Horikawa T, Satoh H, Akira T (September 2011). "MP-124, a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor, ameliorates ischemic brain damage in a non-human primate model". Brain Research. 1410: 122–131. doi:10.1016/j.brainres.2011.05.069. PMID 21741620. S2CID 22390945.
  72. ^ Egi Y, Matsuura S, Maruyama T, Fujio M, Yuki S, Akira T (May 2011). "Neuroprotective effects of a novel water-soluble poly(ADP-ribose) polymerase-1 inhibitor, MP-124, in in vitro and in vivo models of cerebral ischemia". Brain Research. 1389: 169–176. doi:10.1016/j.brainres.2011.03.031. PMID 21420942. S2CID 20524045.
  73. ^ Dirnagl U, Macleod MR (August 2009). "Stroke research at a road block: the streets from adversity should be paved with meta-analysis and good laboratory practice". British Journal of Pharmacology. 157 (7): 1154–1156. doi:10.1111/j.1476-5381.2009.00211.x. PMC 2743833. PMID 19664136.
  74. ^ Clinical trial number NCT01400035 for "The Investigation of Vinpocetine (Cavinton) for Treatment of Acute Cerebral Infarction, an Open, Multicenter, Randomized, Control Study" at ClinicalTrials.gov
  75. ^ Zhang W, Huang Y, Li Y, Tan L, Nao J, Hu H, et al. (September 2016). "Efficacy and Safety of Vinpocetine as Part of Treatment for Acute Cerebral Infarction: A Randomized, Open-Label, Controlled, Multicenter CAVIN (Chinese Assessment for Vinpocetine in Neurology) Trial". Clinical Drug Investigation. 36 (9): 697–704. doi:10.1007/s40261-016-0415-x. PMID 27283947. S2CID 207484127.
  76. ^ Clinical trial number NCT02831088 for "A Phase II, Double-blind, Randomized, Placebo-controlled, Multi-center Study to Assess Efficacy and Safety of Neu2000KWL in Patients With Acute Ischemic Stroke Receiving Endovascular Therapy" at ClinicalTrials.gov
  77. ^ Springer JE, Rao RR, Lim HR, Cho SI, Moon GJ, Lee HY, et al. (January 2010). "The functional and neuroprotective actions of Neu2000, a dual-acting pharmacological agent, in the treatment of acute spinal cord injury". Journal of Neurotrauma. 27 (1): 139–149. doi:10.1089/neu.2009.0952. PMC 3525902. PMID 19772458.
  78. ^ Milani D, Cross JL, Anderton RS, Blacker DJ, Knuckey NW, Meloni BP (January 2017). "Neuroprotective efficacy of poly-arginine R18 and NA-1 (TAT-NR2B9c) peptides following transient middle cerebral artery occlusion in the rat". Neuroscience Research. 114: 9–15. doi:10.1016/j.neures.2016.09.002. PMID 27639457. S2CID 23400287.
  79. ^ Sun HS, Doucette TA, Liu Y, Fang Y, Teves L, Aarts M, et al. (September 2008). "Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat". Stroke. 39 (9): 2544–2553. doi:10.1161/STROKEAHA.107.506048. PMID 18617669. S2CID 6500196.
  80. ^ Soriano FX, Martel MA, Papadia S, Vaslin A, Baxter P, Rickman C, et al. (October 2008). "Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand". The Journal of Neuroscience. 28 (42): 10696–10710. doi:10.1523/JNEUROSCI.1207-08.2008. PMC 2602846. PMID 18923045.
  81. ^ Teves LM, Cui H, Tymianski M (March 2016). "Efficacy of the PSD95 inhibitor Tat-NR2B9c in mice requires dose translation between species". Journal of Cerebral Blood Flow and Metabolism. 36 (3): 555–561. doi:10.1177/0271678X15612099. PMC 4794097. PMID 26661213.
  82. ^ Hill MD, Martin RH, Mikulis D, Wong JH, Silver FL, terBrugge KG, et al. (2012-11-01). "Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial". The Lancet Neurology. 11 (11): 942–950. doi:10.1016/S1474-4422(12)70225-9. ISSN 1474-4422. PMID 23051991. S2CID 19169136.
  83. ^ Cook DJ, Teves L, Tymianski M (February 2012). "Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain". Nature. 483 (7388): 213–217. Bibcode:2012Natur.483..213C. doi:10.1038/nature10841. PMID 22388811. S2CID 4334868.
  84. ^ Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, et al. (October 2002). "Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions". Science. 298 (5594): 846–850. Bibcode:2002Sci...298..846A. doi:10.1126/science.1072873. PMID 12399596. S2CID 35409678.
  85. ^ Bråtane BT, Cui H, Cook DJ, Bouley J, Tymianski M, Fisher M (November 2011). "Neuroprotection by freezing ischemic penumbra evolution without cerebral blood flow augmentation with a postsynaptic density-95 protein inhibitor". Stroke. 42 (11): 3265–3270. doi:10.1161/STROKEAHA.111.618801. PMID 21903963. S2CID 1799582.
  86. ^ Yao X, Derugin N, Manley GT, Verkman AS (January 2015). "Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia". Neuroscience Letters. 584: 368–372. doi:10.1016/j.neulet.2014.10.040. PMC 4737527. PMID 25449874.
  87. ^ Liu G, Song J, Guo Y, Wang T, Zhou Z (October 2013). "Astragalus injection protects cerebral ischemic injury by inhibiting neuronal apoptosis and the expression of JNK3 after cerebral ischemia reperfusion in rats". Behavioral and Brain Functions. 9: 36. doi:10.1186/1744-9081-9-36. PMC 3850702. PMID 24083559.
  88. ^ Clinical trial number NCT01554787 for "Randomized, Double Blind, Placebo Control Trial to Evaluate the Efficacy of Astragalus Membranaceus in the Patients After Stroke With Fatigue" at ClinicalTrials.gov
  89. ^ Wang Y, Yoshimura R, Manabe H, Schretter C, Clarke R, Cai Y, et al. (October 2014). "Trans-sodium crocetinate improves outcomes in rodent models of occlusive and hemorrhagic stroke". Brain Research. 1583: 245–254. doi:10.1016/j.brainres.2014.08.013. PMC 4170841. PMID 25128603.
  90. ^ Manabe H, Okonkwo DO, Gainer JL, Clarke RH, Lee KS (October 2010). "Protection against focal ischemic injury to the brain by trans-sodium crocetinate. Laboratory investigation". Journal of Neurosurgery. 113 (4): 802–809. doi:10.3171/2009.10.JNS09562. PMC 3380430. PMID 19961314.
  91. ^ Deng J, Xiong L, Zuo Z (April 2015). "Trans-sodium crocetinate provides neuroprotection against cerebral ischemia and reperfusion in obese mice". Journal of Neuroscience Research. 93 (4): 615–622. doi:10.1002/jnr.23522. PMC 4329099. PMID 25491171.
  92. ^ Saver JL, Starkman S, Eckstein M, Stratton SJ, Pratt FD, Hamilton S, et al. (February 2015). "Prehospital use of magnesium sulfate as neuroprotection in acute stroke". The New England Journal of Medicine. 372 (6): 528–536. doi:10.1056/NEJMoa1408827. PMC 4920545. PMID 25651247.
  93. ^ Khan M, Sekhon B, Jatana M, Giri S, Gilg AG, Sekhon C, et al. (May 2004). "Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke". Journal of Neuroscience Research. 76 (4): 519–527. doi:10.1002/jnr.20087. PMID 15114624. S2CID 38505912.
  94. ^ a b Shehadah A, Chen J, Cui X, Roberts C, Lu M, Chopp M (July 2010). "Combination treatment of experimental stroke with Niaspan and Simvastatin, reduces axonal damage and improves functional outcome". Journal of the Neurological Sciences. 294 (1–2): 107–111. doi:10.1016/j.jns.2010.03.020. PMC 2885546. PMID 20451219.
  95. ^ Clinical trial number NCT01976936 for "A Phase 2 Safety Study in Which Ischemic Stroke Patients Will be Randomized Within 24 Hours of Symptom Onset to Placebo or Oral Lovastatin 640 mg Per Day for 3 Days. " at ClinicalTrials.gov
  96. ^ Henninger N, Bouley J, Nelligan JM, Sicard KM, Fisher M (September 2007). "Normobaric hyperoxia delays perfusion/diffusion mismatch evolution, reduces infarct volume, and differentially affects neuronal cell death pathways after suture middle cerebral artery occlusion in rats". Journal of Cerebral Blood Flow and Metabolism. 27 (9): 1632–1642. doi:10.1038/sj.jcbfm.9600463. PMID 17311078. S2CID 34948648.
  97. ^ Chen C, Cui H, Li Z, Wang R, Zhou C (November 2013). "Normobaric oxygen for cerebral ischemic injury". Neural Regeneration Research. 8 (31): 2885–2894. doi:10.3969/j.issn.1673-5374.2013.31.001 (inactive 2024-04-26). PMC 4146175. PMID 25206609.{{cite journal}}: CS1 maint: DOI inactive as of April 2024 (link)
  98. ^ Singhal AB, Wang X, Sumii T, Mori T, Lo EH (July 2002). "Effects of normobaric hyperoxia in a rat model of focal cerebral ischemia-reperfusion". Journal of Cerebral Blood Flow and Metabolism. 22 (7): 861–868. doi:10.1097/00004647-200207000-00011. PMID 12142571. S2CID 43081106.
  99. ^ Pasban E, Panahpour H, Vahdati A (June 2017). "Early oxygen therapy does not protect the brain from vasogenic edema following acute ischemic stroke in adult male rats". Scientific Reports. 7 (1): 3221. Bibcode:2017NatSR...7.3221P. doi:10.1038/s41598-017-02748-3. PMC 5468255. PMID 28607351.
  100. ^ Shin HK, Dunn AK, Jones PB, Boas DA, Lo EH, Moskowitz MA, et al. (June 2007). "Normobaric hyperoxia improves cerebral blood flow and oxygenation, and inhibits peri-infarct depolarizations in experimental focal ischaemia". Brain. 130 (Pt 6): 1631–1642. doi:10.1093/brain/awm071. PMC 3023418. PMID 17468117.
  101. ^ Roffe C, Nevatte T, Sim J, Bishop J, Ives N, Ferdinand P, et al. (September 2017). "Effect of Routine Low-Dose Oxygen Supplementation on Death and Disability in Adults With Acute Stroke: The Stroke Oxygen Study Randomized Clinical Trial". JAMA. 318 (12): 1125–1135. doi:10.1001/jama.2017.11463. PMC 5818819. PMID 28973619.
  102. ^ Clinical trial number NCT02248233 for "Nimodipine for Treating Acute Massive Cerebral Infarction: a Randomized, Double-blind, Controlled Clinical Study" at ClinicalTrials.gov
  103. ^ Clinical trial number NCT01220622 for "Nimodipine Preventing Cognitive Impairment in Ischemic Cerebrovascular Events: A Randomized, Placebo-Controlled, Double-Blind Trial (NICE)" at ClinicalTrials.gov
  104. ^ Clinical trial number NCT02430350 for "Compound Edaravone Injection for Acute Ischemic Stroke, a Multi-center, Randomized, Double-blind, Parallel, and Active-controlled Phase III Trial" at ClinicalTrials.gov
  105. ^ Xu J, Wang A, Meng X, Yalkun G, Xu A, Gao Z, et al. (March 2021). "Edaravone Dexborneol Versus Edaravone Alone for the Treatment of Acute Ischemic Stroke: A Phase III, Randomized, Double-Blind, Comparative Trial". Stroke. 52 (3): 772–780. doi:10.1161/STROKEAHA.120.031197. PMID 33588596. S2CID 231937405.
  106. ^ Nighoghossian N, Ovize M, Mewton N, Ong E, Cho TH (2016). "Cyclosporine A, a Potential Therapy of Ischemic Reperfusion Injury. A Common History for Heart and Brain". Cerebrovascular Diseases. 42 (5–6): 309–318. doi:10.1159/000446850. PMID 27245840. S2CID 25272164.
  107. ^ "Biogen Reports Top-Line Results from Phase 2b Study of Natalizumab in Acute Ischemic Stroke | Biogen". media.biogen.com. Retrieved 2022-06-02.
  108. ^ Woitzik J, Weinzierl N, Schilling L (July 2005). "Early administration of a second-generation perfluorochemical decreases ischemic brain damage in a model of permanent middle cerebral artery occlusion in the rat". Neurological Research. 27 (5): 509–515. doi:10.1179/016164105X15677. PMID 15978177. S2CID 21813111.
  109. ^ Barbay S, Plautz EJ, Zoubina E, Frost SB, Cramer SC, Nudo RJ (June 2015). "Effects of postinfarct myelin-associated glycoprotein antibody treatment on motor recovery and motor map plasticity in squirrel monkeys". Stroke. 46 (6): 1620–1625. doi:10.1161/STROKEAHA.114.008088. PMID 25931462. S2CID 9317407.
  110. ^ Montaner J, Bustamante A, García-Matas S, Martínez-Zabaleta M, Jiménez C, de la Torre J, et al. (November 2016). "Combination of Thrombolysis and Statins in Acute Stroke Is Safe: Results of the STARS Randomized Trial (Stroke Treatment With Acute Reperfusion and Simvastatin)". Stroke. 47 (11): 2870–2873. doi:10.1161/STROKEAHA.116.014600. PMID 27758944. S2CID 3704362.
  111. ^ Clinical trial number NCT04091945 for "A Phase IIa, Double-Blind, Single Dose, Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Potential Efficacy of LT3001 Drug Product in Subjects With Acute Ischemic Stroke (AIS) " at ClinicalTrials.gov
  112. ^ "臨床試験情報詳細画面 | 一般財団法人日本医薬情報センター 臨床試験情報". www.clinicaltrials.jp. Retrieved 2022-06-02.
  113. ^ Fierce Biotech (12 May 2021). "Biogen buys midphase drug to challenge Roche for stroke market".
  114. ^ "Genervon Pipeline".
  115. ^ Clinical trial number NCT01221246 for "A Phase 2 Double Blinded, Randomized, Placebo Controlled Dose Escalation Study to Evaluate the Efficacy and the Safety of GM602 in Patients With Acute Middle Cerebral Artery Ischemic Stroke Within an 18-hour Treatment Window" at ClinicalTrials.gov
  116. ^ Clinical trial number NCT02446977 for "Randomized Clinical Trial to Investigate Whether Administration of CBG000592 (Riboflavin/Vitamin B2) in Patients With Acute Ischemic Stroke Causes a Reduction of Glutamate-mediated Excitotoxicity " at ClinicalTrials.gov
  117. ^ Beer C, Blacker D, Bynevelt M, Hankey GJ, Puddey IB (February 2012). "A randomized placebo controlled trial of early treatment of acute ischemic stroke with atorvastatin and irbesartan". International Journal of Stroke. 7 (2): 104–111. doi:10.1111/j.1747-4949.2011.00653.x. PMID 22044557. S2CID 21245997.
  118. ^ Pratap R, Pillai KK, Khanam R, Islam F, Ahmad SJ, Akhtar M (May 2011). "Protective effect of irbesartan, an angiotensin II receptor antagonist, alone and in combination with aspirin on middle cerebral artery occlusion model of focal cerebral ischemia in rats". Human & Experimental Toxicology. 30 (5): 354–362. Bibcode:2011HETox..30..354P. doi:10.1177/0960327110371257. PMID 20488839. S2CID 1651465.
  119. ^ "Stem Cell Therapeutics Stroke Drug, NTx-265 Fails Phase 2 Trial". BioSpace. Retrieved 2022-06-03.
  120. ^ Clinical trial number NCT00827190 for "Ascending Single Dose Study Of The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of ILS-920 Administered Intravenously To Healthy Adult Subjects" at ClinicalTrials.gov
  121. ^ "Clinical efficacy in stroke". www.cerebrolysin.com. Retrieved 2022-06-03.
  122. ^ Diener HC, Schneider D, Lampl Y, Bornstein NM, Kozak A, Rosenberg G (June 2008). "DP-b99, a membrane-activated metal ion chelator, as neuroprotective therapy in ischemic stroke". Stroke. 39 (6): 1774–1778. doi:10.1161/STROKEAHA.107.506378. PMID 18403736. S2CID 19228032.
  123. ^ Clinical trial number NCT01811693 for "The Field Administration of Stroke Therapy-Blood Pressure Lowering Pilot Trial" at ClinicalTrials.gov
  124. ^ Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA (September 1994). "Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase". Science. 265 (5180): 1883–1885. Bibcode:1994Sci...265.1883H. doi:10.1126/science.7522345. PMID 7522345.
  125. ^ Bath P, Woodhouse L, Scutt P, Krishnan K, Wardlaw J, Bereczki D, et al. (ENOS Trial Investigators) (February 2015). "Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial". Lancet. 385 (9968): 617–628. doi:10.1016/S0140-6736(14)61121-1. PMC 4343308. PMID 25465108.
  126. ^ Lapchak PA, Zhang JH (2017-01-12). Neuroprotective Therapy for Stroke and Ischemic Disease. Springer. ISBN 978-3-319-45345-3.
  127. ^ Cheng YD, Al-Khoury L, Zivin JA (January 2004). "Neuroprotection for ischemic stroke: two decades of success and failure". NeuroRx. 1 (1): 36–45. doi:10.1602/neurorx.1.1.36. PMC 534911. PMID 15717006.