ES2690994T3 - Terapia de combinación para isquemia - Google Patents
Terapia de combinación para isquemia Download PDFInfo
- Publication number
- ES2690994T3 ES2690994T3 ES12802409.8T ES12802409T ES2690994T3 ES 2690994 T3 ES2690994 T3 ES 2690994T3 ES 12802409 T ES12802409 T ES 12802409T ES 2690994 T3 ES2690994 T3 ES 2690994T3
- Authority
- ES
- Spain
- Prior art keywords
- psd
- ischemia
- reperfusion
- peptide
- inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 208000028867 ischemia Diseases 0.000 title claims abstract description 86
- 238000002648 combination therapy Methods 0.000 title description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 154
- 230000010410 reperfusion Effects 0.000 claims abstract description 135
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 94
- 238000011282 treatment Methods 0.000 claims abstract description 67
- 229940123119 PSD-95 Inhibitor Drugs 0.000 claims abstract description 60
- 230000000302 ischemic effect Effects 0.000 claims abstract description 28
- 210000003169 central nervous system Anatomy 0.000 claims abstract description 25
- 239000003112 inhibitor Substances 0.000 claims abstract description 23
- 108700019745 Disks Large Homolog 4 Proteins 0.000 claims abstract description 20
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract description 17
- 230000009931 harmful effect Effects 0.000 claims abstract description 15
- 230000000740 bleeding effect Effects 0.000 claims abstract description 14
- 238000004458 analytical method Methods 0.000 claims abstract description 12
- 239000012528 membrane Substances 0.000 claims abstract description 9
- 230000008499 blood brain barrier function Effects 0.000 claims abstract description 5
- 210000001218 blood-brain barrier Anatomy 0.000 claims abstract description 5
- 230000008384 membrane barrier Effects 0.000 claims abstract 2
- 208000006011 Stroke Diseases 0.000 claims description 128
- 239000003795 chemical substances by application Substances 0.000 claims description 74
- 210000004556 brain Anatomy 0.000 claims description 57
- 230000017531 blood circulation Effects 0.000 claims description 21
- 239000003527 fibrinolytic agent Substances 0.000 claims description 19
- 229960000103 thrombolytic agent Drugs 0.000 claims description 15
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 claims description 13
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 claims description 13
- 230000027455 binding Effects 0.000 claims description 12
- 210000004369 blood Anatomy 0.000 claims description 11
- 239000008280 blood Substances 0.000 claims description 11
- XWQVQFBTSBCKLI-FKXNDIMNSA-N dnc008987 Chemical group CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 XWQVQFBTSBCKLI-FKXNDIMNSA-N 0.000 claims description 11
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 201000006474 Brain Ischemia Diseases 0.000 claims description 7
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 7
- 206010008118 cerebral infarction Diseases 0.000 claims description 7
- 229940124549 vasodilator Drugs 0.000 claims description 5
- 239000003071 vasodilator agent Substances 0.000 claims description 5
- 230000002537 thrombolytic effect Effects 0.000 claims description 4
- 108010001014 Plasminogen Activators Proteins 0.000 claims description 3
- 102000001938 Plasminogen Activators Human genes 0.000 claims description 3
- 239000005555 hypertensive agent Substances 0.000 claims description 3
- 201000002818 limb ischemia Diseases 0.000 claims description 3
- 230000007498 myristoylation Effects 0.000 claims description 3
- 229940127126 plasminogen activator Drugs 0.000 claims description 3
- 230000000747 cardiac effect Effects 0.000 claims description 2
- 230000002950 deficient Effects 0.000 claims description 2
- 230000002685 pulmonary effect Effects 0.000 claims description 2
- 102100022264 Disks large homolog 4 Human genes 0.000 claims 2
- 102100022397 Nitric oxide synthase, brain Human genes 0.000 claims 1
- 101710111444 Nitric oxide synthase, brain Proteins 0.000 claims 1
- 108010046423 Tat-NR2B9c Proteins 0.000 claims 1
- 238000010408 sweeping Methods 0.000 claims 1
- 102000047174 Disks Large Homolog 4 Human genes 0.000 abstract description 18
- 241001465754 Metazoa Species 0.000 description 55
- 238000000034 method Methods 0.000 description 54
- 102000004196 processed proteins & peptides Human genes 0.000 description 52
- 238000002595 magnetic resonance imaging Methods 0.000 description 42
- 229940024606 amino acid Drugs 0.000 description 39
- 230000000694 effects Effects 0.000 description 38
- 206010061216 Infarction Diseases 0.000 description 37
- 230000007574 infarction Effects 0.000 description 37
- 150000001413 amino acids Chemical class 0.000 description 35
- 210000001519 tissue Anatomy 0.000 description 30
- 239000000902 placebo Substances 0.000 description 25
- 229940068196 placebo Drugs 0.000 description 25
- 102100022630 Glutamate receptor ionotropic, NMDA 2B Human genes 0.000 description 24
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 24
- 208000032382 Ischaemic stroke Diseases 0.000 description 23
- 241000700159 Rattus Species 0.000 description 23
- 230000010412 perfusion Effects 0.000 description 23
- 108090000623 proteins and genes Proteins 0.000 description 23
- 101710149951 Protein Tat Proteins 0.000 description 22
- 102000004169 proteins and genes Human genes 0.000 description 22
- 108010038912 Retinoid X Receptors Proteins 0.000 description 21
- 210000004204 blood vessel Anatomy 0.000 description 21
- 229940079593 drug Drugs 0.000 description 21
- 239000003814 drug Substances 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 238000001802 infusion Methods 0.000 description 20
- 208000032843 Hemorrhage Diseases 0.000 description 19
- 230000009467 reduction Effects 0.000 description 18
- 208000024891 symptom Diseases 0.000 description 18
- 101150069842 dlg4 gene Proteins 0.000 description 17
- 238000003384 imaging method Methods 0.000 description 17
- 239000000816 peptidomimetic Substances 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- 230000008901 benefit Effects 0.000 description 16
- 241000282412 Homo Species 0.000 description 15
- 230000003993 interaction Effects 0.000 description 15
- 239000002831 pharmacologic agent Substances 0.000 description 15
- 201000003045 paroxysmal nocturnal hemoglobinuria Diseases 0.000 description 14
- 102000005962 receptors Human genes 0.000 description 14
- 108020003175 receptors Proteins 0.000 description 14
- 241000894007 species Species 0.000 description 14
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 13
- 238000001990 intravenous administration Methods 0.000 description 13
- 108050008994 PDZ domains Proteins 0.000 description 12
- 102000000470 PDZ domains Human genes 0.000 description 12
- 238000009792 diffusion process Methods 0.000 description 12
- 230000000926 neurological effect Effects 0.000 description 12
- 208000034158 bleeding Diseases 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 201000004440 congenital dyserythropoietic anemia Diseases 0.000 description 10
- 238000001356 surgical procedure Methods 0.000 description 10
- 208000007536 Thrombosis Diseases 0.000 description 9
- 230000006378 damage Effects 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 230000003902 lesion Effects 0.000 description 9
- 241000282553 Macaca Species 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 230000001976 improved effect Effects 0.000 description 8
- 230000003447 ipsilateral effect Effects 0.000 description 8
- 230000029226 lipidation Effects 0.000 description 8
- -1 methylene, ethylene, propylene Chemical group 0.000 description 8
- 230000004112 neuroprotection Effects 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 7
- 241000288906 Primates Species 0.000 description 7
- 238000010171 animal model Methods 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 210000000170 cell membrane Anatomy 0.000 description 7
- 230000002490 cerebral effect Effects 0.000 description 7
- 230000006735 deficit Effects 0.000 description 7
- 210000003414 extremity Anatomy 0.000 description 7
- 229930195712 glutamate Natural products 0.000 description 7
- 125000005647 linker group Chemical group 0.000 description 7
- 230000000144 pharmacologic effect Effects 0.000 description 7
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 6
- 108700000788 Human immunodeficiency virus 1 tat peptide (47-57) Proteins 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 210000001367 artery Anatomy 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 208000010125 myocardial infarction Diseases 0.000 description 6
- 210000002569 neuron Anatomy 0.000 description 6
- 229920001184 polypeptide Polymers 0.000 description 6
- RAVVEEJGALCVIN-AGVBWZICSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-2-[[(2s)-2-[[(2s)-6-amino-2-[[(2s)-6-amino-2-[[(2s)-2-[[2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-5-(diamino Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 RAVVEEJGALCVIN-AGVBWZICSA-N 0.000 description 5
- AJXONGJARXYRDO-YVNDNENWSA-N (4s)-4-amino-5-[[(2s)-1-[[(2s)-3-carboxy-1-[[(1s)-1-carboxy-2-methylpropyl]amino]-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-oxopentanoic acid Chemical group CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCC(O)=O AJXONGJARXYRDO-YVNDNENWSA-N 0.000 description 5
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 5
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 5
- 150000008574 D-amino acids Chemical class 0.000 description 5
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 5
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- 210000004899 c-terminal region Anatomy 0.000 description 5
- 230000003727 cerebral blood flow Effects 0.000 description 5
- 230000034994 death Effects 0.000 description 5
- 230000007547 defect Effects 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 210000002216 heart Anatomy 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 230000003834 intracellular effect Effects 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 229940012957 plasmin Drugs 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 4
- 206010008190 Cerebrovascular accident Diseases 0.000 description 4
- 108010023197 Streptokinase Proteins 0.000 description 4
- 238000000540 analysis of variance Methods 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 210000005013 brain tissue Anatomy 0.000 description 4
- 238000007675 cardiac surgery Methods 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 238000000749 co-immunoprecipitation Methods 0.000 description 4
- 230000001934 delay Effects 0.000 description 4
- 238000002405 diagnostic procedure Methods 0.000 description 4
- 230000003492 excitotoxic effect Effects 0.000 description 4
- 231100000063 excitotoxicity Toxicity 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 230000017854 proteolysis Effects 0.000 description 4
- 210000003625 skull Anatomy 0.000 description 4
- 230000002123 temporal effect Effects 0.000 description 4
- 230000001052 transient effect Effects 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- 206010002329 Aneurysm Diseases 0.000 description 3
- 208000022211 Arteriovenous Malformations Diseases 0.000 description 3
- 241000283707 Capra Species 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- 102000009123 Fibrin Human genes 0.000 description 3
- 108010073385 Fibrin Proteins 0.000 description 3
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 102000018899 Glutamate Receptors Human genes 0.000 description 3
- 108010027915 Glutamate Receptors Proteins 0.000 description 3
- 101710195187 Glutamate receptor ionotropic, NMDA 2B Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 108010039185 Tenecteplase Proteins 0.000 description 3
- 208000032109 Transient ischaemic attack Diseases 0.000 description 3
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 3
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 description 3
- 239000002260 anti-inflammatory agent Substances 0.000 description 3
- 230000005744 arteriovenous malformation Effects 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000002146 bilateral effect Effects 0.000 description 3
- 239000000090 biomarker Substances 0.000 description 3
- 238000001574 biopsy Methods 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 108091006116 chimeric peptides Proteins 0.000 description 3
- 239000002131 composite material Substances 0.000 description 3
- 238000002591 computed tomography Methods 0.000 description 3
- 230000002596 correlated effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 229950003499 fibrin Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 229960001340 histamine Drugs 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 230000036244 malformation Effects 0.000 description 3
- 230000001537 neural effect Effects 0.000 description 3
- 230000004776 neurological deficiency Effects 0.000 description 3
- 230000007971 neurological deficit Effects 0.000 description 3
- 230000001067 neuroprotector Effects 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 238000002600 positron emission tomography Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 230000009870 specific binding Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 108700012359 toxins Proteins 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 201000010875 transient cerebral ischemia Diseases 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- IJJWOSAXNHWBPR-HUBLWGQQSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-(6-hydrazinyl-6-oxohexyl)pentanamide Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCCCCC(=O)NN)SC[C@@H]21 IJJWOSAXNHWBPR-HUBLWGQQSA-N 0.000 description 2
- 108010058207 Anistreplase Proteins 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- 241000288950 Callithrix jacchus Species 0.000 description 2
- 102000014914 Carrier Proteins Human genes 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 108091006027 G proteins Proteins 0.000 description 2
- 102000030782 GTP binding Human genes 0.000 description 2
- 108091000058 GTP-Binding Proteins 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 108010070875 Human Immunodeficiency Virus tat Gene Products Proteins 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 201000008450 Intracranial aneurysm Diseases 0.000 description 2
- 208000032984 Intraoperative Complications Diseases 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical group OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 2
- 102000003992 Peroxidases Human genes 0.000 description 2
- 102000013566 Plasminogen Human genes 0.000 description 2
- 108010051456 Plasminogen Proteins 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 2
- 206010047555 Visual field defect Diseases 0.000 description 2
- NOSIYYJFMPDDSA-UHFFFAOYSA-N acepromazine Chemical compound C1=C(C(C)=O)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 NOSIYYJFMPDDSA-UHFFFAOYSA-N 0.000 description 2
- 229960005054 acepromazine Drugs 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 229960003318 alteplase Drugs 0.000 description 2
- 238000002583 angiography Methods 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 2
- 210000000709 aorta Anatomy 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 108091008324 binding proteins Proteins 0.000 description 2
- 230000008033 biological extinction Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000000480 calcium channel blocker Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 210000003618 cortical neuron Anatomy 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000007428 craniotomy Methods 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 230000001687 destabilization Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000002008 hemorrhagic effect Effects 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 239000012133 immunoprecipitate Substances 0.000 description 2
- 238000001114 immunoprecipitation Methods 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- NUHSROFQTUXZQQ-UHFFFAOYSA-N isopentenyl diphosphate Chemical compound CC(=C)CCO[P@](O)(=O)OP(O)(O)=O NUHSROFQTUXZQQ-UHFFFAOYSA-N 0.000 description 2
- 229960003299 ketamine Drugs 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 210000003657 middle cerebral artery Anatomy 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000007659 motor function Effects 0.000 description 2
- 230000003188 neurobehavioral effect Effects 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000008447 perception Effects 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 108010092804 postsynaptic density proteins Proteins 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000001525 retina Anatomy 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- 229960005202 streptokinase Drugs 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 229960000216 tenecteplase Drugs 0.000 description 2
- 229960000187 tissue plasminogen activator Drugs 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 230000026683 transduction Effects 0.000 description 2
- 238000010361 transduction Methods 0.000 description 2
- 230000005945 translocation Effects 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Chemical group OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 229960005356 urokinase Drugs 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 2
- 229960001600 xylazine Drugs 0.000 description 2
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- FMCGSUUBYTWNDP-ONGXEEELSA-N (1R,2S)-2-(dimethylamino)-1-phenyl-1-propanol Chemical compound CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-ONGXEEELSA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- VILFTWLXLYIEMV-UHFFFAOYSA-N 1,5-difluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC([N+]([O-])=O)=C(F)C=C1F VILFTWLXLYIEMV-UHFFFAOYSA-N 0.000 description 1
- VZZPYUKWXDLMGI-UHFFFAOYSA-N 1,6-diisothiocyanatohexane Chemical compound S=C=NCCCCCCN=C=S VZZPYUKWXDLMGI-UHFFFAOYSA-N 0.000 description 1
- IPJGAEWUPXWFPL-UHFFFAOYSA-N 1-[3-(2,5-dioxopyrrol-1-yl)phenyl]pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C1=CC=CC(N2C(C=CC2=O)=O)=C1 IPJGAEWUPXWFPL-UHFFFAOYSA-N 0.000 description 1
- KHAWDEWNXJIVCJ-UHFFFAOYSA-N 1-fluoro-4-(4-fluoro-3-nitrophenyl)sulfonyl-2-nitrobenzene Chemical compound C1=C(F)C([N+](=O)[O-])=CC(S(=O)(=O)C=2C=C(C(F)=CC=2)[N+]([O-])=O)=C1 KHAWDEWNXJIVCJ-UHFFFAOYSA-N 0.000 description 1
- OTLLEIBWKHEHGU-UHFFFAOYSA-N 2-[5-[[5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy]-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-4-phosphonooxyhexanedioic acid Chemical compound C1=NC=2C(N)=NC=NC=2N1C(C(C1O)O)OC1COC1C(CO)OC(OC(C(O)C(OP(O)(O)=O)C(O)C(O)=O)C(O)=O)C(O)C1O OTLLEIBWKHEHGU-UHFFFAOYSA-N 0.000 description 1
- FXYZDFSNBBOHTA-UHFFFAOYSA-N 2-[amino(morpholin-4-ium-4-ylidene)methyl]guanidine;chloride Chemical compound Cl.NC(N)=NC(=N)N1CCOCC1 FXYZDFSNBBOHTA-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- RLFPCLMBTQOMLI-UHFFFAOYSA-N 2-iodo-n-[2-[(2-iodoacetyl)amino]ethyl]acetamide Chemical compound ICC(=O)NCCNC(=O)CI RLFPCLMBTQOMLI-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 102000003678 AMPA Receptors Human genes 0.000 description 1
- 108090000078 AMPA Receptors Proteins 0.000 description 1
- 208000035657 Abasia Diseases 0.000 description 1
- 108010066676 Abrin Proteins 0.000 description 1
- 206010060938 Anaesthetic complication Diseases 0.000 description 1
- 108700031308 Antennapedia Homeodomain Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010006100 Bradykinesia Diseases 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 206010008088 Cerebral artery embolism Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 102000000018 Chemokine CCL2 Human genes 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000009016 Cholera Toxin Human genes 0.000 description 1
- 108010049048 Cholera Toxin Proteins 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 206010069729 Collateral circulation Diseases 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- 241001269524 Dura Species 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- 206010051267 Facial paresis Diseases 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- 102100022645 Glutamate receptor ionotropic, NMDA 1 Human genes 0.000 description 1
- 102100029458 Glutamate receptor ionotropic, NMDA 2A Human genes 0.000 description 1
- 102100022631 Glutamate receptor ionotropic, NMDA 2C Human genes 0.000 description 1
- 101710195185 Glutamate receptor ionotropic, NMDA 2C Proteins 0.000 description 1
- 102100022626 Glutamate receptor ionotropic, NMDA 2D Human genes 0.000 description 1
- 101710195184 Glutamate receptor ionotropic, NMDA 2D Proteins 0.000 description 1
- 102100038942 Glutamate receptor ionotropic, NMDA 3A Human genes 0.000 description 1
- 101710195181 Glutamate receptor ionotropic, NMDA 3A Proteins 0.000 description 1
- 102100022758 Glutamate receptor ionotropic, kainate 2 Human genes 0.000 description 1
- 101710112360 Glutamate receptor ionotropic, kainate 2 Proteins 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- 206010018985 Haemorrhage intracranial Diseases 0.000 description 1
- 206010055847 Haemorrhage urinary tract Diseases 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 206010019452 Hemianopia Diseases 0.000 description 1
- 208000007460 Hemianopsia Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 239000005057 Hexamethylene diisocyanate Substances 0.000 description 1
- 101001129187 Homo sapiens Patatin-like phospholipase domain-containing protein 2 Proteins 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- 206010021639 Incontinence Diseases 0.000 description 1
- 208000008574 Intracranial Hemorrhages Diseases 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 241000282567 Macaca fascicularis Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- FMCGSUUBYTWNDP-UHFFFAOYSA-N N-Methylephedrine Natural products CN(C)C(C)C(O)C1=CC=CC=C1 FMCGSUUBYTWNDP-UHFFFAOYSA-N 0.000 description 1
- 102000004129 N-Type Calcium Channels Human genes 0.000 description 1
- 108090000699 N-Type Calcium Channels Proteins 0.000 description 1
- 108010084867 N-methyl D-aspartate receptor subtype 2A Proteins 0.000 description 1
- 125000000729 N-terminal amino-acid group Chemical group 0.000 description 1
- 108010054235 NMDA receptor A1 Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 1
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 238000012879 PET imaging Methods 0.000 description 1
- 208000007542 Paresis Diseases 0.000 description 1
- 102100031248 Patatin-like phospholipase domain-containing protein 2 Human genes 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229940127315 Potassium Channel Openers Drugs 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 206010063897 Renal ischaemia Diseases 0.000 description 1
- 108010039491 Ricin Proteins 0.000 description 1
- 101150001535 SRC gene Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 239000000219 Sympatholytic Substances 0.000 description 1
- 101710192266 Tegument protein VP22 Proteins 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- GYDJEQRTZSCIOI-UHFFFAOYSA-N Tranexamic acid Chemical compound NCC1CCC(C(O)=O)CC1 GYDJEQRTZSCIOI-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 101150066971 UL49 gene Proteins 0.000 description 1
- 208000009443 Vascular Malformations Diseases 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229940099983 activase Drugs 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 238000011256 aggressive treatment Methods 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 239000002160 alpha blocker Substances 0.000 description 1
- 102000015007 alpha-adrenergic receptor activity proteins Human genes 0.000 description 1
- 108040006816 alpha-adrenergic receptor activity proteins Proteins 0.000 description 1
- 229940124308 alpha-adrenoreceptor antagonist Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 229960000983 anistreplase Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 206010061592 cardiac fibrillation Diseases 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 210000001627 cerebral artery Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 230000003788 cerebral perfusion Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000010217 densitometric analysis Methods 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000007435 diagnostic evaluation Methods 0.000 description 1
- 238000011847 diagnostic investigation Methods 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- ZLFRJHOBQVVTOJ-UHFFFAOYSA-N dimethyl hexanediimidate Chemical compound COC(=N)CCCCC(=N)OC ZLFRJHOBQVVTOJ-UHFFFAOYSA-N 0.000 description 1
- 238000011038 discontinuous diafiltration by volume reduction Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000013156 embolectomy Methods 0.000 description 1
- 238000013171 endarterectomy Methods 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 230000009540 excitatory neurotransmission Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 231100000776 exotoxin Toxicity 0.000 description 1
- 239000002095 exotoxin Substances 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 208000010770 facial weakness Diseases 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 230000002600 fibrillogenic effect Effects 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 239000003457 ganglion blocking agent Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 208000030304 gastrointestinal bleeding Diseases 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000006127 geranylation Effects 0.000 description 1
- 230000006130 geranylgeranylation Effects 0.000 description 1
- 230000007946 glucose deprivation Effects 0.000 description 1
- 108010000481 glutamate receptor delta 2 Proteins 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 206010019465 hemiparesis Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- RRAMGCGOFNQTLD-UHFFFAOYSA-N hexamethylene diisocyanate Chemical compound O=C=NCCCCCCN=C=O RRAMGCGOFNQTLD-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000009097 homeostatic mechanism Effects 0.000 description 1
- 230000000260 hypercholesteremic effect Effects 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 201000010849 intracranial embolism Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 230000006122 isoprenylation Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 229960002221 methylephedrine Drugs 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- PNQCMZHRTCNQMO-UHFFFAOYSA-N n'-iodooxamide Chemical compound NC(=O)C(=O)NI PNQCMZHRTCNQMO-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000031990 negative regulation of inflammatory response Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000007658 neurological function Effects 0.000 description 1
- 230000037420 neurological improvement Effects 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000002450 orbitofrontal effect Effects 0.000 description 1
- 230000026792 palmitoylation Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- MCYTYTUNNNZWOK-LCLOTLQISA-N penetratin Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=CC=C1 MCYTYTUNNNZWOK-LCLOTLQISA-N 0.000 description 1
- 108010043655 penetratin Proteins 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 230000033885 plasminogen activation Effects 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 210000003538 post-synaptic density Anatomy 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 208000018299 prostration Diseases 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 238000000730 protein immunoprecipitation Methods 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 231100000654 protein toxin Toxicity 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 229940086526 renin-inhibitors Drugs 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229940116243 retavase Drugs 0.000 description 1
- 108010051412 reteplase Proteins 0.000 description 1
- 208000032253 retinal ischemia Diseases 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- 230000036362 sensorimotor function Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000003307 slaughter Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000004092 somatosensory cortex Anatomy 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000002311 subsequent effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000000948 sympatholitic effect Effects 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229940113038 tnkase Drugs 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 108010062760 transportan Proteins 0.000 description 1
- PBKWZFANFUTEPS-CWUSWOHSSA-N transportan Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(N)=O)[C@@H](C)CC)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CN)[C@@H](C)O)C1=CC=C(O)C=C1 PBKWZFANFUTEPS-CWUSWOHSSA-N 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 108010047303 von Willebrand Factor Proteins 0.000 description 1
- 102100036537 von Willebrand factor Human genes 0.000 description 1
- 229960001134 von willebrand factor Drugs 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
- A61K38/1787—Receptors; Cell surface antigens; Cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/49—Urokinase; Tissue plasminogen activator
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurology (AREA)
- Cell Biology (AREA)
- Zoology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Neurosurgery (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
- Dermatology (AREA)
- Apparatus For Radiation Diagnosis (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Nuclear Medicine (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161501117P | 2011-06-24 | 2011-06-24 | |
| US201161501117P | 2011-06-24 | ||
| US201261617001P | 2012-03-28 | 2012-03-28 | |
| US201261617001P | 2012-03-28 | ||
| PCT/IB2012/053178 WO2012176172A2 (en) | 2011-06-24 | 2012-06-23 | Combination therapy for ischemia |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2690994T3 true ES2690994T3 (es) | 2018-11-23 |
Family
ID=47423033
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES12802409.8T Active ES2690994T3 (es) | 2011-06-24 | 2012-06-23 | Terapia de combinación para isquemia |
| ES18190827T Active ES2912042T3 (es) | 2011-06-24 | 2012-06-23 | Terapia de combinación para isquemia |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES18190827T Active ES2912042T3 (es) | 2011-06-24 | 2012-06-23 | Terapia de combinación para isquemia |
Country Status (19)
| Country | Link |
|---|---|
| US (3) | US10064910B2 (enExample) |
| EP (3) | EP3427748B1 (enExample) |
| JP (5) | JP6401057B2 (enExample) |
| KR (5) | KR102022116B1 (enExample) |
| CN (1) | CN103648518B (enExample) |
| AU (1) | AU2012274910B2 (enExample) |
| CA (1) | CA2839630A1 (enExample) |
| CY (1) | CY1121379T1 (enExample) |
| DK (2) | DK2723363T3 (enExample) |
| ES (2) | ES2690994T3 (enExample) |
| HR (2) | HRP20220519T1 (enExample) |
| HU (2) | HUE058238T2 (enExample) |
| LT (1) | LT2723363T (enExample) |
| PL (2) | PL2723363T3 (enExample) |
| PT (2) | PT3427748T (enExample) |
| RS (1) | RS57798B1 (enExample) |
| SI (1) | SI2723363T1 (enExample) |
| SM (1) | SMT201800592T1 (enExample) |
| WO (1) | WO2012176172A2 (enExample) |
Families Citing this family (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI1010718A2 (pt) | 2009-06-10 | 2016-03-15 | Nono Inc | sistemas modelo e regimes de tratamento para tratar doença neurológica. |
| KR102022116B1 (ko) * | 2011-06-24 | 2019-09-18 | 노노 인코포레이티드 | 허혈에 대한 psd-95 억제제와의 조합 요법 |
| US9241970B2 (en) | 2011-12-13 | 2016-01-26 | Nono Inc. | Therapy for subarachnoid hemorrhage and ischemia |
| CZ2012476A3 (cs) * | 2012-07-12 | 2014-01-22 | Ústav organické chemie a biochemie Akademie věd ČR, v. v. i. | Lipidované peptidy jako antiobezitika |
| US10220008B2 (en) | 2013-08-14 | 2019-03-05 | Stc.Unm | Treatment and prevention of stroke and other neurological disorders |
| EP3074030A4 (en) * | 2013-11-26 | 2017-08-16 | Trustees of Dartmouth College | Method for mitigating or alleviating synaptic and cognitive deficits |
| FR3021319B1 (fr) * | 2014-05-22 | 2018-08-31 | Sederma | Peptides, compositions les comprenant et utilisations notamment cosmetiques |
| CZ309217B6 (cs) * | 2014-05-27 | 2022-06-01 | Ústav Organické Chemie A Biochemie Av Čr, V.V.I. | Lipidované peptidy jako neuroprotektiva |
| KR102605540B1 (ko) | 2014-05-28 | 2023-11-22 | 노노 인코포레이티드 | Tat-nr2b9c의 클로라이드 염 |
| US9526768B2 (en) | 2014-11-13 | 2016-12-27 | Jennifer Mai | Compositions for the treatment of cancer |
| CN104497106B (zh) * | 2014-12-05 | 2017-05-10 | 华中科技大学 | 一种小分子多肽、其应用及产品 |
| KR20180135493A (ko) * | 2016-04-27 | 2018-12-20 | 바이오셀즈(베이징) 바이오테크 코., 엘티디. | 흥분성 신경독성 관련 손상의 치료 방법 |
| ES2869300T3 (es) * | 2016-04-27 | 2021-10-25 | Biocells Beijing Biotech Co Ltd | Péptido terapéutico para las lesiones relacionadas con la neurotoxicidad excitadora |
| CN107312069B (zh) * | 2016-04-27 | 2018-11-06 | 拜西欧斯（北京）生物技术有限公司 | 兴奋性神经毒性相关损伤的治疗肽 |
| CN107446016A (zh) * | 2016-05-30 | 2017-12-08 | 上海交通大学 | 一种硬脂酸修饰的细胞穿膜肽及其制备与应用 |
| CN106265594B (zh) * | 2016-09-21 | 2019-07-26 | 南京医科大学 | 一种缺血性脑卒中靶向的红细胞膜仿生智能药物载体及其制备方法 |
| CN106749559B (zh) * | 2016-11-23 | 2020-09-04 | 郑州大学 | 一种基于细胞穿膜肽Tat(49-57)的抗菌肽及其合成方法 |
| JP7109958B2 (ja) * | 2017-04-04 | 2022-08-01 | キヤノンメディカルシステムズ株式会社 | 磁気共鳴イメージングシステム、磁気共鳴イメージング装置、及び磁気共鳴イメージング方法 |
| EA039314B1 (ru) * | 2017-07-05 | 2022-01-12 | Биоселз (Бейдзин) Биотек Ко., Лтд. | Фармацевтически приемлемые соли полипептидов и их применение |
| WO2019006691A1 (zh) * | 2017-07-05 | 2019-01-10 | 拜西欧斯（北京）生物技术有限公司 | 用于治疗、改善或预防脑出血的肽及其用途 |
| WO2019061395A1 (zh) * | 2017-09-30 | 2019-04-04 | 拜西欧斯（北京）生物技术有限公司 | 兴奋性神经毒性相关损伤的治疗肽组合物 |
| US12122811B2 (en) | 2018-04-06 | 2024-10-22 | Northwestern University | BDNF mimetic peptide amphiphiles |
| JP7158904B2 (ja) * | 2018-06-14 | 2022-10-24 | 社会福祉法人 恩賜財団済生会熊本病院 | 治療方針決定支援装置、治療方針決定支援装置の作動方法、および治療方針決定支援プログラム |
| US12285182B2 (en) | 2018-10-10 | 2025-04-29 | Innova Vascular, Inc. | Devices and methods for removing an embolus |
| CN115279797A (zh) * | 2020-01-09 | 2022-11-01 | 诺诺公司 | 用于治疗中风和相关疾病的抗纤溶酶肽 |
| MX2022010160A (es) * | 2020-02-19 | 2022-10-10 | Nono Inc | Tratamiento de combinación de apoplejia con inhibidor de psd-95 escindible por plasmina y reperfusión. |
| US20230285504A1 (en) * | 2020-02-19 | 2023-09-14 | Nono Inc. | Inhibition of reperfusion injury with a psd-95 inhibitor |
| CN113735938B (zh) * | 2021-07-30 | 2024-11-08 | 英纳氏(珠海)药业有限公司 | 一种神经保护多肽化合物及其应用 |
| WO2023192848A1 (en) * | 2022-03-28 | 2023-10-05 | University Of Maryland, Baltimore | Methods and compositions for the treatment of stroke |
| CN120344552A (zh) | 2023-01-09 | 2025-07-18 | 北京拓界生物医药科技有限公司 | 一种神经保护性psd-95多肽抑制剂及其应用 |
| CN117422722B (zh) * | 2023-12-19 | 2024-03-29 | 北京智源人工智能研究院 | 基于adc图像的肿瘤预后特征评估的方法和装置 |
Family Cites Families (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2742152B1 (fr) | 1995-12-06 | 1998-01-16 | Synthelabo | Derives de 5-naphtalen-1-yl-1,3-dioxanes, leur preparation et leur application en therapeutique |
| US6562345B1 (en) | 1996-11-12 | 2003-05-13 | City Of Hope | Immuno-reactive peptide CTL epitopes of human cytomegalovirus |
| US6903184B1 (en) | 1998-03-02 | 2005-06-07 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Multiple antigenic peptides immunogenic against Streptococcus pneumonia |
| US20060148711A1 (en) | 1999-05-14 | 2006-07-06 | Arbor Vita Corporation | Molecular interactions in neurons |
| US7510824B2 (en) | 1999-06-02 | 2009-03-31 | Nono Inc. | Method of screening peptides useful in treating traumatic injury to the brain or spinal cord |
| GB0025473D0 (en) * | 2000-10-17 | 2000-11-29 | Pfizer Ltd | Pharmaceutical combinations |
| AU2004233862A1 (en) | 2003-04-25 | 2004-11-11 | Mitos Pharmaceuticals, Inc. | Prophylactic pretreatment with antioxidants |
| PL1622639T3 (pl) | 2003-05-02 | 2013-06-28 | Lundbeck H As | Dożylne wstrzyknięcie nieneurotoksycznych aktywatorów plazminogenu do leczenia udaru mózgu |
| EP1633305A2 (en) * | 2003-05-19 | 2006-03-15 | The Kenneth S. Warren Institute, Inc. | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs with an extended therapeutic window |
| TWI395591B (zh) | 2004-04-01 | 2013-05-11 | Oncothyreon Inc | 黏液性糖蛋白（ｍｕｃ-１）疫苗 |
| ES2804424T3 (es) | 2006-07-11 | 2021-02-08 | Nono Inc | Péptido y composición del mismo para usar en el tratamiento del accidente cerebrovascular con fiebre |
| EP1884521A1 (en) | 2006-07-31 | 2008-02-06 | Xigen S.A. | Fusion peptide for inhibiting interaction of neuronal NMDA receptor (NMDAR) and NMDAR interacting proteins |
| CU23630A1 (es) | 2006-10-30 | 2011-02-24 | Ct Ingenieria Genetica Biotech | Moléculas peptídicas quiméricas con propiedades antivirales contra los virus de la familia flaviviridae |
| EP2120987B1 (en) * | 2007-03-02 | 2014-01-15 | NoNO Inc. | Treating stroke and other diseases without inhibiting n-type calcium channels |
| GB0707348D0 (en) | 2007-04-17 | 2007-05-23 | Renovo Ltd | Medicaments and methods for inhibition of scarring |
| WO2009006611A1 (en) | 2007-07-03 | 2009-01-08 | Arbor Vita Corporation | Small molecule inhibitors of pdz interactions |
| CN101855235B (zh) | 2007-10-29 | 2013-04-24 | 赫里克斯生物医疗公司 | 保护性皮肤护理四肽 |
| US8080518B2 (en) | 2007-12-05 | 2011-12-20 | Arbor Vita Corporation | Co-administration of an agent linked to an internalization peptide with an anti-inflammatory |
| NZ600205A (en) | 2008-01-25 | 2013-12-20 | Univ Aarhus | Selective exosite inhibition of papp-a activity against igfbp-4 |
| PL2320927T3 (pl) | 2008-07-09 | 2016-02-29 | Univ Copenhagen | Modyfikowane peptydy jako potencjalne inhibitory w reakcjach receptorów PSD 95 i NMD |
| DE102008037564A1 (de) | 2008-11-19 | 2010-05-20 | Forschungszentrum Jülich GmbH | Zusammensetzung zur Herstellung von anti-Amyloid beta-Peptid-Antikörpern mit D-Peptiden |
| CA2665302A1 (en) | 2009-05-01 | 2010-11-01 | Universite De Montreal | Cd36 modulation and uses thereof |
| AU2010259986B2 (en) | 2009-06-10 | 2015-04-02 | Nono Inc. | Co-administration of an agent linked to an internalization peptide with an anti-inflammatory |
| BRPI1010718A2 (pt) | 2009-06-10 | 2016-03-15 | Nono Inc | sistemas modelo e regimes de tratamento para tratar doença neurológica. |
| US20110144029A1 (en) | 2009-09-30 | 2011-06-16 | Board Of Regents, The University Of Texas System | Model Systems and Materials for the Study and Treatment of Neurodegenerative Diseases |
| KR102022116B1 (ko) | 2011-06-24 | 2019-09-18 | 노노 인코포레이티드 | 허혈에 대한 psd-95 억제제와의 조합 요법 |
| KR102114490B1 (ko) | 2011-12-13 | 2020-05-25 | 노노 인코포레이티드 | 지주막하 출혈 및 허혈에 대한 치료법 |
| US9241970B2 (en) | 2011-12-13 | 2016-01-26 | Nono Inc. | Therapy for subarachnoid hemorrhage and ischemia |
-
2012
- 2012-06-23 KR KR1020147001639A patent/KR102022116B1/ko not_active Expired - Fee Related
- 2012-06-23 EP EP18190827.8A patent/EP3427748B1/en active Active
- 2012-06-23 ES ES12802409.8T patent/ES2690994T3/es active Active
- 2012-06-23 PL PL12802409T patent/PL2723363T3/pl unknown
- 2012-06-23 HR HRP20220519TT patent/HRP20220519T1/hr unknown
- 2012-06-23 KR KR1020217026955A patent/KR102425466B1/ko active Active
- 2012-06-23 DK DK12802409.8T patent/DK2723363T3/en active
- 2012-06-23 EP EP12802409.8A patent/EP2723363B1/en active Active
- 2012-06-23 JP JP2014516487A patent/JP6401057B2/ja not_active Expired - Fee Related
- 2012-06-23 KR KR1020227025470A patent/KR20220106862A/ko active Pending
- 2012-06-23 US US14/128,941 patent/US10064910B2/en active Active
- 2012-06-23 DK DK18190827.8T patent/DK3427748T3/da active
- 2012-06-23 PT PT181908278T patent/PT3427748T/pt unknown
- 2012-06-23 HU HUE18190827A patent/HUE058238T2/hu unknown
- 2012-06-23 LT LTEP12802409.8T patent/LT2723363T/lt unknown
- 2012-06-23 SI SI201231412T patent/SI2723363T1/sl unknown
- 2012-06-23 CN CN201280031302.4A patent/CN103648518B/zh not_active Expired - Fee Related
- 2012-06-23 HU HUE12802409A patent/HUE040564T2/hu unknown
- 2012-06-23 SM SM20180592T patent/SMT201800592T1/it unknown
- 2012-06-23 CA CA2839630A patent/CA2839630A1/en active Pending
- 2012-06-23 AU AU2012274910A patent/AU2012274910B2/en active Active
- 2012-06-23 EP EP22157256.3A patent/EP4052721A1/en not_active Withdrawn
- 2012-06-23 RS RS20181182A patent/RS57798B1/sr unknown
- 2012-06-23 KR KR1020197026571A patent/KR102140169B1/ko not_active Expired - Fee Related
- 2012-06-23 ES ES18190827T patent/ES2912042T3/es active Active
- 2012-06-23 PT PT12802409T patent/PT2723363T/pt unknown
- 2012-06-23 PL PL18190827T patent/PL3427748T3/pl unknown
- 2012-06-23 HR HRP20181526TT patent/HRP20181526T1/hr unknown
- 2012-06-23 KR KR1020207021829A patent/KR102296106B1/ko not_active Expired - Fee Related
- 2012-06-23 WO PCT/IB2012/053178 patent/WO2012176172A2/en not_active Ceased
-
2017
- 2017-04-05 JP JP2017074975A patent/JP2017193535A/ja active Pending
-
2018
- 2018-08-01 US US16/051,971 patent/US10967041B2/en not_active Expired - Fee Related
- 2018-10-30 JP JP2018204034A patent/JP7085457B2/ja active Active
- 2018-11-28 CY CY20181101260T patent/CY1121379T1/el unknown
-
2020
- 2020-08-06 JP JP2020134150A patent/JP7143374B2/ja active Active
-
2021
- 2021-02-17 US US17/177,970 patent/US11878044B2/en active Active
-
2022
- 2022-09-14 JP JP2022146191A patent/JP2022188068A/ja active Pending
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2690994T3 (es) | Terapia de combinación para isquemia | |
| ES2847293T3 (es) | Regímenes de tratamiento para el tratamiento de enfermedades neurológicas | |
| ES2731266T3 (es) | Terapia para hemorragia subaracnoidea e isquemia | |
| HK40003366A (en) | Combination therapy for ischemia | |
| HK40003366B (en) | Combination therapy for ischemia |