US20030072737A1 - Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs - Google Patents
Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs Download PDFInfo
- Publication number
- US20030072737A1 US20030072737A1 US10/188,905 US18890502A US2003072737A1 US 20030072737 A1 US20030072737 A1 US 20030072737A1 US 18890502 A US18890502 A US 18890502A US 2003072737 A1 US2003072737 A1 US 2003072737A1
- Authority
- US
- United States
- Prior art keywords
- erythropoietin
- tissue protective
- protective cytokine
- modified
- molecule
- 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.)
- Abandoned
Links
- 102000004127 Cytokines Human genes 0.000 title claims abstract description 276
- 108090000695 Cytokines Proteins 0.000 title claims abstract description 275
- 230000002669 organ and tissue protective effect Effects 0.000 title claims abstract description 272
- 210000000056 organ Anatomy 0.000 title claims abstract description 103
- 230000004224 protection Effects 0.000 title claims description 18
- 238000000034 method Methods 0.000 claims abstract description 97
- 239000000203 mixture Substances 0.000 claims abstract description 56
- 241000282414 Homo sapiens Species 0.000 claims abstract description 32
- 230000035899 viability Effects 0.000 claims abstract description 18
- 230000002708 enhancing effect Effects 0.000 claims abstract description 17
- 241000124008 Mammalia Species 0.000 claims abstract description 15
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical class [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 501
- 108090000394 Erythropoietin Proteins 0.000 claims description 477
- 229940105423 erythropoietin Drugs 0.000 claims description 475
- 102000003951 Erythropoietin Human genes 0.000 claims description 471
- 210000004027 cell Anatomy 0.000 claims description 183
- 210000001519 tissue Anatomy 0.000 claims description 128
- 238000012986 modification Methods 0.000 claims description 70
- 230000004048 modification Effects 0.000 claims description 66
- 230000004888 barrier function Effects 0.000 claims description 62
- 230000000694 effects Effects 0.000 claims description 52
- 239000008194 pharmaceutical composition Substances 0.000 claims description 50
- 108010027485 asialoerythropoietin Proteins 0.000 claims description 49
- 238000011282 treatment Methods 0.000 claims description 48
- 125000003277 amino group Chemical group 0.000 claims description 47
- 238000006243 chemical reaction Methods 0.000 claims description 46
- 208000014674 injury Diseases 0.000 claims description 38
- 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 claims description 38
- 210000004556 brain Anatomy 0.000 claims description 36
- 150000001720 carbohydrates Chemical class 0.000 claims description 36
- 235000014633 carbohydrates Nutrition 0.000 claims description 36
- 210000002889 endothelial cell Anatomy 0.000 claims description 33
- 230000006378 damage Effects 0.000 claims description 26
- 238000004519 manufacturing process Methods 0.000 claims description 24
- 238000012360 testing method Methods 0.000 claims description 24
- 230000006870 function Effects 0.000 claims description 21
- 125000005629 sialic acid group Chemical group 0.000 claims description 21
- 230000008733 trauma Effects 0.000 claims description 21
- 210000001772 blood platelet Anatomy 0.000 claims description 20
- 210000002216 heart Anatomy 0.000 claims description 20
- 210000004962 mammalian cell Anatomy 0.000 claims description 20
- 230000001537 neural effect Effects 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 20
- 230000002829 reductive effect Effects 0.000 claims description 18
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 17
- 239000004472 Lysine Substances 0.000 claims description 17
- 208000027418 Wounds and injury Diseases 0.000 claims description 17
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims description 17
- 208000028867 ischemia Diseases 0.000 claims description 14
- 210000003734 kidney Anatomy 0.000 claims description 14
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims description 14
- 206010061218 Inflammation Diseases 0.000 claims description 13
- 230000003920 cognitive function Effects 0.000 claims description 13
- 238000005534 hematocrit Methods 0.000 claims description 13
- 230000004054 inflammatory process Effects 0.000 claims description 13
- 230000002207 retinal effect Effects 0.000 claims description 12
- 230000031998 transcytosis Effects 0.000 claims description 12
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 12
- 210000001736 capillary Anatomy 0.000 claims description 11
- 210000005168 endometrial cell Anatomy 0.000 claims description 11
- 210000004072 lung Anatomy 0.000 claims description 11
- 210000001550 testis Anatomy 0.000 claims description 11
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical compound CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 claims description 10
- 108010025020 Nerve Growth Factor Proteins 0.000 claims description 10
- 206010015037 epilepsy Diseases 0.000 claims description 10
- 229940088597 hormone Drugs 0.000 claims description 10
- 239000005556 hormone Substances 0.000 claims description 10
- 108010031186 Glycoside Hydrolases Proteins 0.000 claims description 9
- 102000005744 Glycoside Hydrolases Human genes 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 claims description 9
- 230000008499 blood brain barrier function Effects 0.000 claims description 9
- 210000001218 blood-brain barrier Anatomy 0.000 claims description 9
- 230000003511 endothelial effect Effects 0.000 claims description 9
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 claims description 9
- 210000001672 ovary Anatomy 0.000 claims description 9
- 210000001013 sinoatrial node Anatomy 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 9
- 210000001943 adrenal medulla Anatomy 0.000 claims description 8
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 8
- 229960003067 cystine Drugs 0.000 claims description 8
- 230000002124 endocrine Effects 0.000 claims description 8
- 210000004185 liver Anatomy 0.000 claims description 8
- 230000002947 procoagulating effect Effects 0.000 claims description 8
- 210000000813 small intestine Anatomy 0.000 claims description 8
- 208000010412 Glaucoma Diseases 0.000 claims description 7
- 210000004404 adrenal cortex Anatomy 0.000 claims description 7
- 230000001413 cellular effect Effects 0.000 claims description 7
- 210000003205 muscle Anatomy 0.000 claims description 7
- 208000001953 Hypotension Diseases 0.000 claims description 6
- 206010047139 Vasoconstriction Diseases 0.000 claims description 6
- 239000003443 antiviral agent Substances 0.000 claims description 6
- 238000009534 blood test Methods 0.000 claims description 6
- 239000003018 immunosuppressive agent Substances 0.000 claims description 6
- 239000003550 marker Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 210000000278 spinal cord Anatomy 0.000 claims description 6
- 230000025033 vasoconstriction Effects 0.000 claims description 6
- ZGCHLOWZNKRZSN-NTSWFWBYSA-N 3-deoxyglucosone Chemical compound OC[C@@H](O)[C@@H](O)CC(=O)C=O ZGCHLOWZNKRZSN-NTSWFWBYSA-N 0.000 claims description 5
- UHPMJDGOAZMIID-UHFFFAOYSA-N 3-deoxyglucosone Natural products OCC1OC(O)C(=O)CC1O UHPMJDGOAZMIID-UHFFFAOYSA-N 0.000 claims description 5
- 206010012289 Dementia Diseases 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 5
- 208000018737 Parkinson disease Diseases 0.000 claims description 5
- 208000006011 Stroke Diseases 0.000 claims description 5
- 125000000539 amino acid group Chemical group 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 235000003704 aspartic acid Nutrition 0.000 claims description 5
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 5
- 230000002357 endometrial effect Effects 0.000 claims description 5
- 210000004165 myocardium Anatomy 0.000 claims description 5
- 230000001681 protective effect Effects 0.000 claims description 5
- 208000032253 retinal ischemia Diseases 0.000 claims description 5
- 208000030507 AIDS Diseases 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 102000007072 Nerve Growth Factors Human genes 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 230000036543 hypotension Effects 0.000 claims description 4
- 208000002780 macular degeneration Diseases 0.000 claims description 4
- 239000003900 neurotrophic factor Substances 0.000 claims description 4
- 239000012217 radiopharmaceutical Substances 0.000 claims description 4
- 229940121896 radiopharmaceutical Drugs 0.000 claims description 4
- 230000002799 radiopharmaceutical effect Effects 0.000 claims description 4
- 208000007848 Alcoholism Diseases 0.000 claims description 3
- 208000000044 Amnesia Diseases 0.000 claims description 3
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 3
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 3
- 206010003805 Autism Diseases 0.000 claims description 3
- 208000020706 Autistic disease Diseases 0.000 claims description 3
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 3
- 208000003098 Ganglion Cysts Diseases 0.000 claims description 3
- 208000010496 Heart Arrest Diseases 0.000 claims description 3
- 208000006136 Leigh Disease Diseases 0.000 claims description 3
- 208000026139 Memory disease Diseases 0.000 claims description 3
- 208000019022 Mood disease Diseases 0.000 claims description 3
- 208000005400 Synovial Cyst Diseases 0.000 claims description 3
- 201000007930 alcohol dependence Diseases 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 210000001992 atrioventricular node Anatomy 0.000 claims description 3
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 3
- 210000004375 bundle of his Anatomy 0.000 claims description 3
- 108700001003 carbamylated erythropoietin Proteins 0.000 claims description 3
- 206010008129 cerebral palsy Diseases 0.000 claims description 3
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical group NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 claims description 3
- 210000003494 hepatocyte Anatomy 0.000 claims description 3
- 210000004347 intestinal mucosa Anatomy 0.000 claims description 3
- 230000006984 memory degeneration Effects 0.000 claims description 3
- 208000023060 memory loss Diseases 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 210000003668 pericyte Anatomy 0.000 claims description 3
- 108091008695 photoreceptors Proteins 0.000 claims description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 3
- 210000000130 stem cell Anatomy 0.000 claims description 3
- 210000002536 stromal cell Anatomy 0.000 claims description 3
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 claims description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 2
- 208000017507 Leigh syndrome Diseases 0.000 claims description 2
- 150000001718 carbodiimides Chemical class 0.000 claims description 2
- OILAIQUEIWYQPH-UHFFFAOYSA-N cyclohexane-1,2-dione Chemical compound O=C1CCCCC1=O OILAIQUEIWYQPH-UHFFFAOYSA-N 0.000 claims description 2
- 125000005594 diketone group Chemical group 0.000 claims description 2
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 claims 7
- 150000001510 aspartic acids Chemical class 0.000 claims 7
- 108091034117 Oligonucleotide Proteins 0.000 claims 3
- 239000004599 antimicrobial Substances 0.000 claims 3
- 229940041181 antineoplastic drug Drugs 0.000 claims 3
- 239000000074 antisense oligonucleotide Substances 0.000 claims 3
- 238000012230 antisense oligonucleotides Methods 0.000 claims 3
- 229960003444 immunosuppressant agent Drugs 0.000 claims 3
- 230000001861 immunosuppressant effect Effects 0.000 claims 3
- 239000000018 receptor agonist Substances 0.000 claims 3
- 229940044601 receptor agonist Drugs 0.000 claims 3
- 239000002464 receptor antagonist Substances 0.000 claims 3
- 229940044551 receptor antagonist Drugs 0.000 claims 3
- 206010007558 Cardiac failure chronic Diseases 0.000 claims 1
- 230000036772 blood pressure Effects 0.000 claims 1
- BFSYFTQDGRDJNV-AYHFEMFVSA-N fructosyllysine Chemical compound OC(=O)[C@@H](N)CCCCNCC(=O)[C@@H](O)[C@H](O)[C@H](O)CO BFSYFTQDGRDJNV-AYHFEMFVSA-N 0.000 claims 1
- 230000003716 rejuvenation Effects 0.000 claims 1
- 208000037816 tissue injury Diseases 0.000 claims 1
- 238000011065 in-situ storage Methods 0.000 abstract description 15
- 238000001727 in vivo Methods 0.000 abstract description 11
- 230000009885 systemic effect Effects 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 48
- 239000000243 solution Substances 0.000 description 44
- 241001465754 Metazoa Species 0.000 description 39
- 241000700159 Rattus Species 0.000 description 39
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 35
- 239000000047 product Substances 0.000 description 35
- 201000010099 disease Diseases 0.000 description 31
- 108090000623 proteins and genes Proteins 0.000 description 28
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 150000001875 compounds Chemical class 0.000 description 23
- 239000011780 sodium chloride Substances 0.000 description 22
- 230000000670 limiting effect Effects 0.000 description 21
- 238000001356 surgical procedure Methods 0.000 description 20
- 238000000338 in vitro Methods 0.000 description 19
- -1 markers Substances 0.000 description 19
- 235000018102 proteins Nutrition 0.000 description 19
- 102000004169 proteins and genes Human genes 0.000 description 19
- 229910001868 water Inorganic materials 0.000 description 19
- 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 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- 210000005166 vasculature Anatomy 0.000 description 18
- 235000001014 amino acid Nutrition 0.000 description 17
- 208000035475 disorder Diseases 0.000 description 17
- 229940024606 amino acid Drugs 0.000 description 16
- 150000001413 amino acids Chemical class 0.000 description 16
- 230000000302 ischemic effect Effects 0.000 description 16
- 108020003175 receptors Proteins 0.000 description 16
- 102000005962 receptors Human genes 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 15
- 238000003556 assay Methods 0.000 description 15
- 230000001225 therapeutic effect Effects 0.000 description 15
- 206010021143 Hypoxia Diseases 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 13
- 238000000502 dialysis Methods 0.000 description 13
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 13
- 230000010412 perfusion Effects 0.000 description 13
- 108010075944 Erythropoietin Receptors Proteins 0.000 description 12
- 102100036509 Erythropoietin receptor Human genes 0.000 description 12
- 230000008901 benefit Effects 0.000 description 12
- OJUGVDODNPJEEC-UHFFFAOYSA-N phenylglyoxal Chemical compound O=CC(=O)C1=CC=CC=C1 OJUGVDODNPJEEC-UHFFFAOYSA-N 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
- 210000001185 bone marrow Anatomy 0.000 description 11
- 230000001684 chronic effect Effects 0.000 description 11
- 239000000499 gel Substances 0.000 description 11
- 210000004498 neuroglial cell Anatomy 0.000 description 11
- 125000003396 thiol group Chemical group [H]S* 0.000 description 11
- AIJULSRZWUXGPQ-UHFFFAOYSA-N Methylglyoxal Chemical compound CC(=O)C=O AIJULSRZWUXGPQ-UHFFFAOYSA-N 0.000 description 10
- 230000001154 acute effect Effects 0.000 description 10
- 230000000913 erythropoietic effect Effects 0.000 description 10
- 125000000524 functional group Chemical group 0.000 description 10
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 10
- 238000006722 reduction reaction Methods 0.000 description 10
- 210000002966 serum Anatomy 0.000 description 10
- 230000032258 transport Effects 0.000 description 10
- 208000030886 Traumatic Brain injury Diseases 0.000 description 9
- 230000002411 adverse Effects 0.000 description 9
- 229960002685 biotin Drugs 0.000 description 9
- 235000020958 biotin Nutrition 0.000 description 9
- 239000011616 biotin Substances 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 210000003169 central nervous system Anatomy 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 230000026045 iodination Effects 0.000 description 9
- 238000006192 iodination reaction Methods 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 210000003491 skin Anatomy 0.000 description 9
- 239000012064 sodium phosphate buffer Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 230000001146 hypoxic effect Effects 0.000 description 8
- 238000001990 intravenous administration Methods 0.000 description 8
- 210000000496 pancreas Anatomy 0.000 description 8
- 230000001105 regulatory effect Effects 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 7
- 239000013543 active substance Substances 0.000 description 7
- 230000003110 anti-inflammatory effect Effects 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- 230000003915 cell function Effects 0.000 description 7
- 238000007385 chemical modification Methods 0.000 description 7
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 7
- 229960003957 dexamethasone Drugs 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 7
- 230000000324 neuroprotective effect Effects 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 238000011321 prophylaxis Methods 0.000 description 7
- 238000001959 radiotherapy Methods 0.000 description 7
- 230000002861 ventricular Effects 0.000 description 7
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000004475 Arginine Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 6
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 6
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 6
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 6
- 102100031614 Ciliary neurotrophic factor Human genes 0.000 description 6
- 239000004971 Cross linker Substances 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 6
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 6
- 102000015336 Nerve Growth Factor Human genes 0.000 description 6
- 108010006232 Neuraminidase Proteins 0.000 description 6
- 108090000141 Sialyltransferases Proteins 0.000 description 6
- 102000003838 Sialyltransferases Human genes 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 6
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 description 6
- 230000002612 cardiopulmonary effect Effects 0.000 description 6
- 230000001054 cortical effect Effects 0.000 description 6
- 201000002491 encephalomyelitis Diseases 0.000 description 6
- 230000010437 erythropoiesis Effects 0.000 description 6
- 229940015043 glyoxal Drugs 0.000 description 6
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 6
- 230000007954 hypoxia Effects 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 238000001802 infusion Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 6
- 230000007659 motor function Effects 0.000 description 6
- 229940053128 nerve growth factor Drugs 0.000 description 6
- 239000002581 neurotoxin Substances 0.000 description 6
- 231100000618 neurotoxin Toxicity 0.000 description 6
- 238000007911 parenteral administration Methods 0.000 description 6
- 210000001428 peripheral nervous system Anatomy 0.000 description 6
- 238000004321 preservation Methods 0.000 description 6
- 238000011027 product recovery Methods 0.000 description 6
- 230000010410 reperfusion Effects 0.000 description 6
- 239000012266 salt solution Substances 0.000 description 6
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 6
- 239000001509 sodium citrate Substances 0.000 description 6
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 6
- 229940014800 succinic anhydride Drugs 0.000 description 6
- 235000000346 sugar Nutrition 0.000 description 6
- 210000001578 tight junction Anatomy 0.000 description 6
- 230000000451 tissue damage Effects 0.000 description 6
- 231100000827 tissue damage Toxicity 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 102100039289 Glial fibrillary acidic protein Human genes 0.000 description 5
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 5
- 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 5
- 108010051696 Growth Hormone Proteins 0.000 description 5
- 101000987586 Homo sapiens Eosinophil peroxidase Proteins 0.000 description 5
- 101000920686 Homo sapiens Erythropoietin Proteins 0.000 description 5
- 206010020772 Hypertension Diseases 0.000 description 5
- 206010061216 Infarction Diseases 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- 102000004889 Interleukin-6 Human genes 0.000 description 5
- 108090001005 Interleukin-6 Proteins 0.000 description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 5
- 102000005348 Neuraminidase Human genes 0.000 description 5
- 102100038803 Somatotropin Human genes 0.000 description 5
- 208000005735 Water intoxication Diseases 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 5
- 230000021235 carbamoylation Effects 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 150000007942 carboxylates Chemical group 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 5
- 238000013270 controlled release Methods 0.000 description 5
- 238000012217 deletion Methods 0.000 description 5
- 230000037430 deletion Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 239000000975 dye Substances 0.000 description 5
- 230000004064 dysfunction Effects 0.000 description 5
- 239000013604 expression vector Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 5
- 239000000122 growth hormone Substances 0.000 description 5
- 102000044890 human EPO Human genes 0.000 description 5
- 230000007574 infarction Effects 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 230000033001 locomotion Effects 0.000 description 5
- 210000002569 neuron Anatomy 0.000 description 5
- 230000007170 pathology Effects 0.000 description 5
- 208000020431 spinal cord injury Diseases 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000003053 toxin Substances 0.000 description 5
- 231100000765 toxin Toxicity 0.000 description 5
- 108700012359 toxins Proteins 0.000 description 5
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 5
- 235000002374 tyrosine Nutrition 0.000 description 5
- FJQZXCPWAGYPSD-UHFFFAOYSA-N 1,3,4,6-tetrachloro-3a,6a-diphenylimidazo[4,5-d]imidazole-2,5-dione Chemical compound ClN1C(=O)N(Cl)C2(C=3C=CC=CC=3)N(Cl)C(=O)N(Cl)C12C1=CC=CC=C1 FJQZXCPWAGYPSD-UHFFFAOYSA-N 0.000 description 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- 206010002329 Aneurysm Diseases 0.000 description 4
- 201000006474 Brain Ischemia Diseases 0.000 description 4
- 206010008120 Cerebral ischaemia Diseases 0.000 description 4
- 201000006306 Cor pulmonale Diseases 0.000 description 4
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 4
- 108010074604 Epoetin Alfa Proteins 0.000 description 4
- 102000003886 Glycoproteins Human genes 0.000 description 4
- 108090000288 Glycoproteins Proteins 0.000 description 4
- VLSMHEGGTFMBBZ-OOZYFLPDSA-M Kainate Chemical compound CC(=C)[C@H]1C[NH2+][C@H](C([O-])=O)[C@H]1CC([O-])=O VLSMHEGGTFMBBZ-OOZYFLPDSA-M 0.000 description 4
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 4
- 102100040247 Tumor necrosis factor Human genes 0.000 description 4
- 210000001056 activated astrocyte Anatomy 0.000 description 4
- 210000000988 bone and bone Anatomy 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 206010008118 cerebral infarction Diseases 0.000 description 4
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 230000002950 deficient Effects 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 210000003743 erythrocyte Anatomy 0.000 description 4
- 125000004185 ester group Chemical group 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000002523 gelfiltration Methods 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 230000013595 glycosylation Effects 0.000 description 4
- 238000006206 glycosylation reaction Methods 0.000 description 4
- 210000003141 lower extremity Anatomy 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 230000003818 metabolic dysfunction Effects 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- 210000003061 neural cell Anatomy 0.000 description 4
- 230000016273 neuron death Effects 0.000 description 4
- 238000006396 nitration reaction Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 230000004768 organ dysfunction Effects 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 230000017854 proteolysis Effects 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 230000035322 succinylation Effects 0.000 description 4
- 238000010613 succinylation reaction Methods 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 230000009092 tissue dysfunction Effects 0.000 description 4
- 238000011200 topical administration Methods 0.000 description 4
- 230000000472 traumatic effect Effects 0.000 description 4
- LYRCQNDYYRPFMF-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C LYRCQNDYYRPFMF-UHFFFAOYSA-N 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- UVGHPGOONBRLCX-NJSLBKSFSA-N (2,5-dioxopyrrolidin-1-yl) 6-[5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]hexanoate Chemical compound C([C@H]1[C@H]2NC(=O)N[C@H]2CS1)CCCC(=O)NCCCCCC(=O)ON1C(=O)CCC1=O UVGHPGOONBRLCX-NJSLBKSFSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000000884 Airway Obstruction Diseases 0.000 description 3
- 206010003591 Ataxia Diseases 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
- 229930105110 Cyclosporin A Natural products 0.000 description 3
- 108010036949 Cyclosporine Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 3
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 3
- 241000238631 Hexapoda Species 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 208000013016 Hypoglycemia Diseases 0.000 description 3
- 102000000589 Interleukin-1 Human genes 0.000 description 3
- 108010002352 Interleukin-1 Proteins 0.000 description 3
- 102000000588 Interleukin-2 Human genes 0.000 description 3
- 108010002350 Interleukin-2 Proteins 0.000 description 3
- 102000000646 Interleukin-3 Human genes 0.000 description 3
- 108010002386 Interleukin-3 Proteins 0.000 description 3
- 208000032382 Ischaemic stroke Diseases 0.000 description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 3
- 208000019693 Lung disease Diseases 0.000 description 3
- 201000009906 Meningitis Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910020889 NaBH3 Inorganic materials 0.000 description 3
- 208000037658 Parkinson-dementia complex of Guam Diseases 0.000 description 3
- 208000005374 Poisoning Diseases 0.000 description 3
- 206010038848 Retinal detachment Diseases 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- NYTOUQBROMCLBJ-UHFFFAOYSA-N Tetranitromethane Chemical compound [O-][N+](=O)C([N+]([O-])=O)([N+]([O-])=O)[N+]([O-])=O NYTOUQBROMCLBJ-UHFFFAOYSA-N 0.000 description 3
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 3
- 102000011117 Transforming Growth Factor beta2 Human genes 0.000 description 3
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 3
- 101800000304 Transforming growth factor beta-2 Proteins 0.000 description 3
- 102000056172 Transforming growth factor beta-3 Human genes 0.000 description 3
- 108090000097 Transforming growth factor beta-3 Proteins 0.000 description 3
- 208000009979 Traumatic Amputation Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 230000021736 acetylation Effects 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 208000013968 amyotrophic lateral sclerosis-parkinsonism-dementia complex Diseases 0.000 description 3
- 208000014450 amyotrophic lateral sclerosis-parkinsonism/dementia complex 1 Diseases 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940121357 antivirals Drugs 0.000 description 3
- 230000001363 autoimmune Effects 0.000 description 3
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 3
- 238000003287 bathing Methods 0.000 description 3
- 230000001588 bifunctional effect Effects 0.000 description 3
- 210000002449 bone cell Anatomy 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 230000005779 cell damage Effects 0.000 description 3
- 230000030833 cell death Effects 0.000 description 3
- 229960001265 ciclosporin Drugs 0.000 description 3
- 230000004087 circulation Effects 0.000 description 3
- 208000010877 cognitive disease Diseases 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 239000003431 cross linking reagent Substances 0.000 description 3
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 3
- 229930182912 cyclosporin Natural products 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002148 esters Chemical group 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 230000002518 glial effect Effects 0.000 description 3
- 238000003306 harvesting Methods 0.000 description 3
- 210000005260 human cell Anatomy 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000037417 hyperactivation Effects 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- 229940125721 immunosuppressive agent Drugs 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 229940076264 interleukin-3 Drugs 0.000 description 3
- 229940100601 interleukin-6 Drugs 0.000 description 3
- 239000012948 isocyanate Substances 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 230000000926 neurological effect Effects 0.000 description 3
- 230000004112 neuroprotection Effects 0.000 description 3
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 231100000572 poisoning Toxicity 0.000 description 3
- 230000000607 poisoning effect Effects 0.000 description 3
- 229920005862 polyol Polymers 0.000 description 3
- 150000003077 polyols Chemical class 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 230000008092 positive effect Effects 0.000 description 3
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 230000000541 pulsatile effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 210000001525 retina Anatomy 0.000 description 3
- 230000004264 retinal detachment Effects 0.000 description 3
- 210000004927 skin cell Anatomy 0.000 description 3
- 239000001488 sodium phosphate Substances 0.000 description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 230000035882 stress Effects 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 125000003831 tetrazolyl group Chemical group 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 229940099456 transforming growth factor beta 1 Drugs 0.000 description 3
- 229940072041 transforming growth factor beta 2 Drugs 0.000 description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- 102000003390 tumor necrosis factor Human genes 0.000 description 3
- 230000002485 urinary effect Effects 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- 238000002689 xenotransplantation Methods 0.000 description 3
- 229960002555 zidovudine Drugs 0.000 description 3
- JWDFQMWEFLOOED-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(pyridin-2-yldisulfanyl)propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSSC1=CC=CC=N1 JWDFQMWEFLOOED-UHFFFAOYSA-N 0.000 description 2
- DIGQNXIGRZPYDK-WKSCXVIASA-N (2R)-6-amino-2-[[2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[[(2R,3S)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[2-[(2-amino-1-hydroxyethylidene)amino]-3-carboxy-1-hydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1,5-dihydroxy-5-iminopentylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]hexanoic acid Chemical compound C[C@@H]([C@@H](C(=N[C@@H](CS)C(=N[C@@H](C)C(=N[C@@H](CO)C(=NCC(=N[C@@H](CCC(=N)O)C(=NC(CS)C(=N[C@H]([C@H](C)O)C(=N[C@H](CS)C(=N[C@H](CO)C(=NCC(=N[C@H](CS)C(=NCC(=N[C@H](CCCCN)C(=O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)N=C([C@H](CS)N=C([C@H](CO)N=C([C@H](CO)N=C([C@H](C)N=C(CN=C([C@H](CO)N=C([C@H](CS)N=C(CN=C(C(CS)N=C(C(CC(=O)O)N=C(CN)O)O)O)O)O)O)O)O)O)O)O)O DIGQNXIGRZPYDK-WKSCXVIASA-N 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- FJIGLGLZNXQEDE-GDVGLLTNSA-N (2s)-2,6-diaminooctanedioic acid Chemical compound OC(=O)CC(N)CCC[C@H](N)C(O)=O FJIGLGLZNXQEDE-GDVGLLTNSA-N 0.000 description 2
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 2
- NHJVRSWLHSJWIN-UHFFFAOYSA-N 2,4,6-trinitrobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O NHJVRSWLHSJWIN-UHFFFAOYSA-N 0.000 description 2
- 125000001894 2,4,6-trinitrophenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1[N+]([O-])=O)[N+]([O-])=O)[N+]([O-])=O 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 2
- 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 2
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 206010002199 Anaphylactic shock Diseases 0.000 description 2
- 206010058178 Aortic occlusion Diseases 0.000 description 2
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 2
- 206010003497 Asphyxia Diseases 0.000 description 2
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 2
- 108090001008 Avidin Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 208000031229 Cardiomyopathies Diseases 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 206010008589 Choking Diseases 0.000 description 2
- 102000004420 Creatine Kinase Human genes 0.000 description 2
- 108010042126 Creatine kinase Proteins 0.000 description 2
- 108010000437 Deamino Arginine Vasopressin Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010013654 Drug abuse Diseases 0.000 description 2
- 206010014561 Emphysema Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 208000018522 Gastrointestinal disease Diseases 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- 208000007465 Giant cell arteritis Diseases 0.000 description 2
- 206010018364 Glomerulonephritis Diseases 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 206010019345 Heat stroke Diseases 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- 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 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 102000003792 Metallothionein Human genes 0.000 description 2
- 108090000157 Metallothionein Proteins 0.000 description 2
- 208000021642 Muscular disease Diseases 0.000 description 2
- 201000009623 Myopathy Diseases 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- 208000006079 Near drowning Diseases 0.000 description 2
- 206010051606 Necrotising colitis Diseases 0.000 description 2
- 206010060860 Neurological symptom Diseases 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 2
- 208000003435 Optic Neuritis Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- 206010033892 Paraplegia Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 208000024777 Prion disease Diseases 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 206010037180 Psychiatric symptoms Diseases 0.000 description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 description 2
- 208000004186 Pulmonary Heart Disease Diseases 0.000 description 2
- 206010037437 Pulmonary thrombosis Diseases 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 2
- 208000021063 Respiratory fume inhalation disease Diseases 0.000 description 2
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 2
- 206010038926 Retinopathy hypertensive Diseases 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- 206010040070 Septic Shock Diseases 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 208000004891 Shellfish Poisoning Diseases 0.000 description 2
- 102100028755 Sialidase-2 Human genes 0.000 description 2
- 206010040642 Sickle cell anaemia with crisis Diseases 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 108010022394 Threonine synthase Proteins 0.000 description 2
- 102000000591 Tight Junction Proteins Human genes 0.000 description 2
- 108010002321 Tight Junction Proteins Proteins 0.000 description 2
- 241000723873 Tobacco mosaic virus Species 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 206010053648 Vascular occlusion Diseases 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000003172 aldehyde group Chemical group 0.000 description 2
- 125000003275 alpha amino acid group Chemical group 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 210000000709 aorta Anatomy 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 208000021328 arterial occlusion Diseases 0.000 description 2
- 206010063452 arteriosclerotic retinopathy Diseases 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 210000004781 brain capillary Anatomy 0.000 description 2
- 208000029028 brain injury Diseases 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 229960003150 bupivacaine Drugs 0.000 description 2
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 210000001715 carotid artery Anatomy 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 210000004720 cerebrum Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229960003920 cocaine Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 208000018631 connective tissue disease Diseases 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 201000001981 dermatomyositis Diseases 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- NFLWUMRGJYTJIN-NXBWRCJVSA-N desmopressin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSCCC(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(N)=O)=O)CCC(=O)N)C1=CC=CC=C1 NFLWUMRGJYTJIN-NXBWRCJVSA-N 0.000 description 2
- 229960004281 desmopressin Drugs 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 230000035487 diastolic blood pressure Effects 0.000 description 2
- 102000004419 dihydrofolate reductase Human genes 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000003292 diminished effect Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- VZFRNCSOCOPNDB-AJKFJWDBSA-N domoic acid Chemical compound OC(=O)[C@@H](C)\C=C\C=C(/C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VZFRNCSOCOPNDB-AJKFJWDBSA-N 0.000 description 2
- VZFRNCSOCOPNDB-UHFFFAOYSA-N domoic acid Natural products OC(=O)C(C)C=CC=C(C)C1CNC(C(O)=O)C1CC(O)=O VZFRNCSOCOPNDB-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 206010014599 encephalitis Diseases 0.000 description 2
- 210000003890 endocrine cell Anatomy 0.000 description 2
- 230000008497 endothelial barrier function Effects 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 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 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 210000005153 frontal cortex Anatomy 0.000 description 2
- 230000004914 glial activation Effects 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000004997 halocarbonyl group Chemical group 0.000 description 2
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 2
- 229960003132 halothane Drugs 0.000 description 2
- 230000004217 heart function Effects 0.000 description 2
- 210000005003 heart tissue Anatomy 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 210000001320 hippocampus Anatomy 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 201000001948 hypertensive retinopathy Diseases 0.000 description 2
- 208000021822 hypotensive Diseases 0.000 description 2
- 230000001077 hypotensive effect Effects 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 238000010874 in vitro model Methods 0.000 description 2
- 238000005462 in vivo assay Methods 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000001524 infective effect Effects 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 206010022498 insulinoma Diseases 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 230000002083 iodinating effect Effects 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 208000037906 ischaemic injury Diseases 0.000 description 2
- VZFRNCSOCOPNDB-OXYNIABMSA-N isodomoic acid D Natural products CC(C=C/C=C(/C)C1CNC(C1CC(=O)O)C(=O)O)C(=O)O VZFRNCSOCOPNDB-OXYNIABMSA-N 0.000 description 2
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 238000011694 lewis rat Methods 0.000 description 2
- 244000144972 livestock Species 0.000 description 2
- 230000003137 locomotive effect Effects 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000002418 meninge Anatomy 0.000 description 2
- 230000006371 metabolic abnormality Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 208000012268 mitochondrial disease Diseases 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 210000003928 nasal cavity Anatomy 0.000 description 2
- 208000004995 necrotizing enterocolitis Diseases 0.000 description 2
- 230000007658 neurological function Effects 0.000 description 2
- 230000003961 neuronal insult Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 210000001331 nose Anatomy 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000000162 organ preservation solution Substances 0.000 description 2
- 210000003300 oropharynx Anatomy 0.000 description 2
- 210000000963 osteoblast Anatomy 0.000 description 2
- 210000002997 osteoclast Anatomy 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 208000021255 pancreatic insulinoma Diseases 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 230000003071 parasitic effect Effects 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 201000006195 perinatal necrotizing enterocolitis Diseases 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 208000005987 polymyositis Diseases 0.000 description 2
- 229940029359 procrit Drugs 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 238000003259 recombinant expression Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000001172 regenerating effect Effects 0.000 description 2
- 210000002254 renal artery Anatomy 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 208000017443 reproductive system disease Diseases 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000002271 resection Methods 0.000 description 2
- 208000023504 respiratory system disease Diseases 0.000 description 2
- 210000001927 retinal artery Anatomy 0.000 description 2
- 210000001957 retinal vein Anatomy 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 201000000306 sarcoidosis Diseases 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 230000036303 septic shock Effects 0.000 description 2
- 235000004400 serine Nutrition 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 239000002356 single layer Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000013222 sprague-dawley male rat Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 206010043207 temporal arteritis Diseases 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000005945 translocation Effects 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 208000009174 transverse myelitis Diseases 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 230000006433 tumor necrosis factor production Effects 0.000 description 2
- 210000003932 urinary bladder Anatomy 0.000 description 2
- 208000014001 urinary system disease Diseases 0.000 description 2
- 208000021331 vascular occlusion disease Diseases 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- FXYPGCIGRDZWNR-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-[[3-(2,5-dioxopyrrolidin-1-yl)oxy-3-oxopropyl]disulfanyl]propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSSCCC(=O)ON1C(=O)CCC1=O FXYPGCIGRDZWNR-UHFFFAOYSA-N 0.000 description 1
- GKSPIZSKQWTXQG-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-[1-(pyridin-2-yldisulfanyl)ethyl]benzoate Chemical compound C=1C=C(C(=O)ON2C(CCC2=O)=O)C=CC=1C(C)SSC1=CC=CC=N1 GKSPIZSKQWTXQG-UHFFFAOYSA-N 0.000 description 1
- ZZYYVZYAZCMNPG-MLWJPKLSSA-N (2s)-6-amino-2-(1-carboxyethylamino)hexanoic acid Chemical group OC(=O)C(C)N[C@H](C(O)=O)CCCCN ZZYYVZYAZCMNPG-MLWJPKLSSA-N 0.000 description 1
- UOUBHJRCKHLGFB-DGJUNBOTSA-N (3s)-3-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-5-chloro-4-oxopentanoic acid Chemical compound OC(=O)C[C@@H](C(=O)CCl)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(C)=O)CC1=CC=C(O)C=C1 UOUBHJRCKHLGFB-DGJUNBOTSA-N 0.000 description 1
- VHYRLCJMMJQUBY-UHFFFAOYSA-N 1-[4-[4-(2,5-dioxopyrrol-1-yl)phenyl]butanoyloxy]-2,5-dioxopyrrolidine-3-sulfonic acid Chemical compound O=C1C(S(=O)(=O)O)CC(=O)N1OC(=O)CCCC1=CC=C(N2C(C=CC2=O)=O)C=C1 VHYRLCJMMJQUBY-UHFFFAOYSA-N 0.000 description 1
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 1
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 description 1
- NHJVRSWLHSJWIN-UHFFFAOYSA-M 2,4,6-trinitrobenzenesulfonate Chemical group [O-][N+](=O)C1=CC([N+]([O-])=O)=C(S([O-])(=O)=O)C([N+]([O-])=O)=C1 NHJVRSWLHSJWIN-UHFFFAOYSA-M 0.000 description 1
- KZDCMKVLEYCGQX-UDPGNSCCSA-N 2-(diethylamino)ethyl 4-aminobenzoate;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;hydrate Chemical compound O.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 KZDCMKVLEYCGQX-UDPGNSCCSA-N 0.000 description 1
- MIJDSYMOBYNHOT-UHFFFAOYSA-N 2-(ethylamino)ethanol Chemical compound CCNCCO MIJDSYMOBYNHOT-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical group C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 1
- SHXWCVYOXRDMCX-UHFFFAOYSA-N 3,4-methylenedioxymethamphetamine Chemical compound CNC(C)CC1=CC=C2OCOC2=C1 SHXWCVYOXRDMCX-UHFFFAOYSA-N 0.000 description 1
- FTZIQBGFCYJWKA-UHFFFAOYSA-N 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Chemical class S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 FTZIQBGFCYJWKA-UHFFFAOYSA-N 0.000 description 1
- QRYXYRQPMWQIDM-UHFFFAOYSA-N 3-benzoyl-3-(2,5-dioxopyrrol-1-yl)-1-hydroxypyrrolidine-2,5-dione Chemical compound O=C1N(O)C(=O)CC1(C(=O)C=1C=CC=CC=1)N1C(=O)C=CC1=O QRYXYRQPMWQIDM-UHFFFAOYSA-N 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- LBYBJJOUISDNRJ-UHFFFAOYSA-N 4-isothiocyanatobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(N=C=S)C=C1 LBYBJJOUISDNRJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 206010060933 Adverse event Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 102000012002 Aquaporin 4 Human genes 0.000 description 1
- 108010036280 Aquaporin 4 Proteins 0.000 description 1
- 108010002913 Asialoglycoproteins Proteins 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000030016 Avascular necrosis Diseases 0.000 description 1
- 206010061688 Barotrauma Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010049765 Bradyarrhythmia Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 102100033787 CMP-sialic acid transporter Human genes 0.000 description 1
- 101710150575 CMP-sialic acid transporter Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 description 1
- 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 208000001408 Carbon monoxide poisoning Diseases 0.000 description 1
- 102000003670 Carboxypeptidase B Human genes 0.000 description 1
- 108090000087 Carboxypeptidase B Proteins 0.000 description 1
- 102000000496 Carboxypeptidases A Human genes 0.000 description 1
- 108010080937 Carboxypeptidases A Proteins 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 108090000426 Caspase-1 Proteins 0.000 description 1
- 102100035904 Caspase-1 Human genes 0.000 description 1
- 241000701489 Cauliflower mosaic virus Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 108700027941 Celsior Proteins 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical class ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 108010038061 Chymotrypsinogen Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010010264 Condition aggravated Diseases 0.000 description 1
- 208000002330 Congenital Heart Defects Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010011086 Coronary artery occlusion Diseases 0.000 description 1
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 1
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 208000025962 Crush injury Diseases 0.000 description 1
- 108010025880 Cyclomaltodextrin glucanotransferase Proteins 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 206010011951 Decompression Sickness Diseases 0.000 description 1
- 206010011985 Decubitus ulcer Diseases 0.000 description 1
- 208000031124 Dementia Alzheimer type Diseases 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 230000010777 Disulfide Reduction Effects 0.000 description 1
- 208000003870 Drug Overdose Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 1
- 206010014405 Electrocution Diseases 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 208000003241 Fat Embolism Diseases 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 241000219726 Griffonia simplicifolia Species 0.000 description 1
- 206010056438 Growth hormone deficiency Diseases 0.000 description 1
- 102000015779 HDL Lipoproteins Human genes 0.000 description 1
- 108010010234 HDL Lipoproteins Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000000435 Heart Rupture Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 208000002972 Hepatolenticular Degeneration Diseases 0.000 description 1
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 1
- 101100321817 Human parvovirus B19 (strain HV) 7.5K gene Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 201000002980 Hyperparathyroidism Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 208000004619 Inert Gas Narcosis Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000009773 Insulin Coma Diseases 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 208000009829 Lewy Body Disease Diseases 0.000 description 1
- 201000002832 Lewy body dementia Diseases 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 208000035346 Margins of Excision Diseases 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- 102000009664 Microtubule-Associated Proteins Human genes 0.000 description 1
- 108010020004 Microtubule-Associated Proteins Proteins 0.000 description 1
- 241001602730 Monza Species 0.000 description 1
- 238000012347 Morris Water Maze Methods 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241001049988 Mycobacterium tuberculosis H37Ra Species 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 206010068871 Myotonic dystrophy Diseases 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- SQVRNKJHWKZAKO-LUWBGTNYSA-N N-acetylneuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)CC(O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-LUWBGTNYSA-N 0.000 description 1
- 206010028885 Necrotising fasciitis Diseases 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 208000031264 Nerve root compression Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 101710138657 Neurotoxin Proteins 0.000 description 1
- 206010057852 Nicotine dependence Diseases 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- XCCHFTFMUQWCPL-GXQDVZPWSA-N ON1C(CCC1=O)=O.C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@H]12)(=O)C(C(=O)O)CCCCN Chemical compound ON1C(CCC1=O)=O.C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@H]12)(=O)C(C(=O)O)CCCCN XCCHFTFMUQWCPL-GXQDVZPWSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 206010031252 Osteomyelitis Diseases 0.000 description 1
- 206010031264 Osteonecrosis Diseases 0.000 description 1
- 206010049088 Osteopenia Diseases 0.000 description 1
- 206010033296 Overdoses Diseases 0.000 description 1
- 241001524178 Paenarthrobacter ureafaciens Species 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 108020002230 Pancreatic Ribonuclease Proteins 0.000 description 1
- 102000005891 Pancreatic ribonuclease Human genes 0.000 description 1
- 108010067035 Pancrelipase Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229920000153 Povidone-iodine Polymers 0.000 description 1
- 206010052649 Primary hypogonadism Diseases 0.000 description 1
- 201000001068 Prinzmetal angina Diseases 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 241000219492 Quercus Species 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 206010037742 Rabies Diseases 0.000 description 1
- 206010037779 Radiculopathy Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 239000008156 Ringer's lactate solution Substances 0.000 description 1
- 206010039203 Road traffic accident Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 206010040576 Shock hypoglycaemic Diseases 0.000 description 1
- 108050000175 Sialidase-2 Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010041549 Spinal cord compression Diseases 0.000 description 1
- 208000036982 Spinal cord ischaemia Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 208000037065 Subacute sclerosing leukoencephalitis Diseases 0.000 description 1
- 206010042297 Subacute sclerosing panencephalitis Diseases 0.000 description 1
- 208000002667 Subdural Hematoma Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 101001018322 Sus scrofa Myelin basic protein Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000186338 Thermoanaerobacter sp. Species 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- 208000025569 Tobacco Use disease Diseases 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 208000026911 Tuberous sclerosis complex Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 239000012840 University of Wisconsin (UW) solution Substances 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 208000009325 Variant Angina Pectoris Diseases 0.000 description 1
- 206010047626 Vitamin D Deficiency Diseases 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 208000018839 Wilson disease Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 210000001642 activated microglia Anatomy 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 210000002556 adrenal cortex cell Anatomy 0.000 description 1
- 208000017515 adrenocortical insufficiency Diseases 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 206010068168 androgenetic alopecia Diseases 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 210000002159 anterior chamber Anatomy 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 229940090047 auto-injector Drugs 0.000 description 1
- 230000037424 autonomic function Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 108010064886 beta-D-galactoside alpha 2-6-sialyltransferase Proteins 0.000 description 1
- 108010057005 beta-galactoside alpha-2,3-sialyltransferase Proteins 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000004057 biotinyl group Chemical group [H]N1C(=O)N([H])[C@]2([H])[C@@]([H])(SC([H])([H])[C@]12[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 208000006218 bradycardia Diseases 0.000 description 1
- 230000007177 brain activity Effects 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 238000007816 calorimetric assay Methods 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 210000001326 carotid sinus Anatomy 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 210000003737 chromaffin cell Anatomy 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 210000003703 cisterna magna Anatomy 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 208000028831 congenital heart disease Diseases 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- QTCANKDTWWSCMR-UHFFFAOYSA-N costic aldehyde Natural products C1CCC(=C)C2CC(C(=C)C=O)CCC21C QTCANKDTWWSCMR-UHFFFAOYSA-N 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 210000003674 cytoplasmic vesicle Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 108010004031 deoxyribonuclease A Proteins 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 229960002069 diamorphine Drugs 0.000 description 1
- 230000003205 diastolic effect Effects 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 235000021186 dishes Nutrition 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
- ZWIBGKZDAWNIFC-UHFFFAOYSA-N disuccinimidyl suberate Chemical compound O=C1CCC(=O)N1OC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O ZWIBGKZDAWNIFC-UHFFFAOYSA-N 0.000 description 1
- 125000002228 disulfide group Chemical group 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 231100000725 drug overdose Toxicity 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 208000002296 eclampsia Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 238000002571 electroretinography Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000003073 embolic effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000009144 enzymatic modification Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 229960003388 epoetin alfa Drugs 0.000 description 1
- 229940089118 epogen Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 210000003020 exocrine pancreas Anatomy 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 230000002550 fecal effect Effects 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000003619 fibrillary effect Effects 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 210000004186 follicle cell Anatomy 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000003209 gene knockout Methods 0.000 description 1
- 230000023266 generation of precursor metabolites and energy Effects 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 210000002288 golgi apparatus Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 210000002064 heart cell Anatomy 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 208000010726 hind limb paralysis Diseases 0.000 description 1
- 210000004295 hippocampal neuron Anatomy 0.000 description 1
- 201000008298 histiocytosis Diseases 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229940050526 hydroxyethylstarch Drugs 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 230000002727 hyperosmolar Effects 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 230000003960 inflammatory cascade Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 210000002570 interstitial cell Anatomy 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 description 1
- 208000023569 ischemic bowel disease Diseases 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- ISTFUJWTQAMRGA-UHFFFAOYSA-N iso-beta-costal Natural products C1C(C(=C)C=O)CCC2(C)CCCC(C)=C21 ISTFUJWTQAMRGA-UHFFFAOYSA-N 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
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 210000001865 kupffer cell Anatomy 0.000 description 1
- 238000002684 laminectomy Methods 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 210000002332 leydig cell Anatomy 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000001755 magnesium gluconate Substances 0.000 description 1
- 235000015778 magnesium gluconate Nutrition 0.000 description 1
- 229960003035 magnesium gluconate Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- IAKLPCRFBAZVRW-XRDLMGPZSA-L magnesium;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoate;hydrate Chemical compound O.[Mg+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O IAKLPCRFBAZVRW-XRDLMGPZSA-L 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000006609 metabolic stress Effects 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 210000003657 middle cerebral artery Anatomy 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 230000006677 mitochondrial metabolism Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- ZLVYMPOQNJTFSG-QMMMGPOBSA-N monoiodotyrosine Chemical compound OC(=O)[C@@H](NI)CC1=CC=C(O)C=C1 ZLVYMPOQNJTFSG-QMMMGPOBSA-N 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 230000000869 mutational effect Effects 0.000 description 1
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000002956 necrotizing effect Effects 0.000 description 1
- 201000007970 necrotizing fasciitis Diseases 0.000 description 1
- 230000007302 negative regulation of cytokine production Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 230000016195 neuron homeostasis Effects 0.000 description 1
- 230000003955 neuronal function Effects 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000000508 neurotrophic effect Effects 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 231100001223 noncarcinogenic Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 230000000414 obstructive 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
- 239000003883 ointment base Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 238000002559 palpation Methods 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000009518 penetrating injury Effects 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 208000033300 perinatal asphyxia Diseases 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical group OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 108010055896 polyornithine Proteins 0.000 description 1
- 229920002714 polyornithine Polymers 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229960001621 povidone-iodine Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000001292 preischemic effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 210000005000 reproductive tract Anatomy 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000004243 retinal function Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 208000022610 schizoaffective disease Diseases 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 239000006152 selective media Substances 0.000 description 1
- 229940082569 selenite Drugs 0.000 description 1
- MCAHWIHFGHIESP-UHFFFAOYSA-L selenite(2-) Chemical compound [O-][Se]([O-])=O MCAHWIHFGHIESP-UHFFFAOYSA-L 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 230000009450 sialylation Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229920000260 silastic Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 201000002859 sleep apnea Diseases 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 229940005574 sodium gluconate Drugs 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 208000005198 spinal stenosis Diseases 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 210000004500 stellate cell Anatomy 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000010009 steroidogenesis Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000003699 striated muscle Anatomy 0.000 description 1
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 description 1
- 150000008054 sulfonate salts Chemical class 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000011521 systemic chemotherapy Methods 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 231100000398 testicular damage Toxicity 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- AWLILQARPMWUHA-UHFFFAOYSA-M thiopental sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC([S-])=NC1=O AWLILQARPMWUHA-UHFFFAOYSA-M 0.000 description 1
- 229960000340 thiopental sodium Drugs 0.000 description 1
- 235000008521 threonine Nutrition 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 230000001650 transport into the brain Effects 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 208000009999 tuberous sclerosis Diseases 0.000 description 1
- 230000001173 tumoral effect Effects 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 238000011870 unpaired t-test Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- 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
- A61K38/19—Cytokines; Lymphokines; Interferons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- 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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
- C07K14/505—Erythropoietin [EPO]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- erythropoietin As a member of the cytokine superfamily, performs other important physiologic functions which are mediated through interaction with the erythropoietin receptor (erythropoietin-R). These actions include mitogenesis, modulation of calcium influx into smooth muscle cells and neural cells, production of erythrocytes, hyperactivation of platelets, production of thrombocytes, and effects on intermediary metabolism.
- erythropoietin provides compensatory responses that serve to improve hypoxic cellular microenvironment as well as modulate programmed cell death caused by metabolic stress.
- intracranial administration is an impractical and unacceptable route of administration for therapeutic use, particularly for normal individuals.
- peripherally-administered erythropoietin is not transported into the brain (Marti et al., 1997, Kidney Int. 51:416-8; Juul et al., 1999, Pediatr. Res. 46:543-547; Buemi et al., 2000, Nephrol. Dial. Transplant. 15:422-433).
- the present invention relates to tissue protective cytokines generated by the chemical modification of erythropoietin and their uses for protecting, maintaining, enhancing, or restoring erythropoietin-responsive cells and associated cells, tissues and organs in situ as well as ex vivo, and to delivery of a tissue protective cytokine across an endothelial cell barrier for the purpose of protecting and enhancing erythropoietin-responsive cells and associated cells, tissues and organs distal to the vasculature, or to carry associated molecules across an endothelial cell barrier.
- the present invention is directed to the use of tissue protective cytokines, chemically-modified erythropoietins that lack one or more aspects of erythropoietin's affect on the bone marrow, for the preparation of pharmaceutical compositions for protecting, maintaining, enhancing, or restoring the function or viability of responsive mammalian cells and their associated cells, tissues and organs.
- the responsive mammalian cells and their associated cells, tissues or organs are distal to the vasculature by virtue of a tight endothelial cell barrier.
- the cells, tissues, organs or other bodily parts are isolated from a mammalian body, such as those intended for transplant or reattachment.
- the responsive cell or tissue may be neuronal, retinal, muscle, heart, lung, liver, kidney, small intestine, adrenal cortex, adrenal medulla, capillary endothelial, testes, ovary, pancreas, bone, skin or endometrial cells or tissue.
- responsive cells include photoreceptor (rods and cones), ganglion, bipolar, horizontal, amacrine, Müeller, myocardium, pace maker, sinoatrial node, sinoatrial node, sinus node, junction tissue, atrioventricular node, bundle of His, hepatocytes, stellate, Kupffer, mesangial, renal epithelial, tubular interstitial, goblet, intestinal gland (crypts), enteral, endocrine, glomerulosa, fasciculate, reticularis, chromaffin, pericyte, Leydig, Sertoli, sperm, Graffian follicle, primordial follicle, islets of Langerhans, ⁇ -cells, ⁇ -cells, ⁇ -cells, F-cells, osteoprogenitor, osteoclasts, osteoblasts, endometrial stroma, endometrial, stem and endothelial cells.
- responsive cells are merely illustrative.
- the responsive cell or its associated cells, tissues, or organs are not excitable cells, tissues, or organs, or do not predominantly comprise excitable cells or tissues.
- the mammalian cell, tissue or organ for which an aforementioned tissue protective cytokine is used are those that have expended or will expend a period of time under at least one condition adverse to the viability of the cell, tissue or organ.
- Such conditions include traumatic in-situ hypoxia or metabolic dysfunction, surgically-induced in-situ hypoxia or metabolic dysfunction, or in-situ toxin exposure; the latter may be associated with chemotherapy or radiation therapy.
- the adverse conditions are a result of cardiopulmonary bypass (heart-lung machine), as is used for certain surgical procedures.
- tissue protective cytokines herein are useful for the therapeutic or prophylactic treatment of human diseases of the CNS or peripheral nervous system which have primarily neurological or psychiatric symptoms, as well as ophthalmic diseases, cardiovascular diseases, cardiopulmonary diseases, respiratory diseases, kidney, urinary and reproductive diseases, gastrointestinal diseases and endocrine and metabolic abnormalities, and inflammation.
- the invention is also directed to pharmaceutical compositions comprising particular tissue protective cytokines for administration to a mammalian animal, preferably a human.
- Such pharmaceutical compositions may be formulated for oral, intranasal, or parenteral administration, or in the form of a perfusate solution for maintaining the viability of cells, tissues or organs ex vivo.
- Tissue protective cytokines useful for the aforementioned purposes and pharmaceutical compositions include erythropoietins that have been altered by at least one modification as compared to a native erythropoietin, and preferably as compared to native human erythropoietin.
- the at least one modification may be a modification of at least one amino acid of the erythropoietin molecule, or a modification of at least one carbohydrate of the erythropoietin molecule.
- tissue protective cytokine molecules useful for the purposes herein may have a plurality of modifications compared to a native molecule, such as multiple modifications of the amino acid portion of the molecule, multiple modifications of the carbohydrate portion of the molecule, or at least one modification of the amino acid portion of the molecule and at least one modification of the carbohydrate portion of the molecule.
- the tissue protective cytokine molecule retains its ability of protecting, maintaining, enhancing or restoring the function or viability of responsive mammalian cells, yet one or more properties of the erythropoietin molecule unrelated to the aforementioned, desirable feature may be absent as compared to the native molecule.
- the tissue protective cytokine lacks erythropoietin's affects on the bone marrow, i.e., increased hematocrit (erythropoiesis), vasoconstriction (high blood pressure), increased blood pressure, hyperactivation of platelets, pro-coagulant activities, and increased production of thrombocytes. More preferably, the tissue protective cytokines lack erythropoiesis; most preferably the tissue protective cytokines are devoid of all of erythropoietin's effects on the bone marrow.
- the tissue protective cytokine of the invention may be asialoerythropoietin.
- the tissue protective cytokine of the invention may be erythropoietin or asialoerythropoietin that has been reacted with one or more reagents that modify one or more amino groups of amino acid residues of native erythropoietin or asialoerythropoietin.
- the tissue protective cytokine is nonerythropoietic.
- the tissue protective cytokine is an erythropoietin that has no sialic acid moieties.
- the tissue protective cytokine is asialoerythropoietin, and most preferably, human asialoerythropoietin.
- the tissue protective cytokine has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 sialic acid moieties.
- Such partially desialylated erythropoietins are referred to herein as hyposialoerythropoietins.
- erythropoietin may be prepared by chemical or enzymatic modification of native erythropoietin, or may be obtained by expression in a system which either does not sialylate the molecule at all or only partially sialylates the erythropoietin.
- the asialoerythropoietin and hyposialoerythropoietin of the invention are embraced regardless of the means by which the molecules are prepared.
- the tissue protective cytokine comprises at least one or more modified lysine residues or a modification of the N-terminal amino group of the erythropoietin molecule, such modifications as those resulting from reaction of the lysine epsilon amino group or the N-terminal amino group with an amino-group-modifying agent or agents.
- the modified lysine residue or modified N-terminal amino group further may be chemically reduced.
- an erythropoietin is biotinylated, carbamylated, succinylated or acetylated at one or more lysine groups or at the N-terminus.
- the lysine is reacted with an aldehyde or reducing sugar to form an imine, which optionally is then stabilized by chemical reduction such as by using sodium cyanoborohydride to form an N-alkylated lysine residue such as glucitolyl lysine, or which in the case of reducing sugars may be stabilized by Amadori or Heyns rearrangement to form an alpha-deoxy alpha-amino sugar such as alpha-deoxy-alpha-fructosyllysine.
- the lysine or N-terminal amino group is carbamylated (carbamoylated), such as by virtue of reaction with cyanate ion, alkyl-carbamylated, aryl-carbamylated, or aryl-thiocarbamylated with an alkyl-isocyanate, aryl-isocyanate, or aryl-isothiocyanate, respectively, or it may be acylated by a reactive alkylcarboxylic or arylcarboxylic acid derivative, such as by reaction with acetic anhydride, succinic anhydride or phthalic anhydride.
- At least one lysine group or the N-terminal amino group may also be trinitrophenyl modified by reaction with a trinitrobenzenesulfonic acid, or preferably with one of its salts.
- lysine residues may be modified by reaction with a glyoxal, such as reaction with glyoxal, methylglyoxal or 3-deoxyglucosone to form the corresponding alpha-carboxyalkyl derivatives.
- a tissue protective cytokine can be generated by modifying at least one tyrosine residue of erythropoietin by using an electrophilic reagent, such as but not limited to modification by nitration or iodination, to modify an aromatic ring position.
- tissue protective agent useful for the purposes herein may have at least one of the aforementioned modifications, but may have more than one of the above modifications.
- tissue protective cytokine is carbamylerythropoietin, carbamylasialoerythropoietin, carbamylhyposialoerythropoietin, acetylerythropoietin, acetylasialoerythropoietin, acetylhypoasialoerythropoietin, succinylerythropoietin, succinylasialoerythropoietin, succinylhyposialoerythropoietin, biotinylerythropoietin, biotinylasialoerythropoiiii
- compositions including pharmaceutical compositions, comprising one or more of the aforementioned tissue protective cytokines. Any of such compositions may also include native erythropoietin.
- a method for the protecting, maintaining, enhancing or restoring the function or viability of responsive mammalian cells and their associated cells, tissues and organs, by administering an effective amount of any one or more of the aforementioned tissue protective cytokines.
- the responsive mammalian cells and their associated cells, tissues or organs are distal to the vasculature by virtue of a tight endothelial cell barrier.
- the cells, tissues, organs or other bodily parts are isolated from a mammalian body, such as those intended for transplant or reattachment.
- the responsive cell or tissue may be neuronal, retinal, muscle, heart, lung, liver, kidney, small intestine, adrenal cortex, adrenal medulla, capillary endothelial, testes, ovary, pancreas, skin, bones, or endometrial cells or tissue.
- responsive cells are merely illustrative.
- the responsive cell or its associated cells, tissues, or organs are not excitable cells, tissues, or organs, or do not predominantly comprise excitable cells or tissues.
- the mammalian cell, tissue or organ for which an aforementioned tissue protective cytokine may be administered are those that have expended or will expend a period of time under at least one condition adverse to the viability of the cell, tissue or organ.
- Such conditions may include traumatic in-situ hypoxia or metabolic dysfunction, surgically-induced in-situ hypoxia or metabolic dysfunction, or in-situ toxin exposure; the latter may be associated with chemotherapy or radiation therapy.
- the invention protects against the adverse conditions resulting from cardio-pulmonary bypass.
- any of the foregoing tissue protective cytokines can be used in the preparation of a pharmaceutical composition for ex-vivo treatment of cells, tissues and organs for the purpose of protecting, maintaining, enhancing, or restoring the function or viability of responsive mammalian cells and their associated cells, tissues and organs.
- ex-vivo treatment is useful, for example, for the preservation of cells, tissues or organs for transplant, whether autotransplant or xenotransplant.
- the cells, tissue or organ may be bathed in a solution comprising tissue protective cytokines, or the perfusate instilled into the organ through the vasculature or other means, to maintain cellular functioning during the period wherein the cells, tissue or organ is not integrated with the vasculature of the donor or recipient.
- Administration of the perfusate may be made to a donor prior to organ harvesting, as well as to the harvested organ and to the recipient.
- tissue protective cytokine is useful whenever a cell, tissue or organ is isolated from the vasculature of the individual and thus essentially existing ex vivo for a period of time
- the term isolated referring to restricting or clamping the vasculature of or to the cell, tissue, organ or bodily part, such as may be performed during surgery, including, in particular, cardiopulmonary bypass surgery; bypassing the vasculature of the cell, tissue, organ or bodily part; removing the cell, tissue, organ or bodily part from the mammalian body, such may be done in advance of xenotransplantation or prior to and during autotransplantation; or traumatic amputation of a cell, tissue, organ or bodily part.
- this aspect of the invention pertains both to the perfusion with a tissue protective cytokine in situ and ex vivo.
- the erythropoietin may be provided in a cell, tissue or organ preservation solution.
- the exposing may be by way of continuous perfusion, pulsatile perfusion, infusion, bathing, injection, or catheterization.
- the invention is directed to a method for protecting, maintaining, enhancing, or restoring the viability of a mammalian cell, tissue, organ or bodily part which includes a responsive cell or tissue, in which the cell, tissue, organ or bodily part is isolated from the mammalian body.
- the method includes at least exposing the isolated mammalian cell, tissue, organ or bodily part to an amount of a tissue protective cytokine as mentioned above for a duration which is effective to protect, maintain, enhance, or restore the aforesaid viability.
- isolated refers to restricting or clamping the vasculature of or to the cell, tissue, organ or bodily part, such as may be performed during surgery, in particular, cardio-pulmonary bypass surgery; bypassing the vasculature of the cell, tissue, organ or bodily part; removing the cell, tissue, organ or bodily part from the mammalian body, such may be done in advance of xenotransplantation or prior to and during autotransplantation; or traumatic amputation of a cell, tissue, organ or bodily part.
- this aspect of the invention pertains both to the perfusion with a tissue protective cytokine in situ and ex vivo.
- the tissue protective cytokine may be provided in a cell, tissue or organ preservation solution.
- the exposing may be by way of continuous perfusion, pulsatile perfusion, infusion, bathing, injection, or catheterization.
- the aforementioned ex-vivo responsive cell or tissue may be or comprise neuronal, retinal, muscle, heart, lung, liver, kidney, small intestine, adrenal cortex, adrenal medulla, capillary endothelial, testes, ovary, pancreas, skin, bone, bone marrow, umbilical chord blood or endometrial cells or tissue.
- responsive cells are merely illustrative.
- All of the foregoing methods and uses are preferably applicable to human beings, but are useful as well for any mammal, such as but not limited to companion animals, domesticated animals, livestock and zoo animals.
- Routes of administration of the aforementioned pharmaceutical compositions include oral, intravenous, intranasal, topical, intraluminal, inhalation or parenteral administration, the latter including intravenous, intraarterial, subcutaneous, intramuscular, intraperitoneal, submucosal or intradermal.
- a perfusate or bath solution is preferred. This includes perfusing an isolated portion of the vasculature in situ.
- any of the aforementioned tissue protective cytokines are useful in preparing a pharmaceutical composition for restoring a dysfunctional cell, tissue or organ when administered after the onset of the disease or condition responsible for the dysfunction.
- administration of a pharmaceutical composition comprising tissue protective cytokines restores cognitive function in animals previously having brain trauma, even when administered long after (e.g., three days, five days, a week, a month, or longer) the trauma has subsided.
- the invention provides methods for the use of the aforementioned tissue protective cytokine for restoring a dysfunctional cell, tissue or organ when administered after the onset of the disease or condition responsible for the dysfunction.
- tissue protective cytokine for restoring a dysfunctional cell, tissue or organ when administered after the onset of the disease or condition responsible for the dysfunction.
- methods for administration of a pharmaceutical composition comprising a tissue protective cytokine restores cognitive function in animals previously having brain trauma, even when administered long after (e.g., three days, five days, a week, a month, or longer) the trauma has subsided.
- Tissue protective cytokines useful for such methods include any of the particular aforementioned modified erythropoietins
- tissue protective cytokine as described hereinabove.
- the association between the molecule to be transported and the tissue protective cytokine may be, for example, a labile covalent bond, a stable covalent bond, or a noncovalent association with a binding site for the molecule.
- Endothelial cell barriers may be the blood-brain barrier, the blood-eye barrier, the blood-testes barrier, the blood-ovary barrier and the blood-placenta barrier.
- Suitable molecules for transport by the method of the present invention include hormones such as growth hormone, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (bFGF), transforming growth factor ⁇ 1 (TGF ⁇ 1), transforming growth factor ⁇ 2 (TGF ⁇ 2), transforming growth factor ⁇ 3 (TGF ⁇ 3), interleukin 1, interleukin 2, interleukin 3, and interleukin 6, AZT, antibodies against tumor necrosis factor, antiviral, and immunosuppressive agents such as cyclosporin. Additionally, dyes or markers may be attached to erythropoietin or one of the tissue protective cytokines of the present invention in order to visualize cells, tissues, or organs within the brain and other barriered organs for diagnostic purposes.
- hormones such as growth hormone, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (b
- the association may be, for example, a labile covalent bond, a stable covalent bond, or a noncovalent association with a binding site for the molecule.
- Endothelial cell barriers may be the blood-brain barrier, the blood-eye barrier, the blood-testes barrier, the blood-ovary barrier and the blood-placenta barrier.
- Suitable molecules for transport by the method of the present invention include hormones such as growth hormone, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (bFGF), transforming growth factor ⁇ 1 (TGF ⁇ 1), transforming growth factor ⁇ 2 (TGF ⁇ 2), transforming growth factor ⁇ 3 (TGF ⁇ 3), interleukin 1, interleukin 2, interleukin 3, and interleukin 6, AZT, antibodies against tumor necrosis factor, antiviral, and immunosuppressive agents such as cyclosporin. Additionally, dyes or markers may be attached to erythropoietin or one of the tissue protective cytokines of the present invention in order to visualize cells, tissues, or organs within the brain and other barriered organs for diagnostic purposes.
- hormones such as growth hormone, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (b
- any of the aforementioned tissue protective cytokines is useful in preparing a pharmaceutical composition for facilitating the transcytosis of a molecule across an endothelial cell barrier in a mammal.
- the association may be, for example, a labile covalent bond, a stable covalent bond, or a noncovalent association with a binding site for the molecule.
- Endothelial cell barriers may be the blood-brain barrier, the blood-eye barrier, the blood-testes barrier, the blood-ovary barrier and the blood-placenta barrier.
- Suitable molecules for transport by the method of the present invention include hormones, such as growth hormone, antibiotics, antivirals, dyes, markers, and anti-cancer agents, to name but a few non-limiting examples.
- FIG. 1 shows the distribution of erythropoietin receptor in normal human brain, in thin sections stained with an anti-erythropoietin antibody.
- FIG. 2 is a higher power magnification of the image in FIG. 1.
- FIG. 3 shows, using gold-labeled secondary antibodies, the ultramicroscopic distribution of erythropoietin receptors.
- FIG. 4 prepared similarly to FIG. 3, shows high density erythropoietin receptors at the luminal and anti-luminal surfaces of human brain capillaries.
- FIG. 5 compares the in-vitro efficacy of erythropoietin and asialoerythropoietin on the viability of serum-starved P19 cells.
- FIG. 6 is another experiment which compares the in-vitro efficacy of erythropoietin and asialoerythropoietin on the viability of serum-starved P19 cells.
- FIG. 7 shows protection of erythropoietin and asialoerythropoietin in a rat focal cerebral ischemia model.
- FIG. 8 shows a dose response comparing the efficacy of human erythropoietin and human asialoerythropoietin in middle cerebral artery occlusion in a model of ischemic stroke
- FIG. 9 shows the activity of iodinated erythropoietin in the P19 assay.
- FIG. 10 shows the effect of biotinylated erythropoietin and asialoerythropoietin in the P19 assay.
- FIG. 11 compares the in-vitro efficacy of erythropoietin and phenylglyoxal-modified erythropoietin on the viability of serum-starved P19 cells.
- FIG. 12 shows the effect of tissue protective cytokines in the water intoxication assay.
- FIG. 13 depicts the translocation of parenterally-administered erythropoietin into the cerebrospinal fluid.
- FIG. 14 shows the maintenance of the function of a heart prepared for transplantation by erythropoietin.
- FIG. 15 shows the protection of the myocardium from ischemic damage by erythropoietin after temporary vascular occlusion.
- FIG. 16 depicts the effects of erythropoietin treatment in a rat glaucoma model.
- FIG. 17 shows the extent of preservation of retinal function by erythropoietin in the rat glaucoma model.
- FIG. 18 depicts the restoration of cognitive function following brain trauma by administration of erythropoietin starting five days after trauma.
- FIG. 19 depicts the restoration of cognitive function following brain trauma by administration of erythropoietin starting 30 days after trauma.
- FIG. 20 depicts the efficacy of human asialoerythropoietin in a kainate model of cerebral toxicity.
- FIG. 21 depicts the efficacy of tissue protective cytokines in a rat spinal cord injury model.
- FIG. 22 shows the efficacy of tissue protective cytokines within a rabbit spinal cord injury model.
- FIG. 23 shows a coronal section of the brain cortical layer stained by hematoxilyn and eosin.
- FIG. 24 shows coronal sections of frontal cortex adjacent to the region of infarction stained by GFAP antibody.
- FIG. 25 shows coronal sections of brain cortical layer stained by OX-42 antibody.
- FIG. 26 shows coronal sections of brain cortical layer adjacent to the region of infarction stained by OX-42 antibody.
- FIG. 27 shows the efficacy of erythropoietin against inflammation in an EAE model.
- FIG. 28 compares the affects of dexamethasone and erythropoietin on inflammation in the EAE model.
- FIG. 29 shows that erythropoietin suppresses inflammation associated with neuronal death.
- the methods of the invention provide for the local or systemic protection or enhancement of cells, tissues and organs within a mammalian body, under a wide variety of normal and adverse conditions, or protection of those which are destined for relocation to another mammalian body.
- restoration or regeneration of dysfunction is also provided.
- the ability of an erythropoietin to cross a tight endothelial cell barrier and exert its positive effects on responsive cells (as well as other types of cells) distal to the vasculature offers the potential to prevent as well as treat a wide variety of conditions and diseases which otherwise cause significant cellular and tissue damage in an animal, including human, and moreover, permit success of heretofore unattemptable surgical procedures for which risk traditionally outweighed the benefits.
- Erythropoietin is a glycoprotein hormone which in humans has a molecular weight of about 34 kDa.
- the mature protein comprises 165 amino acids, and the glycosyl residues comprise about 40% of the weight of the molecule.
- Erythropoietin can be obtained commercially, for example, under the trademarks of PROCRIT, available from Ortho Biotech Inc., Raritan, N.J., and EPOGEN, available from Amgen, Inc., Thousand Oaks, Calif.
- host systems may be used for expression and production of recombinant erythropoietin, including, but not limited to, bacteria, yeast, insect, plant, and mammalian, including human, cell systems.
- recombinant erythropoietin produced in bacteria which do not glycosylate or sialate the product, could be used to produce non-glycosylated forms of erythropoietin.
- recombinant erythropoietin can be produced in other systems that do glycosylate, e.g., plants, including human cells.
- the forms of erythropoietin useful in the practice of the present invention encompass chemical modifications and/or expression-system-mediated glycosylation modifications of naturally-occurring, synthetic and recombinant forms of human and other mammalian erythropoietins.
- Responsive cell refers to a mammalian cell whose function or viability may be maintained, promoted, enhanced, regenerated, or in any other way benefited, by exposure to an erythropoietin.
- Non-limiting examples of such cells include neuronal, retinal, muscle, heart, lung, liver, kidney, small intestine, adrenal cortex, adrenal medulla, capillary endothelial, testes, ovary, pancreas, skin, bone and endometrial cells.
- responsive cells include, without limitation, neuronal cells; retinal cells: photoreceptor (rods and cones), ganglion, bipolar, horizontal, amacrine, and Müeller cells; muscle cells; heart cells: myocardium, pace maker, sinoatrial node, sinoatrial node, sinus node, and junction tissue cells (atrioventricular node and bundle of his); lung cells; liver cells: hepatocytes, stellate, and Kupffer cells; kidney cells: mesangial, renal epithelial, and tubular interstitial cells; small intestine cells: goblet, intestinal gland (crypts) and enteral endocrine cells; adrenal cortex cells: glomerulosa, fasciculate, and reticularis cells; adrenal medulla cells: chromaffin cells; capillary cells: pericyte cells; testes cells: Leydig, Sertoli, and sperm cells and their precursors; ovary cells: Graffian follicle and primordial follicle and
- responsive cells and the benefits provided thereto by an erythropoietin may be extended to provide protection or enhancement indirectly to other cells that are not directly responsive, or of tissues or organs which contain such non-responsive cells.
- benefits of an erythropoietin as described herein may be provided as a result of the presence of a small number or proportion of responsive cells in a tissue or organ, for example, excitable or neuronal tissue present in such tissue, or the Leydig cells of the testis, which makes testosterone.
- the responsive cell or its associated cells, tissues, or organs are not excitable cells, tissues, or organs, or do not predominantly comprise excitable cells or tissues.
- the duration and degree of purposeful adverse conditions induced for ultimate benefit may be carried out by taking advantage of the invention herein.
- the invention is not so limited, but includes as one aspect, methods or compositions wherein the target responsive cells are distal to the vasculature by virtue of an endothelial-cell barrier or endothelial tight junctions.
- the invention is directed to any responsive cells and associated cells, tissues and organs which may benefit from exposure to erythropoietin.
- cellular, tissue or organ dysfunction may be restored or regenerated after an acute adverse event (such as trauma) by exposure to erythropoietin.
- the invention is directed generally to the use of erythropoietin for the preparation of pharmaceutical compositions for the aforementioned purposes in which cellular function is maintained, promoted, enhanced, regenerated, or in any other way benefited.
- the invention is also directed to methods for maintaining, enhancing, promoting, or regenerating cellular function by administering to a mammal an effective amount of erythropoietin as described herein.
- the invention is further directed to methods for maintaining, promoting, enhancing, or regenerating cellular function ex vivo by exposing cells, a tissue or organ to erythropoietin.
- the invention is also directed to a perfusate composition comprising erythropoietin for use in organ or tissue preservation.
- the various methods of the invention utilize a pharmaceutical composition which at least includes erythropoietin at an effective amount for the particular route and duration of exposure to exert positive effects or benefits on responsive cells within or removed from a mammalian body.
- the pharmaceutical composition includes erythropoietin at a concentration which is capable, after crossing the endothelial cell barrier, of exerting its desirable effects upon the responsive cells.
- erythropoietin or erythropoietin receptor activity modulators are useful in the context of the present invention. These molecules may be, for example, naturally-occurring, synthetic, or recombinant forms of erythropoietin molecules, as described above, or other molecules which may not necessarily resemble erythropoietin in any manner, except to modulate erythropoietin responsive cell activity, as described herein.
- erythropoietin is more commonly associated with its effects on the bone marrow, i.e., increased hematocrit (erythropoiesis), vasoconstriction (high blood pressure), hyperactivation of platelets, pro-coagulant activity, and increased production of thrombocytes.
- these effects on the bone marrow may pose a risk in the chronic and acute administration of erythropoietin to treat the cellular, tissue, or organ dysfunctions discussed above.
- the invention is directed generally to the use of tissue protective cytokines that consist of chemically modified erythropoietin, which preferably lack one or more of erythropoietin's effects on the bone marrow. More preferably, the tissue protective cytokines lack erythropoiesis; most preferably the tissue protective cytokines are devoid of all of erythropoietin's effects on the bone marrow. In other embodiments, the tissue protective cytokine lacks any two of the aforesaid effects, or any three of the aforesaid effects.
- tissue protective cytokines desirable for the uses described herein may be generated by guanidination, amidination, carbamylation (carbamoylation), trinitrophenylation, acetylation, succinylation, nitration, or modification of arginine, lysine, tyrosine, tryptophan, or cysteine residues or carboxyl groups, among other procedures, such as limited proteolysis, removal of amino groups, and/or mutational substitution of arginine, lysine, tyrosine, tryptophan, or cysteine residues of erythropoietin by molecular biological techniques.
- these chemical modifications affect the four recognized receptor regions—VLQRY (SEQ ID NO: 1), TKVNFYAW (SEQ ID NO: 2), SGIRSLTTL (SEQ ID NO: 3), or SNFLRG (SEQ ID NO: 4). More preferably, these receptor regions, which are basic in nature, are modified by chemical modification of the basic amino acids, arginine and lysine, within these regions. Additionally, the areas of the molecule surrounding these receptor regions may be chemically modified as well to affect the kinetics or receptor binding properties of the molecule. This produces tissue protective cytokines which maintain an adequate level of activities for specific organs and tissues but not for others, such as erythrocytes (e.g., Satake et al; 1990, Biochim.
- tissue protective cytokine molecule fully retains its neurotrophic effect.
- tissue protective cytokine molecules are fully embraced for the various uses and compositions described herein.
- the activity (in units) of erythropoietin and erythropoietin-like molecules is traditionally defined based on its effectiveness in stimulating red cell production in rodent models (and as derived by international standards of erythropoietin).
- One unit (U) of regular erythropoietin (MW of ⁇ 34,000) is about 8 ng of protein (1 mg protein is approximately 125,000 U).
- MW of ⁇ 34,000 regular erythropoietin
- protein 1 mg protein is approximately 125,000 U.
- a definition of activity of certain tissue protective cytokines of the invention based on erythropoietic activity is inappropriate.
- the activity unit of erythropoietin or the tissue protective cytokines is defined as the amount of protein required to elicit the same activity in neural or other responsive cellular systems as is elicited by WHO international standard erythropoietin in the same system.
- the skilled artisan will readily determine the units of a non-erythropoietic erythropoietin or related tissue protective cytokine molecule following the guidance herein.
- tissue protective cytokines [0063] Further to the above-mentioned tissue protective cytokines, the following discussion expands on the various tissue protective cytokines of the invention.
- a tissue protective cytokine of the invention may consist of erythropoietin having at least no sialic acid moieties, referred to as asialoerythropoietin.
- a tissue protective cytokine of the invention is human asialoerythropoietin. It may be prepared by desialylating erythropoietin using a sialidase, such as is described in the manufacturer's packaging for Sialydase A from ProZyme Inc., San Leandro, Calif.
- PROZYME® GLYCOPRO® sequencing-grade SIALYDASE ATM (N-acetylneuraminate glycohydrolase, EC 3.2.1.18) is used to cleave all non-reducing terminal sialic acid residues from complex carbohydrates and glycoproteins such as erythropoietin. It will also cleave branched sialic acids (linked to an internal residue).
- Sialydase A is isolated from a clone of Arthrobacter ureafaciens.
- erythropoietin may be subjected to desialylation by sialidase (0.025 U/mg EPO) at 37 C. for 3 h, after which the erythropoietin may be desalted and concentrated.
- sialidase 0.025 U/mg EPO
- the erythropoietin may be desalted and concentrated.
- the fractions containing only the top two bands identified by imunoelectrophoresis migrating at pI ⁇ 8.5 and ⁇ 7.9 on IEF gel) are selected. No significant amount of sialic acid should be detected in this preparation of the tissue protective cytokine.
- the tissue protective cytokine of the invention may be an erythropoietin having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 sialic acid residues, by partial desialylation by the aforementioned method.
- tissue protective cytokines resulting form the partial desialylation of erythropoietin may also be referred to herein as hyposialoerythropoietins, and may be a homogeneous composition, with, for example, only 2 sialic acids per erythropoietin molecule, or may be a heterogeneous mixture of a variety of different degrees of sialylation, or, for example, having a low number, such as about 1 to about 4 sialic acid molecules on average per erythropoietin, or, in another example, a higher number, such as about 10 to about 13 sialic acids on average per erythropoietin molecule.
- Such mixtures may include asialoerythropoietin or erythropoietin.
- An erythropoietin for the aforementioned uses may have at least one or more modified arginine residues.
- the modified erythropoietin may comprise an R-glyoxal moiety on the one or more arginine residues, where R may be an aryl, heteroaryl, lower alkyl, lower alkoxy, or cycloalkyl group, or an alpha-deoxyglycitolyl group.
- R may be an aryl, heteroaryl, lower alkyl, lower alkoxy, or cycloalkyl group, or an alpha-deoxyglycitolyl group.
- the term lower “alkyl” means a straight- or branched-chain saturated aliphatic hydrocarbon group preferably containing 1-6 carbon atoms.
- alkoxy means a lower alkyl group as defined above attached to the remainder of the molecule by oxygen. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy and the like.
- cycloalkyl refers to cyclic alkyl groups with from three to up to about 8 carbons, including for example cyclopropyl, cyclobutyl, cyclohexyl and the like.
- aryl refers to phenyl and naphthyl groups.
- heteroaryl refers to heterocyclic groups containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. Examples include but are not limited to isoxazolyl, phenylisoxazolyl, furyl, pyrimidinyl, quinolyl, tetrahydroquinolyl, pyridyl, imidazolyl, pyrrolidinyl, 1,2,4-triazoylyl, thiazolyl, thienyl, and the like.
- the R group may be substituted, as for example the 2,3,4-trihydroxybutyl group of 3-deoxyglucosone.
- R-glyoxal compounds are glyoxal, methylglyoxal, 3-deoxyglucosone, and phenylglyoxal.
- Preferred R-glyoxal compounds are methylglyoxal or phenylglyoxal.
- An exemplary method for such modification may be found in 1997r et al., 1975, Isr. J. Med. Sci. 11(11): 1169-70, using phenylglyoxal.
- At least one arginine residue may be modified by reaction with a vicinal diketone such as 2,3-butanedione or cyclohexanedione, preferably in ca. 50 millimolar borate buffer at pH 8-9.
- a procedure for the latter modification with 2,3-butanedione may be carried out in accordance with Riordan, 1973, Biochemistry 12(20): 3915-3923; and that with cyclohexanone according to Patthy et al., 1975, J. Biol. Chem 250(2): 565-9.
- a tissue protective cytokine of the invention may comprise at least one or more modified lysine residues or a modification of the N-terminal amino group of the erythropoietin molecule, such modifications as those resulting from reaction of the lysine residue with an amino-group-modifying agent.
- erythropoietin or aforementioned asialoerythropoietin or hyposialoerythropoietin may be modified by acetylation, carbamylation, succinylation, oxidation and subsequent carboxymethyllysination, among other methods, to modify amino groups.
- tissue protective cytokine may be generated by carbamylating an erythropoietin, or a desialylated erythropoietin such as asialoerythropoietin, with recrystallized potassium cyanate in borate buffer, after which thorough dialysis is performed.
- an aforementioned erythropoietin may be succinylated by reaction with succinic anhydride, followed by dialysis to form a tissue protective cytokine of the present invention.
- a tissue protective cytokine may be generated by reacting erythropoietin with acetic anhydride in phosphate buffer to acetylate the erythropoietin. This reaction may be stopped by dialysis against water. The method is described in Satake et al, (1990). Chemical modification of erythropoietin: an increase in in-vitro activity by guanidination. Biochimica et Biophysica Acta. 1038: 125-129.
- the tissue protective cytokines are N ⁇ -(carboxymethyl)lysine (CML) adducts from erythropoietin or asialoerythropoietin prepared by reaction with glyoxylic acid and NaBH 3 CN in sodium phosphate buffer, followed by dialysis.
- CML N ⁇ -(carboxymethyl)lysine
- a tissue protective cytokine is generated by modifying the lysine residues of erythropoietin by reaction with glyoxal derivatives, such as reaction with glyoxal, methylglyoxal and 3-deoxyglucosone to form alpha-carboxyalkyl derivatives.
- glyoxal derivatives such as reaction with glyoxal, methylglyoxal and 3-deoxyglucosone to form alpha-carboxyalkyl derivatives.
- Examples include reaction with glyoxal to form a carboxymnethyllysine residue as in Glomb and Monnier, 1995, J. Biol. Chem. 270(17): 10017-26, or with methylglyoxal to form a (1-carboxyethyl)lysine residue as in Degenhardt et al., 1998, Cell. Mol. Biol.
- the modified lysine residue further may be chemically reduced.
- the erythropoietin may be biotinylated via lysine groups, such as in accordance with the method described in Example 2, in which D-biotinoyl- ⁇ -aminocaproic acid-N-hydroxysuccinimide ester was reacted with erythropoietin, followed by removal of unreacted biotin by gel filtration on a Centricon 10 column, as described by Wojchowski and Caslake, 1989, Blood 74(3):952-8.
- Biotin may be added to (1) the sialic acid moieties (2) carboxylate groups or (3) amino groups.
- the lysine may be reacted with an aldehyde or reducing sugar to form an imine, which may be stabilized by reduction as with sodium cyanoborohydride to form an N-alkylated lysine residue such as glucitolyl lysine, or which in the case of reducing sugars may be stabilized by Amadori or Heyns rearrangement to form an alpha-deoxy alpha-amino sugar such as alpha-deoxy-alpha-fructosyllysine residue in the erythropoietin molecule.
- fructosyllysine-modified protein preparation of a fructosyllysine-modified protein by incubation with 0.5 M glucose in sodium phosphate buffer at pH 7.4 for 60 days is described by Makita et al., 1992, J. Biol. Chem. 267:5133-5138.
- the lysine group may be carbamylated, such as by virtue of reaction with cyanate ion, or alkyl- or aryl-carbamylated or -thiocarbamylated with an alkyl- or aryl-isocyanate or -isothiocyanate, or it may be acylated by a reactive alkyl- or arylcarboxylic acid derivative, such as by reaction with acetic anhydride or succinic anhydride or phthalic anhydride.
- Lysine groups may also be trinitrophenyl modified by reaction with trinitrobenzenesulfonic acid or preferably its salts. Such methods are described below in Example 2.
- At least one tyrosine residue of an erythropoietin may be modified in an aromatic ring position by an electrophilic reagent, such as by nitration or iodination to generate a tissue protective cytokine.
- an electrophilic reagent such as by nitration or iodination to generate a tissue protective cytokine.
- erythropoietin may be reacted with tetranitromethane (Nestler et al., 1985, J. Biol. Chem. 260(12):7316-21; or iodinated as described in Example 3.
- iodination with NaI and IODO-GEN Pre-Coated Iodination Tube may be carried out using erythropoietin or asialoerythropoietin in sodium phosphate buffer.
- At least an aspartic acid or a glutamic acid residue of an erythropoietin may be modified, such as by reaction with a carbodiimide followed by reaction with an amine such as but not limited to glycinamide.
- a tryptophan residue of an erythropoietin may be modified, such as by reaction with n-bromosuccinimide or n-chlorosuccinimide, following methods such as described in Josse et al., Chem Biol Interact May 14, 1999;119-120.
- tissue protective cytokine may be prepared by removing at least one amino group of a native erythropoietin, such may be achieved by reaction with ninhydrin followed by reduction of the subsequent carbonyl group by reaction with borohydride.
- a tissue protective cytokine that has at least an opening of at least one of the cystine linkages in the erythropoietin molecule by reaction with a reducing agent such as dithiothreitol, followed by reaction of the subsequent sulfhydryls with iodoacetamide, iodoacetic acid or another electrophile to prevent reformation of the disulfide linkages.
- a reducing agent such as dithiothreitol
- disulfide linkages may be abolished by altering a cysteine molecule that participates in the actual cross-link or at least one other amino acid residue that results in the inability of the erythropoietin to form at least one of the disulfide linkages present in the native molecule.
- a tissue protective cytokine may be prepared by subjecting an erythropoietin to a limited chemical proteolysis that targets specific residues, for example, to cleave after tryptophan residues. Such resulting erythropoietin fragments are embraced herein.
- tissue protective cytokine useful for the purposes herein may have at least one of the aforementioned modifications, but may have more than one of the above modifications.
- a tissue protective cytokine with one modification to the carbohydrate portion of the molecule and one modification to the amino acid portion, a tissue protective cytokine may be asialoerythropoietin and have its lysine residues biotinylated or carbamylated.
- the chemically modified erythropoietin may be further modified by mutating at least one amino acid of the erythropoietin.
- Such mutations may include substitutions, deletions, including internal deletions, additions, including additions yielding fusion proteins, or conservative substitutions of amino acid residues within and/or adjacent to the amino acid sequence, but that result in a “silent” change, in that the change produces a functionally equivalent erythropoietin.
- Conservative amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved.
- nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine; polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid.
- non-conservative amino acid changes, and larger insertions and deletions may be used to create functionally altered erythropoietin.
- an erythropoietin useful for the practice of the invention can be altered in one or more amino acids within the four functional domains of erythropoietin which affect receptor binding: VLQRY (SEQ ID NO: 1) and/or TKVNFYAW (SEQ ID NO: 2) and/or SGLRSLTTL (SEQ ID NO: 3) and/or SNFLRG (SEQ ID NO: 4).
- erythropoietins containing mutations in the surrounding areas of the molecule which affect the kinetics or receptor-binding properties of the molecule can be used.
- tissue protective cytokines of the invention are merely illustrative and non-limiting, and these or other methods may be used to prepare the compounds of the invention.
- the names hereinabove wherein the method of preparation is contained within the name, such as “acetylated” or “biotinylated,” are provided herein merely as a means for understanding how the compound was made, yet the present invention is directed to the compounds that are products of the aforementioned reactions.
- One of skill in the art would readily recognize the compounds that are the products of the reactions mentioned above.
- Carbamylated erythropoietins The following compounds represent carbamoyl moieties on the N-terminal amino acid of an erythropoietin molecule (“alpha-N-carbamoyl-”) or on one (or more) epsilon amino groups of lysyl residues of erythropoietin (“N-epsilon-carbamoyl-”). Of course, multiple N-epsilon modifications with or without the alpha-N-modification may be present.
- Succinylated erythropoietins The following compounds represent succinyl moieties on the N-terminal amino acid of an erythropoietin molecule (“alpha-N-succinyl-”) or on one (or more) epsilon amino groups of lysyl residues of erythropoietin (“N-epsilon-succinyl-”). Of course, multiple N-epsilon modifications with or without the alpha-N-modification may be present.
- Acetylated erythropoietins The following compounds represent acetyl moieties on the N-terminal amino acid of an erythropoietin molecule (“alpha-N-acetyl-”) or on one (or more) epsilon amino groups of lysyl residues of erythropoietin (“N-epsilon-acetyl-”). Of course, multiple N-epsilon modifications with or without the alpha-N-modification may be present.
- Biotinylated erythropoietins The following compounds represent biotinyl moieties on the N-terminal amino acid of an erythropoietin molecule (“alpha-N-biotinyl-”) or on one (or more) epsilon amino groups of lysyl residues of erythropoietin (“N-epsilon-biotinyl-”). Of course, multiple N-epsilon modifications with or without the alpha-N-modification may be present.
- Iodinated erythropoietins Of course, one of ordinary skill in the art would recognize that several different tyrosine residues as well as combinations of tyrosine residues within erythropoietin may be iodinated and that ones provided are merely illustrative.
- Carboxymethyllysyl-erythropoietins The following compounds represent carboxyrnethyl moieties on one (or more) epsilon amino groups of lysyl residues of erythropoietin (“N-epsilon-carboxymethyl-”). Of course, multiple N-epsilon modifications may be present.
- host-expression vector systems may be utilized to produce the erythropoietins and erythropoietin-related molecules of the invention.
- host-expression systems represent vehicles by which the erythropoietins of interest may be produced and subsequently purified, but also represent cells that may, when transformed or transfected with the appropriate nucleotide coding sequences, exhibit the modified erythropoietin gene product in situ.
- bacteria, insect, plant, mammalian including human host systems, such as, but not limited to, insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing the modified erythropoietin product coding sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing erythropoietin-related molecule coding sequences; or mammalian cell systems, including human cell systems, (e.g., HT1080, COS, CHO, BHK, 293, 3T3) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the
- a host cell strain may be chosen that modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may be important for the function of the protein.
- Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed.
- eukaryotic host cells that possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used.
- mammalian host cells including human host cells, include but are not limited to HT1080, CHO, VERO, BHK, HeLa, COS, MDCK, 293, 3T3, and W138.
- cell lines that stably express the erythropoietin-related molecule gene product may be engineered.
- host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker.
- appropriate expression control elements e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.
- engineered cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media.
- the selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci that in turn can be cloned and expanded into cell lines.
- This method may advantageously be used to engineer cell lines that express the erythropoietin-related molecule gene product.
- Such engineered cell lines may be particularly useful in screening and evaluation of compounds that affect the endogenous activity of the erythropoietin-related molecule gene product.
- the expression characteristic of an endogenous erythropoietin gene within a cell line or microorganism may be modified by inserting a heterologous DNA regulatory element into the genome of a stable cell line or cloned microorganism such that the inserted regulatory element is operatively linked with the endogenous erythropoietin gene.
- an endogenous erythropoietin gene which is normally “transcriptionally silent,” i.e., an erythropoietin gene which is normally not expressed, or is expressed only a very low levels in a cell line may be activated by inserting a regulatory element which is capable of promoting the expression of a normally expressed gene product in that cell line or microorganism.
- a transcriptionally silent, endogenous erythropoietin gene may be activated by insertion of a promiscuous regulatory element that works across cell types.
- a heterologous regulatory element may be inserted into a stable cell line or cloned microorganism, such that it is operatively linked with an endogenous erythropoietin gene, using techniques, such as targeted homologous recombination, which are well known to those of skill in the art, and described e.g., in French Patent No. 2646438 to Institut Pasteur, U.S. Pat. No. 4,215,051 to Chappel; U.S. Pat. No. 5,578,461 to Sherwin et al.; International Application No. PCT/US92/09627 (WO93/09222) by Selden et al.; and International Application No. PCT/US90/06436 (WO91/06667) by Skoultchi et al., each of which is incorporated by reference herein in its entirety.
- a tissue protective cytokine is a chemically modified erythropoietin molecule deficient in sialic residues, or completely lacking sialic residues, and may be produced in mammalian cell, including a human cell.
- Such cells may be engineered to be deficient in, or lacking, the enzymes that add sialic acids, i.e., the ⁇ -galactoside ⁇ 2,3 sialyltransferase (A ⁇ 2,3 sialyltransferase@) and the ⁇ -galactoside ⁇ 2,6 sialyltransferase (A ⁇ 2,6 sialyltransferase@) activity.
- a mammalian cell in which either or both the ⁇ 2,3 sialyltransferase gene and/or the ⁇ 2,6 sialyltransferase gene, is deleted. Such deletions may be constructed using gene knock-out techniques well known in the art.
- dihydrofolate reductase (DHFR) deficient Chinese Hamster Ovary (CHO) cells are used as the host cell for the production of recombinant erythropoietin-related molecules. CHO cells do not express the enzyme ⁇ 2,6 sialyltransferase and therefore do not add sialic acid in the 2,6 linkage to N-linked oligosaccharides of glycoproteins produced in these cells.
- recombinant proteins produced in CHO cells lack sialic acid in the 2,6 linkage to galactose (Sasaki et al. (1987; Takeuchi et al. supra; Mutsaers et al Eur. J. Biochem. 156, 651 (1986); Takeuchi et al. J. Chromotgr. 400, 207 (1987).
- the gene encoding ⁇ 2, 3 sialyltransferase in CHO cells is deleted.
- Such ⁇ 2, 3 sialyltransferase knock-out CHO cells completely lack sialyltransferase activity, and as a result, are useful for the recombinant expression and production of a tissue protective cytokine consists of asialo-erythropoietin.
- asialo glycoproteins can be produced by interfering with sialic acid transport into the Golgi apparatus e.g., Eckhardt et al., 1998, J. Biol. Chem. 273:20189-95).
- sialic acid transport into the Golgi apparatus e.g., Eckhardt et al., 1998, J. Biol. Chem. 273:20189-95.
- mutagenesis of the nucleotide sugar CMP-sialic acid transporter can be accomplished to produce mutants of Chinese hamster ovary cells. These cells cannot add sialic acid residues to glycoproteins such as erythropoietin and produce only asialoerythropoietin.
- Transfected mammalian cells producing erythropoietin also produce cytosolic sialidase which if it leaks into the culture medium degrades sialoerythropoietin with high efficiency (e.g., Gramer et al, 1995 Biotechnology 13:692-698).
- cell lines can be transfected, mutated or otherwise caused to constitutively produce sialidase. In this manner, asialoerythropoietin can be produced during the manufacture of asialoerythropoietin.
- a tissue protective cytokine of the invention has at least one modification of an amino acid residue in erythropoietin, regardless of the glycosylation state of the molecule.
- the chemical modification may be at least a modification of at least one amino group of at least one amino acid, such as a lysine residue, or the N-terminal amino group, or iodination of at least one tyrosine residue.
- tissue protective cytokines and chemically modified recombinant tissue protective cytokines of the present invention can verify the tissue protective attributes of the cytokines and the absence of an effect on the bone marrow using well known assays.
- TF-1 assay TF-1 cells are grown in a complete RPMI medium supplemented with 5 ng/ml of GM-CSF and 10% FCS for a day at 37 C. in a CO 2 incubator. The cells are then washed in and suspended at a density of 10 6 cells/ml for 16 hours in starvation medium (5% FCS without GM-CSF).
- a 96 well plate is prepared by: (1) adding 100 ⁇ l of sterile water to the outer wells to maintain moisture; (2) adding medium (10% FCS without cells or GM-CSF) alone to 5 wells; and (3) seeding 25,000 cells/well with medium containing 10% FCS and the recombinant tissue protective cytokines in remaining wells (five wells per cytokine being tested). If the cells proliferate, the recombinant tissue protective cytokine may be erythropoietic. The in vivo affect of the compound should then be tested on an in vivo assay monitoring an increase of hematocrit due to the recombinant tissue protective cytokine.
- a negative result non-proliferation of cells in the TF-1 assay in vitro assay or no increase in hematocrit within the in vivo assay-means that the recombinant tissue protective cytokine is nonerythropoietic.
- tissue protective properties of the recombinant tissue protective cytokine may be verified using a P-19 in vitro assay or a water intoxication in vivo assay in rats, both of which are outlined in further detail below.
- the above assays are provided merely as examples, and other suitable assays to determine the effect of the cytokines on bone marrow and tissue protection are known to those of ordinary skill in the art are contemplated by the present invention as well.
- a pharmaceutical composition as described above containing a tissue protective cytokine may be administrable to a mammal by any route which provides a sufficient level of a tissue protective cytokine in the vasculature to permit translocation across an endothelial cell barrier and beneficial effects on responsive cells.
- tissue protective cytokine When used for the purpose of perfusing a tissue or organ, similar results are desired.
- the tissue protective cytokine may be any of the aforementioned chemically-modified erythropoietins.
- the pharmaceutical composition provides an effective responsive-cell-beneficial amount of a tissue protective cytokine.
- tissue protective cytokine The endothelial cell barriers across which a tissue protective cytokine may translocate include tight junctions, perforated junctions, fenestrated junctions, and any other types of endothelial barriers present in a mammal.
- a preferred barrier is an endothelial cell tight junction, but the invention is not so limiting.
- tissue protective cytokines are useful generally for the therapeutic or prophylactic treatment of human diseases of the central nervous system or peripheral nervous system which have primarily neurological or psychiatric symptoms, ophthalmic diseases, cardiovascular diseases, cardiopulmonary diseases, respiratory diseases, kidney, urinary and reproductive diseases, bone diseases, skin diseases, gastrointestinal diseases and endocrine and metabolic abnormalities.
- conditions and diseases include hypoxic conditions, which adversely affect excitable tissues, such as excitable tissues in the central nervous system tissue, peripheral nervous system tissue, or cardiac tissue or retinal tissue such as, for example, brain, heart, or retina/eye. Therefore, the invention can be used to treat or prevent damage to excitable tissue resulting from hypoxic conditions in a variety of conditions and circumstances. Non-limiting examples of such conditions and circumstances are provided in the table herein below.
- pathologies include those which result from reduced oxygenation of neuronal tissues. Any condition which reduces the availability of oxygen to neuronal tissue, resulting in stress, damage, and finally, neuronal cell death, can be treated by the methods of the present invention.
- hypoxia and/or ischemia these conditions arise from or include, but are not limited to stroke, vascular occlusion, prenatal or postnatal oxygen deprivation, suffocation, choking, near drowning, carbon monoxide poisoning, smoke inhalation, trauma, including surgery and radiotherapy, asphyxia, epilepsy, hypoglycemia, chronic obstructive pulmonary disease, emphysema, adult respiratory distress syndrome, hypotensive shock, septic shock, anaphylactic shock, insulin shock, sickle cell crisis, cardiac arrest, dysrhythmia, nitrogen narcosis, and neurological deficits caused by heart-lung bypass procedures.
- the specific tissue protective cytokine compositions can be administered to prevent injury or tissue damage resulting from risk of injury or tissue damage during surgical procedures, such as, for example, tumor resection or aneurysm repair.
- Other pathologies caused by or resulting from hypoglycemia which are treatable by the methods described herein include insulin overdose, also referred to as iatrogenic hyperinsulinemia, insulinoma, growth hormone deficiency, hypocortisolism, drug overdose, and certain tumors.
- Other pathologies resulting from excitable neuronal tissue damage include seizure disorders, such as epilepsy, convulsions, or chronic seizure disorders.
- Other treatable conditions and diseases include diseases such as stroke, multiple sclerosis, hypotension, cardiac arrest, Alzheimer's disease, Parkinson's disease, cerebral palsy, brain or spinal cord trauma, AIDS dementia, age-related loss of cognitive function, memory loss, amyotrophic lateral sclerosis, seizure disorders, alcoholism, retinal ischemia, optic nerve damage resulting from glaucoma, and neuronal loss.
- compositions and methods of the present invention may be used to treat inflammation resulting from disease conditions or various traumas, such as physically or chemically induced inflammation.
- traumas could include angitis, chronic bronchitis, pancreatitis, osteomyclitis, rheumatoid arthritis, glomerulonephritis, optic neuritis, temporal arteritis, encephalitis, meningitis, transverse myelitis, dermatomyositis, polymyositis, necrotizing fascilitis, hepatitis, and necrotizing enterocolitis.
- glial activation and subsequent production of inflammatory cytokines depends upon primary neuronal damage (see Viviani, B., Corsini, E., Galli, C. L., Padovani, A., Ciusani, E., and Marinovich, M. 2000.
- Dying neural cells activate glia through the release of a protease product.
- Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-chloromethyl ketone includes long lasting neuroprotection in cerebral ischemia through apoptosis reduction and decrease of proinflammatory cytokines. J Neurosci 20:4398-4404). Inflammation and glial activation is common to different forms of neuro degenerative disorders, including cerebral ischemia, brain trauma and experimental allergic encephalomyelitis, disorders in which erythropoietin exerts a neuroprotective effect. Inhibition of cytokine production by erythropoietin could, at least in part, mediate its protective effect. However, unlike “classical” anti-inflammatory cytokines such as I1-10 and IL-13, which inhibit tumor necrosis factor production directly, erythropoietin appears to be active only in the presence of neuronal death.
- erythropoietin prevents apoptosis, inflammatory events triggered by apoptosis would be prevented. Additionally, erythropoietin may prevent the release of molecular signals from dying neurons which stimulate the glia cells or could act directly on the glial cells reducing their reaction to these products. Another possibility is that erythropoietin targets more proximal members of the inflammatory cascade (e.g., caspase 1, reactive oxygen or nitrogen intermediates) that trigger both apoptosis and inflammation.
- caspase 1 e.g., caspase 1, reactive oxygen or nitrogen intermediates
- erythropoietin appears to provide anti-inflammatory protection without the rebound affect typically associated with other anti-inflammatory compounds such as dexamethasone.
- erythropoietin's affect on multipurpose neuro toxins such as nitric oxide (NO).
- NO nitric oxide
- activated astrocytes and microglia produce neurotoxic quatities of NO in response to various traumas, NO serves many purposes within the body including the modulation of essential physiological functions.
- an anti-inflammatory may alleviate inflammation by suppressing NO or other neuro toxins
- the anti-inflammatory may also interfere with these chemical's roles in repairing the damage resulting from the trauma that led to the inflammation.
- the tissue protective cytokines of the present invention are able to alleviate the inflammation without interfering with the restorative capabilities of neurotoxins such as NO.
- compositions and methods of the invention may be used to treat conditions of, and damage to, retinal tissue.
- disorders include, but are not limited to retinal ischemia, macular degeneration, retinal detachment, retinitis pigmentosa, arteriosclerotic retinopathy, hypertensive retinopathy, retinal artery blockage, retinal vein blockage, hypotension, and diabetic retinopathy.
- the methods and principles of the invention may be used to protect or treat injury resulting from radiation damage to excitable tissue.
- a further utility of the methods of the present invention is in the treatment of neurotoxin poisoning, such as domoic acid shellfish poisoning, neurolathyrism, and Guam disease, amyotrophic lateral sclerosis, and Parkinson's disease.
- the present invention is also directed to a method for enhancing excitable tissue function in a mammal by peripheral administration of a tissue protective cytokine as described above.
- a tissue protective cytokine as described above.
- Various diseases and conditions are amenable to treatment using this method, and further, this method is useful for enhancing cognitive function in the absence of any condition or disease.
- These uses of the present invention are describe in further detail below and include enhancement of learning and training in both human and non-human mammals.
- Conditions and diseases treatable by the methods of this aspect of the present invention directed to the central nervous system include but are not limited to mood disorders, anxiety disorders, depression, autism, attention deficit hyperactivity disorder, and cognitive dysfunction. These conditions benefit from enhancement of neuronal function.
- Other disorders treatable in accordance with the teachings of the present invention include sleep disruption, for example, sleep apnea and travel-related disorders; subarachnoid and aneurismal bleeds, hypotensive shock, concussive injury, septic shock, anaphylactic shock, and sequelae of various encephalitides and meningitides, for example, connective tissue disease-related cerebritides such as lupus.
- neurotoxins such as domoic acid shellfish poisoning, neurolathyrism, and Guam disease, amyotrophic lateral sclerosis, Parkinson's disease; posloperative treatment for embolic or ischemic injury; whole brain irradiation; sickle cell crisis; and eclampsia.
- a further group of conditions treatable by the methods of the present invention include mitochondrial dysfunction, of either a hereditary or acquired nature, which are the cause of a variety of neurological diseases typified by neuronal injury and death.
- mitochondrial dysfunction of either a hereditary or acquired nature, which are the cause of a variety of neurological diseases typified by neuronal injury and death.
- Leigh disease subacute necrotizing encephalopathy
- myopathy due to neuronal drop out, and myopathy.
- defective mitochondrial metabolism fails to supply enough high energy substrates to fuel the metabolism of excitable cells.
- An erythropoietin receptor activity modulator optimizes failing function in a variety of mitochondrial diseases.
- hypoxic conditions adversely affect excitable tissues.
- the excitable tissues include, but are not limited to, central nervous system tissue, peripheral nervous system tissue, and heart tissue.
- the methods of the present invention are useful in the treatment of inhalation poisoning such as carbon monoxide and smoke inhalation, severe asthma, adult respiratory distress syndrome, and choking and near drowning.
- inhalation poisoning such as carbon monoxide and smoke inhalation
- severe asthma, adult respiratory distress syndrome, and choking and near drowning Further conditions which create hypoxic conditions or by other means induce excitable tissue damage include hypoglycemia that may occur in inappropriate dosing of insulin, or with insulin-producing neoplasms (insulinoma).
- Chronic disorders in which neuronal damage is involved and for which treatment by the present invention is provided include disorders relating to the central nervous system and/or peripheral nervous system including age-related loss of cognitive function and senile dementia, chronic seizure disorders, Alzheimer's disease, Parkinson's disease, dementia, memory loss, amyotrophic lateral sclerosis, multiple sclerosis, tuberous sclerosis, Wilson's Disease, cerebral and progressive supranuclear palsy, Guam disease, Lewy body dementia, prion diseases, such as spongiform encephalopathies, e.g., Creutzfeldt-Jakob disease, Huntington's disease, myotonic dystrophy, Freidrich's ataxia and other ataxias, as well as Gilles de la Tourette's syndrome, seizure disorders such as epilepsy and chronic seizure disorder, stroke, brain or spinal cord trauma, AIDS dementia, alcohol
- recombinant chimeric toxin molecules comprising erythropoietin can be used for therapeutic delivery of toxins to treat a proliferative disorder, such as cancer, or viral disorder, such as subacute sclerosing panencephalitis.
- Embryonic and fetal Asphyxia disorders Ischemia CNS Chronic fatigue syndrome, acute and chronic hypoosmolar and hyperosmolar syndromes, AIDS Dementia, Electrocution Encephalitis Rabies, Herpes Meningitis Subdural hematoma Nicotine addiction Drug abuse and Cocaine, heroin, crack, withdrawal marijuana, LSD, PCP, poly-drug abuse, ecstasy, opioids, sedative hypnotics, amphetamines, caffeine Obsessive-compulsive disorders Spinal stenosis, Transverse myelitis, Guillian Barre, Trauma, Nerve root compression, Tumoral compression, Heat stroke ENT Tinnitus Meuniere's syndrome Hearing loss Traumatic injury, barotrauma Kidney Renal failure Acute, chronic Vascular/ischemic, interstitial disease, diabetic kidney disease, nephrotic syndromes, infections Henoch S.
- this invention generally provides therapeutic or prophylactic treatment of the consequences of mechanical trauma or of human diseases.
- Therapeutic or prophylactic treatment for diseases, disorders or conditions of the CNS and/or peripheral nervous system are preferred.
- Therapeutic or prophylactic treatment for diseases, disorders or conditions which have a psychiatric component is provided.
- Therapeutic or prophylactic treatment for diseases, disorders or conditions including but not limited to those having an ophthalmic, cardiovascular, cardiopulmonary, respiratory, kidney, urinary, reproductive, gastrointestinal, endocrine, or metabolic component is provided.
- composition of the present invention may be made of a mixture of the tissue protective cytokines of the present invention as well as erythropoietin.
- such a pharmaceutical composition of erythropoietin or tissue protective cytokine may be administered systemically to protect or enhance the target cells, tissue or organ.
- Such administration may be parenterally, via inhalation, or transmucosally, e.g., orally, nasally, rectally, intravaginally, sublingually, submucosally or transdermally.
- administration is parenteral, e.g., via intravenous or intraperitoneal injection, and also including, but is not limited to, intra-arterial, intramuscular, intradermal and subcutaneous administration.
- a pharmaceutical composition for other routes of administration, such as by use of a perfusate, injection into an organ, or other local administration, a pharmaceutical composition will be provided which results in similar levels of a tissue protective cytokine as described above.
- a level of about 15pM -30 nM is preferred.
- compositions of the invention may comprise a therapeutically effective amount of a compound, and a pharmaceutically acceptable carrier.
- pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized foreign pharmacopeia for use in animals, and more particularly in humans.
- carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
- Such pharmaceutical carriers can be sterile liquids, such as saline solutions in water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
- a saline solution is a preferred carrier when the pharmaceutical composition is administered intravenously.
- Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
- Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
- the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
- compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
- the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
- the compounds of the invention can be formulated as neutral or salt forms.
- Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
- compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
- suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin.
- Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
- the formulation should suit the mode of administration.
- compositions adapted for oral administration may be provided as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (in aqueous or non-aqueous liquids); as edible foams or whips; or as emulsions.
- Tablets or hard gelatine capsules may comprise lactose, starch or derivatives thereof, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, stearic acid or salts thereof.
- Soft gelatine capsules may comprise vegetable oils, waxes, fats, semi-solid, or liquid polyols etc. Solutions and syrups may comprise water, polyols and sugars.
- An active agent intended for oral administration may be coated with or admixed with a material that delays disintegration and/or absorption of the active agent in the gastrointestinal tract (e.g., glyceryl monostearate or glyceryl distearate may be used).
- a material that delays disintegration and/or absorption of the active agent in the gastrointestinal tract e.g., glyceryl monostearate or glyceryl distearate may be used.
- a material that delays disintegration and/or absorption of the active agent in the gastrointestinal tract e.g., glyceryl monostearate or glyceryl distearate may be used.
- glyceryl monostearate or glyceryl distearate may be used.
- compositions adapted for transdermal administration may be provided as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
- Pharmaceutical compositions adapted for topical administration may be provided as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
- a topical ointment or cream is preferably used for topical administration to the skin, mouth, eye or other external tissues .
- the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
- the active ingredient may be formulated in a cream with an oil-in-water base or a water-in-oil base.
- Pharmaceutical compositions adapted for topical administration to the eye include eye drops.
- the active ingredient can be dissolved or suspended in a suitable carrier, e.g., in an aqueous solvent.
- Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouthwashes.
- compositions adapted for nasal and pulmonary administration may comprise solid carriers such as powders (preferably having a particle size in the range of 20 to 500 microns). Powders can be administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nose from a container of powder held close to the nose.
- compositions adopted for nasal administration may comprise liquid carriers, e.g., nasal sprays or nasal drops.
- inhalation of compounds directly into the lungs may be accomplished by inhalation deeply or installation through a mouthpiece into the oropharynx.
- These compositions may comprise aqueous or oil solutions of the active ingredient.
- compositions for administration by inhalation may be supplied in specially adapted devices including, but not limited to, pressurized aerosols, nebulizers or insufflators, which can be constructed so as to provide predetermined dosages of the active ingredient.
- pharmaceutical compositions of the invention are administered into the nasal cavity directly or into the lungs via the nasal cavity or oropharynx.
- compositions adapted for rectal administration may be provided as suppositories or enemas.
- Pharmaceutical compositions adapted for vaginal administration may be provided as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
- compositions adapted for parenteral administration include aqueous and non-aqueous sterile injectable solutions or suspensions, which may contain antioxidants, buffers, bacteriostats and solutes that render the compositions substantially isotonic with the blood of an intended recipient.
- Other components that may be present in such compositions include water, alcohols, polyols, glycerine and vegetable oils, for example.
- compositions adapted for parenteral administration may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, e.g., sterile saline solution for injections, immediately prior to use.
- a sterile liquid carrier e.g., sterile saline solution for injections, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
- an autoinjector comprising an injectable solution of an erythropoietin may be provided for emergency use by ambulances, emergency rooms, and battlefield situations, and even for self-administration in a domestic setting, particularly where the possibility of traumatic amputation may occur, such as by imprudent use of a lawn mower.
- the likelihood that cells and tissues in a severed foot or toe will survive after reattachment may be increased by administering erythropoietin or a tissue protective cytokine to multiple sites in the severed part as soon as practicable, even before the arrival of medical personnel on site, or arrival of the afflicted individual with severed toe in tow at the emergency room.
- the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings.
- compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
- the composition may also include a solubilizing agent and a local anesthetic such as lidocaine to ease pain at the site of the injection.
- the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically-sealed container such as an ampule or sachette indicating the quantity of active agent.
- composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
- an ampule of sterile saline can be provided so that the ingredients may be mixed prior to administration.
- Suppositories generally contain active ingredient in the range of 0.5% to 10% by weight; oral formulations preferably contain 10% to 95% active ingredient.
- a perfusate composition may be provided for use in transplanted organ baths, for in situ perfusion, or for administration to the vasculature of an organ donor prior to organ harvesting.
- Such pharmaceutical compositions may comprise levels of erythropoietin, tissue protective cytokines, or a form of either erythropoietin or tissue protective cytokines not suitable for acute or chronic, local or systemic administration to an individual, but will serve the functions intended herein in a cadaver, organ bath, organ perfusate, or in situ perfusate prior to removing or reducing the levels of the erythropoietin contained therein before exposing or returning the treated organ or tissue to regular circulation.
- the erythropoietin for this aspect of the invention may be any erythropoietin, such as naturally-occurring forms such as human erythropoietin, or any of tissue protective cytokines hereinabove described, such as asialoerythropoietin and phenylglyoxal-erythropoietins, as non-limiting examples.
- the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
- Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
- a tissue protective cytokine can be delivered in a controlled-release system.
- the polypeptide may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
- a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med. 321:574).
- the compound in another embodiment, can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); WO 91/04014; U.S. Pat. No. 4,704,355; Lopez-Berestein, ibid., pp. 317-327; see generally ibid.).
- a liposome see Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); WO 91/04014; U.S. Pat. No. 4,704,355; Lopez-Berestein, ibid., pp
- polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Press: Boca Raton, Florida, 1974; Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley: New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61, 1953; see also Levy et al., 1985, Science 228:190; During etal., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105).
- a controlled release system can be placed in proximity of the therapeutic target, i.e., the target cells, tissue or organ, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, pp. 115-138 in Medical Applications of Controlled Release, vol. 2, supra, 1984).
- Other controlled release systems are discussed in the review by Langer (1990, Science 249:1527-1533).
- tissue protective cytokine as properly formulated, can be administered by nasal, oral, rectal, vaginal, or sublingual administration.
- erythropoietin and/or the tissue protective cytokines of the invention may be desirable to administer erythropoietin and/or the tissue protective cytokines of the invention locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as silastic membranes, or fibers.
- the preferred effective dose will be readily determinable by a skilled artisan based upon considering several factors, which will be known to one of ordinary skill in the art. Such factors include the particular form of erythropoietin or the tissue protective cytokine, and its pharmacokinetic parameters such as bioavailability, metabolism, half-life, etc., which will have been established during the usual development procedures typically employed in obtaining regulatory approval for a pharmaceutical compound. Further factors in considering the dose include the condition or disease to be treated or the benefit to be achieved in a normal individual, the body mass of the patient, the route of administration, whether administration is acute or chronic, concomitant medications, and other factors well known to affect the efficacy of administered pharmaceutical agents. Thus the precise dosage should be decided according to the judgment of the practitioner and each patient's circumstances, e.g., depending upon the condition and the immune status of the individual patient, and according to standard clinical techniques.
- a perfusate or perfusion solution for perfusion and storage of organs for transplant, the perfusion solution includes an amount of erythropoietin or a tissue protective cytokine effective to protect responsive cells and associated cells, tissues or organs.
- Transplant includes but is not limited to xenotransplantation, where an organ (including cells, tissue or other bodily part) is harvested from one donor and transplanted into a different recipient; and autotransplant, where the organ is taken from one part of a body and replaced at another, including bench surgical procedures, in which an organ may be removed, and while ex vivo, resected, repaired, or otherwise manipulated, such as for tumor removal, and then returned to the original location.
- the perfusion solution is the University of Wisconsin (UW) solution (U.S. Pat. No. 4,798,824) which contains from about 1 to about 25 U/ml erythropoietin, 5% hydroxyethyl starch (having a molecular weight of from about 200,000 to about 300,000 and substantially free of ethylene glycol, ethylene chlorohydrin, sodium chloride and acetone); 25 mM KH 2 PO 4 , 3 mM glutathione; 5 mM adenosine; 10 mM glucose; 10 mM HEPES buffer; 5 mM magnesium gluconate; 1.5 mM CaCl 2 , 105 mM sodium gluconate; 200,000 units penicillin; 40 units insulin; 16 mg dexamethasone; 12 mg Phenol Red; and has a pH of 7.4-7.5 and an osmolality of about 320 mOsm/l.
- UW University of Wisconsin
- the solution is used to maintain cadaveric kidneys and pancreases prior to transplant. Using the solution, preservation can be extended beyond the 30-hour limit recommended for cadaveric kidney preservation.
- This particular perfusate is merely illustrative of a number of such solutions that can be adapted for the present use by inclusion of an effective amount of erythropoietin and/or a tissue protective cytokine.
- the perfusate solution contains from about 1 to about 500 ng/ml erythropoietin, or from about 40 to about 320 ng/ml erythropoietin.
- any form of erythropoietin or tissue protective cytokines can be used in this aspect of the invention.
- tissue protective cytokine for the purposes herein throughout is a human
- the methods herein apply equally to other mammals, particularly domesticated animals, livestock, companion, and zoo animals.
- the invention is not so limiting and the benefits can be applied to any mammal.
- erythropoietin and any tissue protective cytokine such as but not limited to the ones described above may be employed.
- methods and compositions for enhancing the viability of cells, tissues or organs which are not isolated from the vasculature by an endothelial cell barrier are provided by exposing the cells, tissue or organs directly to a pharmaceutical composition comprising erythropoietin or a tissue protective cytokine, or administering or contacting a pharmaceutical composition containing erythropoietin or a tissue protective cytokine to the vasculature of the tissue or organ.
- Enhanced activity of responsive cells in the treated tissue or organ is responsible for the positive effects exerted.
- the invention is based, in part, on the discovery that erythropoietin molecules can be transported from the luminal surface to the basement membrane surface of endothelial cells of the capillaries of organs with endothelial cell tight junctions, including, for example, the brain, retina, and testis.
- responsive cells across the barrier are susceptible targets for the beneficial effects of erythropoietin or tissue protective cytokines, and others cell types or tissues or organs that contain and depend in whole or in part on responsive cells therein are targets for the methods of the invention.
- erythropoietin or the tissue protective cytokine can interact with an erythropoietin receptor on a responsive cell, for example, neuronal, retinal, muscle, heart, lung, liver, kidney, small intestine, adrenal cortex, adrenal medulla, capillary endothelial, testes, ovary, or endometrial cell, and receptor binding can initiate a signal transduction cascade resulting in the activation of a gene expression program within the responsive cell or tissue, resulting in the protection of the cell or tissue, or organ, from damage, such as by toxins, chemotherapeutic agents, radiation therapy, hypoxia, etc.
- a responsive cell for example, neuronal, retinal, muscle, heart, lung, liver, kidney, small intestine, adrenal cortex, adrenal medulla, capillary endothelial, testes, ovary, or endometrial cell
- receptor binding can initiate a signal transduction cascade resulting in the activation of a gene expression program within the
- a mammalian patient is undergoing systemic chemotherapy for cancer treatment, including radiation therapy, which commonly has adverse effects such as nerve, lung, heart, ovarian or testicular damage.
- Administration of a pharmaceutical composition comprising erythropoietin and/or a tissue protective cytokine as described above is performed prior to and during chemotherapy and/or radiation therapy, to protect various tissues and organs from damage by the chemotherapeutic agent, such as to protect the testes. Treatment may be continued until circulating levels of the chemotherapeutic agent have fallen below a level of potential danger to the mammalian body.
- various organs were planned to be harvested from a victim of an automobile accident for transplant into a number of recipients, some of which required transport for an extended distance and period of time.
- the victim Prior to organ harvesting, the victim was infused with a pharmaceutical composition comprising erythropoietin and/or tissue protective cytokines as described herein.
- Harvested organs for shipment were perfused with a perfusate containing erythropoietin and/or tissue protective cytokines as described herein, and stored in a bath comprising erythropoietin and/or tissue protective cytokines.
- Certain organs were continuously perfused with a pulsatile perfusion device, utilizing a perfusate containing erythropoietin and/or tissue protective cytokines in accordance with the present invention. Minimal deterioration of organ function occurred during the transport and upon implant and reperfusion of the organs in situ.
- a surgical procedure to repair a heart valve required temporary cardioplegia and arterial occlusion.
- the patient Prior to surgery, the patient was infused with a tissue protective cytokine, 4 ⁇ g of carbamylated asialoerythropoietin per kg body weight.
- a tissue protective cytokine 4 ⁇ g of carbamylated asialoerythropoietin per kg body weight.
- Such treatment prevented hypoxic ischemic cellular damage, particularly after reperfusion.
- erythropoietin or a tissue protective cytokine of the invention in any surgical procedure, such as in cardiopulmonary bypass surgery, can be used.
- administration of a pharmaceutical composition comprising erythropoietin and/or tissue protective cytokines as described above is performed prior to, during, and/or following the bypass procedure, to protect the function of brain, heart, and other organs.
- the invention provides a pharmaceutical composition in dosage unit form adapted for protection or enhancement of responsive cells, tissues or organs distal to the vasculature which comprises an amount within the range from about 1 pg to 5 mg, 500 pg to 5 mg, 1 ng to 5 mg, 500 ng to 5 mg, 1 ⁇ g to 5 mg, 500 ⁇ g to 5 mg, or 1 mg to 5 mg of a tissue protective cytokine, and a pharmaceutically acceptable carrier.
- the amount of tissue protective cytokine is within the range from about 1 pg to 1 mg.
- tissue protective cytokines were found to restore cognitive function in animals having undergone brain trauma. After a delay of either 5 days or 30 days, administration of erythropoietin was still able to restore function as compared to sham-treated animals, indicating the ability of an erythropoietin to regenerate or restore brain activity.
- the invention is also directed to the use of erythropoietin and/or tissue protective cytokines for the preparation of a pharmaceutical composition for the treatment of brain trauma and other cognitive dysfunctions, including treatment well after the injury (e.g. three days, five days, a week, a month, or longer).
- the invention is also directed to a method for the treatment of cognitive dysfunction following injury by administering an effective amount of erythropoietin and/or tissue protective cytokines. Any erythropoietin and/or tissue protective cytokine as described herein may be used for this aspect of the invention.
- this restorative aspect of the invention is directed to the use of any erythropoietins and/or tissue protective cytokines herein for the preparation of a pharmaceutical composition for the restoration of cellular, tissue or organ dysfunction, wherein treatment is initiated after, and well after, the initial insult responsible for the dysfunction.
- treatment using erythropoietin and/or tissue protective cytokines of the invention can span the course of the disease or condition during the acute phase as well as a chronic phase.
- erythropoietin may be administered systemically at a dosage between about 1 ⁇ g and about 100 ⁇ g/kg body weight, preferably about 5-50 ⁇ g/kg-body weight, most preferably about 10-30 ⁇ g/kg-body weight, per administration.
- This effective dose should be sufficient to achieve serum levels of erythropoietin greater than about 10,000, 15,000, or 20,000 mU/ml (80, 120, or 160 ng/ml) of serum after erythropoietin administration.
- Such serum levels may be achieved at about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours post-administration.
- dosages may be repeated as necessary.
- administration may be repeated daily, as long as clinically necessary, or after an appropriate interval, e.g., every 1 to 12 weeks, preferably, every 1 to 3 weeks.
- the effective amount of erythropoietin and a pharmaceutically acceptable carrier may be packaged in a single dose vial or other container.
- the tissue protective cytokines which are capable of exerting the activities described herein but not causing an increase in hemoglobin concentration or hematocrit, are used. Such tissue protective cytokines are preferred in instances wherein the methods of the present invention are intended to be provided chronically.
- an erythropoietin is given at a dose greater than that necessary to maximally stimulate erythropoiesis.
- a tissue protective cytokine of the invention does not necessarily have erythropoietic activity, and therefore the above dosages expressed in hematopoietic units are merely exemplary for erythropoietins that are erythropoietic; hereinabove weight equivalents for dosages are provided which are applicable to tissue protective cytokines.
- the present invention is further directed to a method for facilitating the transport of a molecule across an endothelial cell barrier in a mammal by administering a composition which comprises the particular molecule in association with an erythropoietin or tissue protective cytokine as described hereinabove.
- a composition which comprises the particular molecule in association with an erythropoietin or tissue protective cytokine as described hereinabove.
- tight junctions between endothelial cells in certain organs in the body create a barrier to the entry of certain molecules.
- means for facilitating passage of pharmaceutical agents is desired.
- Erythropoietin or tissue protective cytokines of the invention are useful as carriers for delivering other molecules across the blood-brain and other similar barriers.
- a composition comprising a molecule desirous of crossing the barrier with erythropoietin or a tissue protective cytokine is prepared and peripheral administration of the composition results in the transcytosis of the composition across the barrier.
- the association between the molecule to be transported across the barrier and the erythropoietin or tissue protective cytokine may be a labile covalent bond, in which case the molecule is released from association with the erythropoietin or tissue protective cytokine after crossing the barrier. If the desired pharmacological activity of the molecule is maintained or unaffected by association with erythropoietin and or tissue protective cytokine, such a complex can be administered.
- association of molecules with erythropoietin or a tissue protective cytokine may be achieved by any number of means, including labile, covalent binding, cross-linking, etc.
- Biotin/avidin interactions may be employed; for example, a biotinylated erythropoietin of the invention may be complexed with a labile conjugate of avidin and a molecule desirably transported.
- a hybrid molecule may be prepared by recombinant or synthetic means, for example, a fusion or chimeric polypeptide which includes both the domain of the molecule with desired pharmacological activity and the domain responsible for erythropoietin receptor activity modulation. Protease cleavage sites may be included in the molecule.
- a molecule may be conjugated to erythropoietin or a tissue protective cytokine of the invention through a polyfunctional molecule, i.e., a polyfunctional crosslinker.
- a polyfunctional molecule encompasses molecules having one functional group that can react more than one time in succession, such as formaldehyde, as well as molecules with more than one reactive group.
- the term “reactive group” refers to a functional group on the crosslinker that reacts with a functional group on a molecule (e.g., peptide, protein, carbohydrate, nucleic acid, particularly a hormone, antibiotic, or anti-cancer agent to be delivered across an endothelial cell barrier) so as to form a covalent bond between the cross-linker and that molecule.
- a functional group on a molecule e.g., peptide, protein, carbohydrate, nucleic acid, particularly a hormone, antibiotic, or anti-cancer agent to be delivered across an endothelial cell barrier
- the term “functional group” retains its standard meaning in organic chemistry.
- the polyfunctional molecules that can be used are preferably biocompatible linkers, i.e., they are noncarcinogenic, nontoxic, and substantially non-immunogenic in vivo.
- the polyfunctional molecule is preferably bifunctional.
- the term “bifunctional molecule” refers to a molecule with two reactive groups.
- the bifunctional molecule may be heterobifunctional or homobifunctional.
- a heterobifunctional cross-linker allows for vectorial conjugation. It is particularly preferred for the polyfunctional molecule to be sufficiently soluble in water for the cross-linking reactions to occur in aqueous solutions such as in aqueous solutions buffered at pH 6 to 8, and for the resulting conjugate to remain water soluble for more effective bio-distribution.
- the polyfunctional molecule covalently bonds with an amino or a sulfhydryl functional group.
- polyfunctional molecules reactive with other functional groups such as carboxylic acids or hydroxyl groups, are contemplated in the present invention.
- the homobifunctional molecules have at least two reactive functional groups, which are the same.
- the reactive functional groups on a homobifunctional molecule include, for example, aldehyde groups and active ester groups.
- Homobifunctional molecules having aldehyde groups include, for example, glutaraldehyde and subaraldehyde. The use of glutaraldehyde as a cross-linking agent was disclosed by Poznansky et al., Science 223, 1304-1306 (1984).
- Homobifunctional molecules having at least two active ester units include esters of dicarboxylic acids and N-hydroxysuccinimide.
- N-succinimidyl esters include disuccinimidyl suberate and dithio-bis-(succinimidyl propionate), and their soluble bis-sulfonic acid and bis-sulfonate salts such as their sodium and potassium salts. These homobifunctional reagents are available from Pierce, Rockford, Ill.
- the heterobifunctional molecules have at least two different reactive groups.
- the reactive groups react with different functional groups, e.g., present on the erythropoietin and the molecule.
- These two different functional groups that react with the reactive group on the heterobifunctional cross-linker are usually an amino group, e.g., the epsilon amino group of lysine; a sulfhydryl group, e.g., the thiol group of cysteine; a carboxylic acid, e.g., the carboxylate on aspartic acid; or a hydroxyl group, e.g., the hydroxyl group on serine.
- tissue protective cytokines of the invention may not have suitable reactive groups available for use with certain cross-linking agent; however, one of skill in the art will be amply aware of the choice of cross-linking agents based on the available groups for cross-linking in erythropoietin or tissue protective cytokines of the invention.
- the covalent bond will usually be an amido or imido bond.
- the reactive group that forms a covalent bond with an amino group may, for example, be an activated carboxylate group, a halocarbonyl group, or an ester group.
- the preferred halocarbonyl group is a chlorocarbonyl group.
- the ester groups are preferably reactive ester groups such as, for example, an N-hydroxy-succinimide ester group.
- the other functional group typically is either a thiol group, a group capable of being converted into a thiol group, or a group that forms a covalent bond with a thiol group.
- the covalent bond will usually be a thioether bond or a disulfide.
- the reactive group that forms a covalent bond with a thiol group may, for example, be a double bond that reacts with thiol groups or an activated disulfide.
- a reactive group containing a double bond capable of reacting with a thiol group is the maleimido group, although others, such as acrylonitrile, are also possible.
- a reactive disulfide group may, for example, be a 2-pyridyldithio group or a 5,5′-dithio-bis-(2-nitrobenzoic acid) group.
- Some examples of heterobifunctional reagents containing reactive disulfide bonds include N-succinimidyl 3-(2-pyridyl-dithio) propionate (Carlsson, et al., 1978, Biochem J., 173:723-737), sodium S-4-succinimidyloxycarbonyl-alpha-methylbenzylthiosulfate, and 4-succinimidyloxycarbonyl-alpha-methyl-(2-pyridyldithio)toluene.
- N-succinimidyl 3-(2-pyridyldithio)propionate is preferred.
- heterobifunctional reagents comprising reactive groups having a double bond that reacts with a thiol group include succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate and succinimidyl m-maleimidobenzoate.
- heterobifunctional molecules include succinimidyl 3-(maleimido) propionate, sulfosuccinimidyl 4-(p-maleimido-phenyl) butyrate, sulfosuccinimidyl 4-(N-maleimidomethyl-cyclohexane)-1-carboxylate, maleimidobenzoyl-N-hydroxy-succinimide ester.
- the sodium sulfonate salt of succinimidyl m-maleimidobenzoate is preferred.
- Many of the above-mentioned heterobifunctional reagents and their sulfonate salts are available from Pierce Chemical Co., Rockford, Ill. USA.
- conjugated may be tested in vitro for both the erythropoietin, and for the desirable pharmacological activity. If the conjugate retains both properties, its suitability may then be tested in vivo. If the conjugated molecule requires separation from erythropoietin or the tissue protective cytokine for activity, a labile bond or reversible association with erythropoietin or the tissue protective cytokine will be preferable. The lability characteristics may also be tested using standard in vitro procedures before in vivo testing.
- Barriers which are crossed by the above-described methods and compositions of the present invention include but are not limited to the blood-brain barrier, the blood-eye barrier, the blood-testes barrier, the blood-ovary barrier, and the blood-uterus barrier.
- Candidate molecules for transport across an endothelial cell barrier include, for example, hormones, such as growth hormone, neurotrophic factors, antibiotics, antivirals, or antifungals such as those normally excluded from the brain and other barriered organs, peptide radiopharmaceuticals, antisense drugs, antibodies and antivirals against biologically-active agents, pharmaceuticals, and anti-cancer agents.
- hormones such as growth hormone, neurotrophic factors, antibiotics, antivirals, or antifungals such as those normally excluded from the brain and other barriered organs
- peptide radiopharmaceuticals such as growth hormone, neurotrophic factors, antibiotics, antivirals, or antifungals such as those normally excluded from the brain and other barriered organs
- antisense drugs such as those normally excluded from the brain and other barriered organs
- antibodies and antivirals against biologically-active agents such as those normally excluded from the brain and other barriered organs
- antisense drugs such as those normally excluded from the brain and other barriered organs
- Non-limiting examples of such molecules include hormones such as growth hormone, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (bFGF), transforming growth factor ⁇ 1 (TGF ⁇ 1), transforming growth factor ⁇ 2 (TGF ⁇ 2), transforming growth factor ⁇ 3 (TGF ⁇ 3), interleukin 1, interleukin 2, interleukin 3, and interleukin 6, AZT, antibodies against tumor necrosis factor, and immunosuppressive agents such as cyclosporin.
- hormones such as growth hormone, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (bFGF), transforming growth factor ⁇ 1 (TGF ⁇ 1), transforming growth factor ⁇ 2 (TGF ⁇ 2), transforming growth factor ⁇ 3 (TGF ⁇ 3), interleukin 1, interleukin 2, interleukin 3, and interleukin 6, AZT,
- dyes or markers may be attached to erythropoietin or one of the tissue protective cytokines of the present invention in order to visualize cells, tissues, or organs within the brain and other barriered organs for diagnostic purposes.
- a marker used to visualize plaque within the brain could be attached to erythropoietin or a tissue protective cytokine in order to determine the progression of Alzheimer's disease within a patient.
- the present invention is also directed to a composition comprising a molecule to be transported via transcytosis across an endothelial cell tight junction barrier and an erythropoietin or tissue protective cytokine as described above.
- the invention is further directed to the use of a conjugate between a molecule and an erythropoietin or a tissue protective cytokine as described above for the preparation of a pharmaceutical composition for the delivery of the molecule across a barrier as described above.
- tissue protective cytokines of the invention include in vitro models using P-19 cells to determine the neuroprotective affects of the tissue protective cytokines, and in-vivo water intoxication model in mice to determine the in vivo neuroprotective affects of the tissue protective cytokines of the present invention.
- model proteins conjugated to the erythropoietins of the invention are evaluated for transport into the brain following parenteral administration.
- These tests in in-vitro models and animal models are predictive of the efficacy of the present compounds in other mammalian species including humans.
- Example 1 demonstrates that the human brain has an abundance of erythropoietin receptors that provide the mechanism for the transcytosis of erythropoietin as well as tissue protective cytokines.
- FIG. 1 shows that capillaries of the human brain express very high levels of EPO receptor, as determined by immunohistochemistry using specific anti-EPO receptor antibodies. This provides a mechanism whereby EPO is able to penetrate into the brain from the systemic circulation, in spite of the blood brain barrier.
- FIG. 2 shows the EPO receptor is densely localized within and around capillaries forming the blood brain barrier in the human brain.
- FIG. 3 shows that there is a high density of EPO receptor at the luminal and anti-luminal surfaces of human brain capillaries, forming the anatomical basis for transport of EPO from the circulation into the brain.
- FIG. 4 was obtained following a similar protocol as in FIG. 3 except that the tissue was sectioned on an ultramicrotome for electron microscopy and the secondary antibody was labeled with colloidal gold particles.
- This figure shows that EPO receptor is found upon the endothelial surface (*), within cytoplasmic vesicles (arrows) and upon glial endfeet (+) in human brain, providing the anatomical basis for transport of EPO from within the circulation into the brain.
- Tissue protective cytokines desirable for the uses described herein may be generated by guanidination, carbamylation, amidination, trinitrophenylation, acetylation, succinylation, nitration, or modification of arginine or lysine residues or carboxyl groups, among other procedures as mentioned herein above, of erythropoietin. These modifications produce tissue protective cytokines that maintain their activities for specific organs and tissues but not for others, such as erythrocytes.
- erythropoietin as the starting material, one of ordinary skill in the art would recognize that erythropoietin derivatives such as desialylated, guanidinated, carbamylated, amidinated, trinitrophenylated, acetylated, succinylated, and nitrated erythropoietin can be used as well.
- Erythropoietin may be desialylated by the following exemplary procedure.
- Sialidase isolated from Streptococcus sp 6646K.
- SEIKAGAKU AMERICA Code No. 120050
- Erythropoietin is subjected to desialylation by sialidase (0.05 U/mg EPO) at 37 C for 3 h.
- the reaction mixture is desalted and concentrated using an Ultrafree Centrifugal Filter Unit.
- the sample is then applied to an ion exchange column in AKTAprimeTM system.
- the protein is eluted with selected buffers.
- the eluted fractions containing a significant amount of protein are then subjected to IEF gel analysis.
- the fractions containing only the top two bands are pooled.
- the protein content of the pooled fractions was determined and ⁇ fraction (1/9) ⁇ volumes of 10 ⁇ salt solution (1 M NaCl, 0.2 M sodium citrate, 3 mM citric acid) was added.
- the sialic acid content of the solution was then determined. No significant sialic content should be detected.
- Asialoerythropoietin and phenylglyoxalerythropoietin were as effective as native erythropoietin for neural cells in vitro as shown in FIGS. 5 - 6 .
- In-vitro testing was carried out using neural-like embryonal carcinoma cells (P19) that undergo apoptosis upon the withdrawal of serum. Twenty-four hours before the removal of serum, 1-1000 ng/ml of erythropoietin or a modified erythropoietin was added to the cultures.
- FIG. 7 shows the results of another focal ischemia model in which a comparative dose response was performed with erythropoietin and asialoerythropoietin. At the lowest dose of 250 U (2 ⁇ g)/kg, asialoerythropoietin afforded protection whereas unmodified erythropoietin did not.
- Native erythropoietin may be used to prepare the respective carbamylated molecules, in accordance with the following procedure, as described in Jin Zeng (1991). Lysine modification of metallothionein by carbamylation and guanidination. Methods in Enzymology 205:433-437. First, potassium cyanate was recrystallized. A 1 M Borate buffer (pH 8.8) was prepared. An erythropoietin solution was mixed with an equal volume of the borate buffer. Potassium cyanate was added directly to the reaction tube to a final concentration of 0.5 M. The solution was mixed well and incubated at 37 C. for 6 h. The solution was then dialyzed thoroughly using distilled water.
- the product was removed from the dialysis tubing and collected into a fresh tube. The volume was measured and ⁇ fraction (1/9) ⁇ volume of 10 ⁇ salt solution (1 M NaCl, 0.2 M sodium citrate, 3 mM citric acid)is added to the solution. The protein content is determined and the product recovery rate is calculated. The products were analyzed by IEF gel followed by an in vitro test with TF-1 cells.
- Native erythropoietin may be used to prepare the respective succinylated molecules, in accordance with the following procedure, as described in Alcalde et al. (2001). Succinylation of cyclodextrin glycosyltransferase from Thermoanaerobacter sp. 501 enhances its transferase activity using starch as donor. J. Biotechnology 86: 71-80. Erythropoietin (100 ug) in 0.5 M NaHCO3 (pH 8.0) was incubated with a 15 molar excess of succinic anhydride at 15 C. for 1 hour. The reaction was stopped by dialysis against distilled water.
- Another method for succinylating erythropoietin is to dissolve succinic anhydride in dry acetone at 27 mg/ml.
- the reaction is performed in an eppendorf tube in 10 mM sodium phosphate buffer (pH 8.0). Erythropoietin and 50-fold molar of succinic anhydride are added to the tube.
- the solution is mixed well and the tube is rotated at 4 C. for 1 h.
- the reaction is stopped by dialysis against 10 mM sodium phosphate buffer, using a Dialysis cassette (Slide-A-Laze 7K, Pierce 66373).
- the product is removed from the dialysis cassette and collected into a fresh tube.
- the volume is measured and ⁇ fraction (1/9) ⁇ volume of 10 ⁇ salt solution (1 M NaCl, 0.2 M sodium citrate, 3 mM citric acid) is added. Determine the protein content and calculate the product recovery rate.
- the products were analyzed by IEF gel followed by an in vitro test with TF-1 cells.
- Native erythropoietin may be used to prepare the respective acetylated molecules, in accordance with the following procedure, as described in Satake et al (1990). Chemical modification of erythropoietin: an increase in in-vitro activity by guanidination. Biochimica et Biophysica Acta. 1038:125-129.
- the reaction was performed in an eppendorf tube in 80 mM sodium phosphate buffer (pH 7.2). Erythropoietin and equal molar of acetic anhydride were added to the tube. After mixing well, the solution was incubated on ice for 1 h. The reaction was stopped by dialysis against water, using a Dialysis cassette (Slide-A-Laze 7K, Pierce 66373). The product was removed from the dialysis cassette and collected into a fresh tube. After measuring the volume of product, ⁇ fraction (1/9) ⁇ volume of 10 ⁇ salt solution (1 M NaCl, 0.2 M sodium citrate, 3 mM citric acid) was added. The protein content is determined, and the product recovery rate was calculated. The product was analyzed by IEF gel followed by an in vitro test with TF-1 cells.
- Native erythropoietin may be used to prepare the respective N ⁇ -(carboxymethyl)lysine (CML) modified molecules in which one or more lysyl residues of the erythropoietin are modified, in accordance with the following procedure, as described in Akhtar et al (1999) Conformational study of N ⁇ -(carboxymethyl)lysine adducts of recombinant a-crystallins. Current Eye Research, 18: 270-276.
- CML N ⁇ -(carboxymethyl)lysine
- Glyoxylic acid (200 mM) and NaBH 3 CN (120 mM) were prepared in sodium phosphate buffer (50 mM, pH 7.5).
- erythropoietin was added (in phosphate buffer).
- the lysine equivalent in the solution was then calculated.
- 3-times greater NaBH 3 CN and 5 or 10-times greater glyoxylic acid was added to the tube.
- Each tube was vortexed and incubated at 37 C. for 5 h.
- the samples were dialated against phosphate buffer overnight at 4 C.
- the volume of each product was measured after dialysis.
- the protein concentration was determined, and the product recovery rate was calculated.
- the product was analyzed by IEF gel followed by an in vitro test with TF-1 cells.
- Native erythropoietin may be used to prepare the respective iodinated molecules, in accordance with the following procedure, as described in instruction provided by Pierce Chemical Company (Rockford, Ill.) for IODO-Gen Pre-Coated Iodination Tubes (product #28601).
- 0.1 M of NaI was prepared, and iodination was performed in an IODO-Gen Pre-Coated Iodination Tube (Pierce, 28601), with a total reaction volume of 0.1 ml/tube in sodium phosphate buffer (40 mM, pH 7.4).
- the protein substrate (erythropoietin) was mixed with sodium phosphate buffer and then transfered to an IODO-Gen Pre-Coated Iodination Tube.
- NaI was added to a final concentration of 1-2 mM, making the molar ration of NaI/protein as 14-20. The solution was then mixed well and incubated at room temperature for 15 min with gentle agitation.
- the reaction was stopped by removing the reaction mixture and adding to it a tube containing 3.9 ml of sodium buffer (i.e., a 40-fold dilution).
- the product was concentrated by a pre-wet Ultrafree centrifugal filter unit. The volume of concentrate was measured and ⁇ fraction (1/9) ⁇ volume of 10 ⁇ salt solution (1 M NaCl, 0.2 M sodium citrate, 3 mM citric acid) was added. The protein concentration was determined, and the product recovery was then calculated.
- the products were analyzed by IEF gel followed by an in vitro test with TF-1 cells.
- Another method for iodinating erythropoietin involves incubating one Iodo Bead (Pierce, Rockford, Ill.) in 100 ul PBS (20 mM sodium phosphate, 0.1 SM NaCl, pH7.5) containing 1 mCi free Na 125 I for 5 minutes. Erythropoietin (100 ug) in 100 ul PBS was then added to the mixture. After a ten minute incubation period at room temperature, the reaction was stopped by removing the 200 ul solution from the reaction vessel (leaving the iodo bead behind). The excess iodine was then removed by gel filtration on a Centricon 10 column. As shown in FIG. 9, iodo-erythropoietin produced in this manner is efficacious in protecting P19 cells from serum withdrawal.
- Erythropoietin may also be iodinated using Chloramine T.
- Erythropoietin 100 ug in 100 ul PBS was added to 500 uCi Na 125 I, and the mixture was then mixed together in an eppendorf tube. 25 ul chloramines T (2 mg/ml) were then added and the mixture was incubated for 1 minute at room temperature.
- 50 ul of Chloramine T stop buffer (2.4 mg/ml sodium metabisulfite, 10 mg/ml tyrosine, 10% glycerol, 0. 1% xylene in PBS was then added.
- the iodotyrosine and iodinated erythropoietin were then separated by gel filtration on a Centricon 10 column.
- FIG. 10 shows the activity of biotinylated erythropoietin and asialoerythropoietin in the serum-starved P19 assay.
- native erythropoietin may be used to prepare the respective biotinylated molecules, in accordance with the following procedure, as described in instruction provided by Pierce Chemical Company (Rockford, Ill.) for EZ-Link NHS-LC-Biotin (product #21336).
- EZ-Link NHS-LC-Biotin (pierce, 21336) in DMSO at 2 mg/ml was dissolved.
- the reaction was performed in a tube (17 ⁇ 100 mm) with total volume of 1 ml containing 50 mM sodium bicarbonate (pH 8.3). Erythropoietin and ⁇ 10% of EZ-Link NHS-LC-Biotin were added to generate a solution with a molar ratio of Biotin/protein at ⁇ 20.
- the solution was mixed well and incubated on ice for 2 h.
- the solution was desalted and concentrated using an Ultrafree centrifugal filter unit.
- the product was then collected into a fresh tube.
- the volume of the product was measured, and ⁇ fraction (1/9) ⁇ volume of 10 ⁇ salt solution (1 M NaCl, 0.2 M sodium citrate, 3 mM citric acid) was added to the product.
- the protein content of the product was determined and the product recovery rate was calculated.
- the products were analyzed by IEF gel followed by an in vitro test with TF-1 cells.
- the free amino groups of erythropoietin can also be biotinylated using the following method. First, 0.2 mg D-biotinoyl-e-aminocaproic acid-N-hydroxysuccinimide ester (Boehringer Mannheim #1418165) was dissolved in 100 ul DMSO. This solution was then combined with 400 ul PBS containing approximately 0.2 mg erythropoietin in a foil covered tube. After incubating this solution for 4 hours at room temperature, the unreacted biotin was separated by gel filtration on a Centricon 10 column.
- erythropoietin or an erythropoietin derivative in order to arrive at a tissue protective cytokine.
- erythropoietin can be desialylated in accordance with the procedure listed above at Example 2(A) and carbamylated in accordance with the procedure listed above at Example 2(B) to generate an asialo carbamoylerythropoietin.
- erythropoietin 100 ug was incubated with 0.1M sodium borohydride in PBS for 30 minutes at room temperature. The reduction was terminated by cooling the samples on ice for 10 minutes and dialyzing it against PBS, three times, overnight.
- Reduction using lithium aluminum hydride was accomplished by incubating erythropoietin (100 ug) with 0.1M lithium aluminum hydride in PBS for 30 minutes at room temperature. The reduction was terminated by cooling the samples on ice for 10 minutes and dialyzing the samples against PBS, three times, overnight.
- Erythropoietin can be subjected to a limited chemical proteolysis that targets specific residues. Erythropoietin was reacted with 2-(2-nitrophenylsulfenyl)-3-methyl-3′-bromoindolenine which cleaves specifically after tryptophan residues in a 50 times excess in 50% acetic acid for 48 hours in the dark at room temperature in tubes capped under nitrogen pressure. The reaction was terminated by quenching with tryptophan and desalting.
- erythropoietin or asialoerythropoietin may be modified, yet multiple modifications as well as additional modifications of the erythropoietin molecule may also be performed without deviating from the spirit of the present invention.
- Any of the foregoing examples may be carried out with partially desialylated erythropoietin, which may be prepared as described below.
- any of the aforementioned modified erythropoietins may be modified at one or more arginine residues by using, for example, phenylglyoxal according to the protocol of Takahashi (1977, J. Biochem.
- the neuroprotective affects of the tissue protective cytokines of the present invention was evaluated using a water intoxication assay in accordance with Manley et al., 2000, Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke, Nat Med February 2000;6(2):159-63.
- Female C3H/HEN mice were used. The mice were given 20% of their body weight as water IP with 400 ng/kg bw DDAVP (desmopressin).
- mice were administered erythropoietin (A) or a tissue protective cytokine: asialoerythropoietin (B), carbamylated asialoerythropoietin (C), succinylated asialoerythropoietin (D), acetylated asialoerythropoietin (E), iodinated asialoerythropoietin (F), carboxymethylated asialoerythropoietin (G), carbamylated erythropoietin (H), acetylated erythropoietin (I), iodinated erythropoietin (J), or N ⁇ -carboxy methyl erythropoietin (K).
- A erythropoietin
- B tissue protective cytokine
- C carbamylated asialoerythropoietin
- mice were given a 100 microgram/kg dose of erythropoietin or tissue protective cytokine intraperitoneally 24 hrs before administration of the water and again at the time of the water administration.
- a modified scale from Manley et al. was used to evaluate the mice. The modified scale is as listed below: 1. Explores cage/table Yes 0 No 1 2. Visually tracks objects Yes 0 No 1 3. Whisker movement Present 0 Absent 1 4. Leg-tail movements Normal 0 Stiff 1 Paralyzed 2 5. Pain withdrawal (toe pinch) Yes 0 No 1 6. Coordination of movement Normal 0 Abnormal 1 7. Stops at edge of table Yes 0 No 1 Total score possible: 8
- FIG. 12 shows the scores of the mice who received erythropoietin or one of the tissue protective cytokines of the present invention as a percentage of the score obtained by the control mice.
- the mice who received the tissue protective cytokines of the present invention exhibited less neurological damage and therefore scored better on the modified scale.
- FIG. 12 shows that the tissue protective cytokines of the present invention protect neuronal tissue.
- the peak level of about 100 mU/ml is within the range known to exert protective effects in vitro (0.1 to 100 mU/ml).
- the time to peak occurs at about 3.5 hrs, which is delayed significantly from the peak serum levels (less than 1 hr).
- the results of this experiment illustrate that significant levels of erythropoietin can be accomplished across a tight cellular junction by bolus parenteral administration of erythropoietin at appropriate concentrations.
- tissue protective cytokines of the present invention would recognize that similar results would be expected from the tissue protective cytokines of the present invention.
- Wistar male rats weighing 300 to 330 g are given erythropoietin (5000 U/kg body weight) or vehicle 24 h prior to removal of the heart for ex vivo studies, done in accordance with the protocol of Delcayre et al., 1992, Amer. J. Physiol. 263:H 1537-45. Animals are sacrificed with pentobarbital (0.3 mL), and intravenously heparinized (0.2 mL). The hearts are initially allowed to equilibrate for 15 min. The left ventricular balloon is then inflated to a volume that gives an end-diastolic pressure of 8 mm Hg.
- a left ventricular pressure-volume curve is constructed by incremental inflation of the balloon volume by 0.02 ml aliquots. Zero volume is defined as the point at which the left ventricular end-diastolic pressure is zero.
- the left ventricular balloon is deflated to set end-diastolic pressure back to 8 mmHg and the control period is pursued for 15 min., after check of coronary flow.
- the heart is arrested with 50 mL Celsior+molecule to rest at 4° C. under a pressure of 60 cm H 2 0.
- the heart is then removed and stored 5 hours at 4° C. in plastic container filled with the same solution and surrounded with crushed ice.
- the heart On completion of storage, the heart is transferred to a Langendorff apparatus.
- the balloon catheter is re-inserted into the left ventricle and re-inflated to the same volume as during preischemic period.
- the heart is re-perfused for at least 2 hours at 37° C.
- the re-perfusion pressure is set at 50cm H 2 O for 15 min of re-flow and then back to 100cm H 2 0 for the 2 next hours.
- Pacing (320 beats per minute) is re-instituted. Isovolumetric measurements of contractile indexes and diastolic pressure are taken in triplicate at 25, 45, 60, 120 min of reperfusion.
- Retinal cells are very sensitive to ischemia such that many will die after 30 minutes of ischemic stress. Further, subacute or chronic ischemia underlies the deterioration of vision which accompanies a number of common human diseases, such as diabetes mellitus, glaucoma, and macular degeneration. At the present time there are no effective therapies to protect cells from ischemia. A tight endothelial barrier exists between the blood and the retina that excludes most large molecules. To test whether peripherally-administered erythropoietin will protect cells sensitive to ischemia, an acute, reversible glaucoma rat model was utilized as described by Rosenbaum et al. (1997; Vis. Res. 37:3443-51).
- FIG. 16- 17 illustrate that the administration of erythropoietin is associated with good preservation of the electroretinogram (ERG) (Panel D), in contrast to animals treated with saline alone (Panel C), for which very little function remained.
- ERP electroretinogram
- Wistar rats male weighing 180-300 g were used in this study. The animals were fasted for 12 h before surgery, and were humanely restrained and anesthesized with an intraperitoneal injection of thiopental sodium (40 mg/kg-bw). After infiltration of the skin (bupivacaine 0.25%), a complete single level (T-3) laminectomy was performed through a 2 cm incision with the aid of a dissecting microscope. Traumatic spinal cord injury was induced by the extradural application of a temporary aneurysm clip exerting a 0.6 newton (65 grams) closing force on the spinal cord for 1 minute. After removal of the clip, the skin incision was closed and the animals allowed to recover fully from anethesia and returned to their cages. The rats were monitored continuously with bladder palpation at least twice daily until spontaneous voiding resumed.
- FIG. 21 is a graph demonstrating the locomotor ratings of the rats recovering from the spinal cord trauma over a period of thirty days. As can be seen from the graph, the rats that were given erythropoietin (group II) or tissue protective cytokines (groups III-V) recovered from the injury more readily and demonstrated better overall recovery from the injury than the control rats. Similar results would be expected from the therapeutic treatment with the tissue protective cytokines of the present invention.
- the animals were placed in the right lateral decubitus position, the skin prepared with povidone iodine, infiltrated with bupivacaine (0.25%) and a flank skin incision was made parallel to the spine at the 12th costal level. After incision of the skin and subcutaneous thoracolumbar fascia, the longissimus lumborum and iliocostalis lumborum muscles were retracted. The abdominal aorta was exposed via a left retroperitoneal approach and mobilized just inferior to the left renal artery. A piece of PE-60 tubing was looped around the aorta immediately distal to the left renal artery and both ends passed through a larger rubber tube.
- the aorta was non-traumatically occluded for 20 minutes.
- Heparin 400 IU was administrated as an intravenous bolus before aortic occlusion. After 20 minutes of occlusion, the tube and catheter were removed, the incision was closed and the animals were monitored until full recovery and then were serially assessed for neurological function.
- mice were randomly divided into six groups.
- Group (II) received rhEPO @ 6.5 microgram/kg-bw;
- group (III) received a tissue protective cytokine (carbamylated erythropoietin) @ 6.5 microgram/kg-bw;
- group (IV) received another tissue protective cytokine (asialoerythropoietin) @ 6.5 microgram/kg-bw;
- FIG. 22 is a graph plotting motor function of the recovering rabbits. The graph demonstrates that even over a period of only two days erythropoietin and the tissue protective cytokines of the present invention permit the rabbits to recover more fully from the spinal cord injury. Similar results would be expected from the therapeutic treatment with the tissue protective cytokines of the present invention.
- the rats were anesthetized with chloral hydrate (400 mg/kg-bw, i.p.), the carotid arteries were visualized, and the right carotid was occluded by two sutures and cut. A burr hole adjacent and rostral to the right orbit allowed visualization of the MCA, which was cauterized distal to the rhinal artery.
- the contralateral carotid artery was occluded for 1 hour by using traction provided by a fine forceps and then re-opened.
- PBS or rhEPO (5,000 U/kg-bw, i.p.; previously shown to be protective in this model (1)) were administered immediately after the MCAO.
- TNF and IL-6 were quantified in brain cortex homogenates as previously described (8).
- MCP-1 was measured in the homogenates using a commercially available ELISA kit (biosource, Camarillo, Calif.).
- hematoxylin-eosin staining Free floating sections were processed for immunoreactivity both with anti-glial fibrillary acid protein (GFAP) mouse monoclonal antibody (1:250, Boehringher Mannheim, Monza, Italy) and with anti-cd11b (MRC OX-42) mouse monoclonal antibody (1:50, Serotec, UK), according to the protocols described by Houser et al. and the manufacturer's protocol respectively. All sections were mounted for light microscopy in saline on coated slides, dehydrated through graded alcohols, fixed in xylene and coverslipped using DPX mountant (BDH, Poole, UK). Adjacent sections were stained with hematoxylin-eosin as described (10).
- GFAP anti-glial fibrillary acid protein
- FIG. 23 shows a coronal section of the brain cortical layer stained by hematoxilyn and eosin.
- Control rat A
- ischemic rat treated with PBS B
- ischemic rat treated with rhEPO 5,000 U/kg-bw, i.p., immediately following MCAO
- C The section B shows a marked decrease in tissue staining consistent with inflammation, accompanied by a loss of neuronal component compared to the control (A).
- FIG. 24 shows coronal sections of frontal cortex adjacent to the region of infarction stained by GFAP antibody.
- Control rat A
- ischemic rat treated with PBS B
- ischemic rat treated with rhEPO C
- Activated astrocytes are visualized by their GFAP-positive processes (Panel B).
- Magnnification 10 ⁇ . Size bar 200 ⁇ m.
- FIG. 25 shows coronal sections of brain cortical layer stained by OX-42 antibody.
- FIG. 26 shows coronal sections of brain cortical layer adjacent to the region of infarction stained by OX-42 antibody.
- A much higher density of mononuclear inflammatory cells are observed in the tissue from an ischemic rat treated with PBS (A) compared to an ischemic rat treated with rhEPO (B).
- the infiltrating leukocytes, with typical round shape, potentially will extend the volume of infarction. (Magnification 10 ⁇ ; Size bar 200 ⁇ m)
- mice Female Lewis rats, 6-8 weeks of age, were purchased from Charles River (Calco, Italy). EAE was induced in rats by injecting 50 ⁇ g of guinea pig MBP (Sigma, St. Louis, Mo.) in water emulsified in equal volumes of complete Freund's adjuvant (CFA, Sigma) additioned with 7 mg/ml of heat-killed M. tuberculosis H37Ra (Difco, Detroit, Mich.) in a final volume of 100 ⁇ under light ether anesthesia into both hind footpads.
- CFA complete Freund's adjuvant
- Rats were examined in a blinded fashion for signs of EAE and scored as follows: 0, no disease; 1, flaccid tail; 2, ataxia; 3, complete hind limb paralysis with urinary incontinence.
- rats were given r-Hu-EPO (EPOetin alfa, Procrit, Ortho Biotech, Raritan, N.J.) intraperitoneally (i.p.) once a day at the indicated doses, in PBS. Since the clinical-grade EPO contained human serum albumin, control animals were always given PBS containing an identical amount of human serum albumin.
- Daily administration of 5,000 U/kg-bw of EPO increased the hematocrit by 30% (data not shown).
- FIG. 27 shows the protective effect on the clinical signs of EAE of different doses of EPO, given from day 3 after immunization with MBP until day 18.
- EPO in a dose-dependent fashion, delayed the onset of disease and decreased disease severity. But, EPO did not delay the time to greatest severity.
- glial cells were prepared from new born Sprague-Dawley rats 1-2 days old. Cerebral hemispheres were freed from the meninges and mechanically disrupted. Cells were dispersed in a solution of trypsin 2.5% and DNAase 1%, filtered through a 100 ⁇ m nylon mesh and plated (140,000 cells per 35 mm dish) in Eagle's minimum essential medium supplemented with 10% fecal calf serum, 0.6% glucose, streptomycin (0.1 mg/ml) and penicillin (100 Ul/ml). Glial cultures were fed twice a week and grown at 37° C. in a humidified incubator with 5% CO 2 .
- coverslips were transferred to dishes containing a glial monolayer in neuron maintenance medium (Dulbecco's modified Eagle's medium and Ham's nutrient mix F12 supplemented with 5 ⁇ g/ml insulin, 100 ⁇ g/ml transferrin, 100 ⁇ g/ml putrescin, 30 nM Na selenite, 20 nM progesterone and penicillin 100 U/ml) supplemented with cytosine arabinoside 5 ⁇ M.
- neuron maintenance medium Dulbecco's modified Eagle's medium and Ham's nutrient mix F12 supplemented with 5 ⁇ g/ml insulin, 100 ⁇ g/ml transferrin, 100 ⁇ g/ml putrescin, 30 nM Na selenite, 20 nM progesterone and penicillin 100 U/ml
- Paraffin dots adhering to the coverslips supported them above the glia, creating a narrow gap that prevented the two cell types from contacting each other but allowed the diffusion of soluble substances.
- These culture conditions allowed the growth of differentiated neuronal cultures with >98% homogeneity, as assessed by immunochemistry of microtubule-associated protein 2 and GFAP.
- Cells were then treated for 24 hours with 1 ⁇ M Trimethyl tin (TMT), in the presence or absence of rhEPO (10 U (80 ng)/ml), the supernatants used for TNF assay and cellular viability evaluated as described below.
- TTT Trimethyl tin
- rhEPO 10 U (80 ng)/ml
- MTT 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide
- FIG. 29 shows that rhEPO prevents neuronal death-induced TNF production in mixed neuron-glia cultures.
- Panel A Percentage of neural cell death induced by TMT 1 ⁇ M without or with treatment with rhEPO (10 U/ml).
- Panel B Release of TNF-_ from glial cells exposed to TMT 1 ⁇ M in the presence (hatched bars) or absence (filled bars) of neurons, with or without rhEPO (10 U/ml). Similar results would be expected from the therapeutic treatment with the tissue protective cytokines of the present invention.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- Gastroenterology & Hepatology (AREA)
- Cardiology (AREA)
- Immunology (AREA)
- Zoology (AREA)
- Ophthalmology & Optometry (AREA)
- Physical Education & Sports Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Hematology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Psychiatry (AREA)
- Obesity (AREA)
- Genetics & Genomics (AREA)
- Rheumatology (AREA)
- Psychology (AREA)
- Addiction (AREA)
- Urology & Nephrology (AREA)
- Molecular Biology (AREA)
- Pain & Pain Management (AREA)
Priority Applications (19)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/188,905 US20030072737A1 (en) | 2000-12-29 | 2002-07-03 | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs |
EA200500149A EA010371B1 (ru) | 2002-07-03 | 2003-07-03 | Тканевые протективные цитокины для защиты, восстановления и стимуляции реактивных клеток, тканей и органов |
JP2004520026A JP2006515268A (ja) | 2002-07-03 | 2003-07-03 | 応答性細胞、組織および器官の保護、回復および増強用の組織保護性サイトカイン |
US10/520,140 US8404226B2 (en) | 2002-07-03 | 2003-07-03 | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs |
CA002491406A CA2491406A1 (en) | 2002-07-03 | 2003-07-03 | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs |
KR1020057000099A KR20050049467A (ko) | 2002-07-03 | 2003-07-03 | 응답 세포, 조직 및 기관을 보호, 회복 및 향상시키기위한 조직 보호 사이토카인 |
BRPI0311939-4A BR0311939A (pt) | 2002-07-03 | 2003-07-03 | composição farmacêutica, método para tratar inflamação em um mamìfero e uso de uma citocina protetora de tecido orgánico |
AU2003247934A AU2003247934A1 (en) | 2002-07-03 | 2003-07-03 | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs |
ZA200500131A ZA200500131B (en) | 2002-07-03 | 2003-07-03 | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs |
EP03763353A EP1575528A4 (en) | 2002-07-03 | 2003-07-03 | TREATMENT PROTECTIVE CYTOKINS FOR THE PROTECTION, RECOVERY AND STRENGTHENING OF RESPECTIVE CELLS, TISSUE AND ORGANS |
CNA038204045A CN1852731A (zh) | 2002-07-03 | 2003-07-03 | 用于保护、恢复和增强效应细胞、组织和器官的组织保护性细胞因子 |
PCT/US2003/021350 WO2004004656A2 (en) | 2002-07-03 | 2003-07-03 | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs |
PL377146A PL377146A1 (pl) | 2002-07-03 | 2003-07-03 | Cytokiny ochronne dla tkanek do ochrony, odnowy i wzmacniania reaktywnych komórek, tkanek i narządów |
MXPA05000060A MXPA05000060A (es) | 2002-07-03 | 2003-07-03 | Citocinas protectoras de tejido para la proteccion, restauracion y mejora de celulas, tejidos y organos respondedores. |
ARP030102422A AR040396A1 (es) | 2002-07-03 | 2003-07-04 | Citoquinas protectoras de tejidos para la proteccion, restauracion y mejoramiento de celulas, tejidos y organos receptivos |
IS7619A IS7619A (is) | 2002-07-03 | 2004-12-29 | Vefjaverndandi frumuboðar til þess að vernda, endurheimta og bæta svarbúnar frumur, vefi og líffæri |
IL16606704A IL166067A0 (en) | 2002-07-03 | 2004-12-30 | Tissue protective cytokines for the protection restoration and enhancement of responsive cells tissues and organs |
NO20050550A NO20050550L (no) | 2002-07-03 | 2005-02-01 | Vevsbeskyttende cytokiner for beskyttelse, gjennoppbygging og oking av responsive celler, vev og organer |
US13/195,757 US20120142589A1 (en) | 2000-12-29 | 2011-08-01 | Tissue-protective cytokines for the protection, restoration and enhancement of responsive cells, tissues and organs |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US25924500P | 2000-12-29 | 2000-12-29 | |
US09/753,132 US6531121B2 (en) | 2000-12-29 | 2000-12-29 | Protection and enhancement of erythropoietin-responsive cells, tissues and organs |
PCT/US2001/049479 WO2002053580A2 (en) | 2000-12-29 | 2001-12-28 | Protection, restoration, and enhancement of erythropoietin-responsive cells, tissues and organs |
US10/188,905 US20030072737A1 (en) | 2000-12-29 | 2002-07-03 | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/753,132 Continuation-In-Part US6531121B2 (en) | 2000-12-29 | 2000-12-29 | Protection and enhancement of erythropoietin-responsive cells, tissues and organs |
PCT/US2001/049479 Continuation-In-Part WO2002053580A2 (en) | 2000-12-29 | 2001-12-28 | Protection, restoration, and enhancement of erythropoietin-responsive cells, tissues and organs |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/520,140 Continuation-In-Part US8404226B2 (en) | 2002-07-03 | 2003-07-03 | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs |
US13/195,757 Continuation US20120142589A1 (en) | 2000-12-29 | 2011-08-01 | Tissue-protective cytokines for the protection, restoration and enhancement of responsive cells, tissues and organs |
Publications (1)
Publication Number | Publication Date |
---|---|
US20030072737A1 true US20030072737A1 (en) | 2003-04-17 |
Family
ID=30114016
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/188,905 Abandoned US20030072737A1 (en) | 2000-12-29 | 2002-07-03 | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs |
US10/520,140 Expired - Fee Related US8404226B2 (en) | 2002-07-03 | 2003-07-03 | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs |
US13/195,757 Abandoned US20120142589A1 (en) | 2000-12-29 | 2011-08-01 | Tissue-protective cytokines for the protection, restoration and enhancement of responsive cells, tissues and organs |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/520,140 Expired - Fee Related US8404226B2 (en) | 2002-07-03 | 2003-07-03 | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs |
US13/195,757 Abandoned US20120142589A1 (en) | 2000-12-29 | 2011-08-01 | Tissue-protective cytokines for the protection, restoration and enhancement of responsive cells, tissues and organs |
Country Status (17)
Country | Link |
---|---|
US (3) | US20030072737A1 (zh) |
EP (1) | EP1575528A4 (zh) |
JP (1) | JP2006515268A (zh) |
KR (1) | KR20050049467A (zh) |
CN (1) | CN1852731A (zh) |
AR (1) | AR040396A1 (zh) |
AU (1) | AU2003247934A1 (zh) |
BR (1) | BR0311939A (zh) |
CA (1) | CA2491406A1 (zh) |
EA (1) | EA010371B1 (zh) |
IL (1) | IL166067A0 (zh) |
IS (1) | IS7619A (zh) |
MX (1) | MXPA05000060A (zh) |
NO (1) | NO20050550L (zh) |
PL (1) | PL377146A1 (zh) |
WO (1) | WO2004004656A2 (zh) |
ZA (1) | ZA200500131B (zh) |
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030104988A1 (en) * | 2000-12-29 | 2003-06-05 | Michael Brines | Protection, restoration, and enhancement of erythropoietin-responsive cells, tissues and organs |
US20040122216A1 (en) * | 2002-07-01 | 2004-06-24 | Jacob Nielsen | Recombinant tissue protective cytokines and encoding nucleic acids thereof for protection, restoration, and enhancement of responsive cells, tissues, and organs |
US20060034799A1 (en) * | 2002-07-03 | 2006-02-16 | Michael Brines | Tissue protective cytokines for the protection, restoration, and enhancement fo responsive cells, tissues and organs |
US20060135754A1 (en) * | 2004-07-07 | 2006-06-22 | H. Lundbeck A/S | Novel carbamylated EPO and method for its production |
US20060216757A1 (en) * | 2003-04-25 | 2006-09-28 | The Kenneth S. Warren Institute, Inc. | Tissue protective cytokine receptor complex, assays for identifying tissue protective compounds and uses thereof |
US20070072795A1 (en) * | 2005-09-28 | 2007-03-29 | Anton Haselbeck | Treatment of neurodegenerative disorders |
US20070129293A1 (en) * | 2003-09-29 | 2007-06-07 | The Kenneth S. Warren Institute, Inc. | Tissue protective cytokines for the treatment and prevention of sepsis and the formation of adhesions |
US20070254838A1 (en) * | 2002-09-09 | 2007-11-01 | Rene Gantier | Rational evolution of cytokines for higher stability, the cytokines and encoding nucleic acid molecules |
US20080014193A1 (en) * | 1999-04-13 | 2008-01-17 | Michael Brines | Modulation of excitable tissue function by peripherally administered erythropoietin |
US7514072B1 (en) | 1998-12-14 | 2009-04-07 | Hannelore Ehrenreich | Method for the treatment of cerebral ischaemia and use of erythropoietin or erythropoietin derivatives for the treatment of cerebral ischaemia |
US20090258821A1 (en) * | 2003-05-19 | 2009-10-15 | The Kenneth S. Warren Institute, In | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs with an extended therapeutic window |
US7718363B2 (en) | 2003-04-25 | 2010-05-18 | The Kenneth S. Warren Institute, Inc. | Tissue protective cytokine receptor complex and assays for identifying tissue protective compounds |
US20100310626A1 (en) * | 2008-01-24 | 2010-12-09 | Remedor Biomed Ltd. | Erythropoietin and fibronectin compositions for bone regeneration |
EP2371855A1 (en) | 2005-08-05 | 2011-10-05 | Araim Pharmaceuticals, Inc. | Tissue protective peptides and uses thereof |
WO2012069474A2 (en) | 2010-11-24 | 2012-05-31 | H. Lundbeck A/S | A method for reducing potential virus burden in a sample by cyanate treatment |
US8252743B2 (en) | 2006-11-28 | 2012-08-28 | Hanall Biopharma Co., Ltd. | Modified erythropoietin polypeptides and uses thereof for treatment |
US8524508B2 (en) | 2003-11-25 | 2013-09-03 | Mayo Foundation For Medical Education And Research | Methods of treating neuromyelitis optica (NMO) |
US20140178335A1 (en) * | 2011-07-27 | 2014-06-26 | Neumedicines, Inc. | Use of il-12 to generate endogenous erythropoietin |
EP2933264A2 (en) | 2008-01-22 | 2015-10-21 | Araim Pharmaceuticals, Inc. | Tissue protective peptides and peptide analogs for preventing and treating diseases and disorders associated with tissue damage |
US10792338B2 (en) | 2007-08-16 | 2020-10-06 | Remedor Biomed Ltd. | Erythropoietin and fibronectin compositions for therapeutic and cosmetic applications |
US10864253B2 (en) | 2016-04-29 | 2020-12-15 | Araim Pharmaceuticals, Inc. | Tissue protective peptides for preventing and treating diseases and disorders associated with tissue damage |
US11129906B1 (en) | 2016-12-07 | 2021-09-28 | David Gordon Bermudes | Chimeric protein toxins for expression by therapeutic bacteria |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT1781697E (pt) * | 2004-07-07 | 2009-06-25 | Lundbeck & Co As H | Nova epo carbamilada e método para a sua produção |
AT500929B1 (de) | 2004-11-09 | 2007-03-15 | Medizinische Uni Wien Muw | Pharmazeutische zubereitung die erythropoietin enthält |
CN102512665A (zh) * | 2005-06-01 | 2012-06-27 | 新潟Tlo株式会社 | 含有epo衍生物的血液相关疾病的治疗剂 |
WO2007096782A2 (en) * | 2006-02-22 | 2007-08-30 | Valorisation Recherche Hscm, Limited Partnership | Compositions for disorders associated wtth metachromatic cell activation |
GR1005808B (el) * | 2006-11-27 | 2008-02-06 | Bionature E.A. Limited | Επιταση της δρασεως της ερυθροποιητινης με αγωνιστες των μεμβρανικων στεροειδων υποδοχεων |
AR060424A1 (es) * | 2007-04-11 | 2008-06-18 | Consejo Nac Invest Cient Tec | Lineas celulares , composiciones para el tratamiento de melanomas que las comprenden procedimientos para preparar las composiciones y metodos de tratamiento |
CA3014633C (en) | 2007-10-08 | 2022-05-17 | Aurinia Pharmaceuticals Inc. | Ophthalmic compositions comprising calcineurin inhibitors or mtor inhibitors |
WO2009102021A1 (ja) * | 2008-02-14 | 2009-08-20 | Kyoto University | 骨髄由来幹細胞、前駆細胞機能賦活による網膜疾患治療 |
WO2009140382A2 (en) * | 2008-05-15 | 2009-11-19 | Edison Pharmaceuticals, Inc. | Treatment of hearing and balance impairments using compounds having erythropoietin activity |
UA106731C2 (uk) | 2008-09-26 | 2014-10-10 | Амбркс, Інк. | Модифіковані поліпептиди еритропоетину тварин та їх застосування |
AU2010259184B2 (en) * | 2009-06-09 | 2015-08-13 | Aurinia Pharmaceuticals Inc. | Topical drug delivery systems for ophthalmic use |
AU2011227613B2 (en) * | 2010-03-15 | 2015-09-03 | Virginia Commonwealth University | Aerosolized dapsone as a therapy for inflammation of the airway and abnormal mucociliary transport |
EP2590666B1 (en) * | 2010-07-06 | 2017-04-26 | Augustinus Bader | Topical application of erythropoietin for use in the treatment of injuries of the cornea |
WO2013128002A1 (en) * | 2012-03-01 | 2013-09-06 | Medical Device Works Nv | Organ perfusion device |
JP2012193207A (ja) * | 2012-07-13 | 2012-10-11 | New York Univ | インターフェロンを用いる肺疾患の処置方法 |
GB201214007D0 (en) * | 2012-08-07 | 2012-09-19 | Scancell Ltd | Anti-tumour immune responses to modified self-epitopes |
EP3747358A3 (en) | 2013-03-14 | 2021-03-10 | Universite Laval | Use of electroretinography (erg) for the assessment of psychiatric disorders |
CN104232571B (zh) * | 2014-01-29 | 2018-01-12 | 中国人民解放军第二军医大学 | 一种组织工程化搏动组织的构建方法 |
US20190224275A1 (en) | 2017-05-12 | 2019-07-25 | Aurinia Pharmaceuticals Inc. | Protocol for treatment of lupus nephritis |
WO2019149245A1 (zh) * | 2018-02-01 | 2019-08-08 | 江苏恒瑞医药股份有限公司 | 含人胰岛素类似物的酰化衍生物的药物组合物及其制备方法 |
CN113648418B (zh) * | 2021-05-08 | 2022-08-05 | 南方医科大学 | Apelin-APJ抑制剂在制备治疗血睾屏障损伤药物中的应用 |
Citations (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4377513A (en) * | 1980-08-25 | 1983-03-22 | Ken Hayashibara | Process for the production of human erythropoietin |
US4703008A (en) * | 1983-12-13 | 1987-10-27 | Kiren-Amgen, Inc. | DNA sequences encoding erythropoietin |
US4806524A (en) * | 1984-10-18 | 1989-02-21 | Chugai Seiyaku Kabushiki Kaisha | Stable erythropoietin preparation and process for formulating the same |
US4835260A (en) * | 1987-03-20 | 1989-05-30 | Genetics Institute, Inc. | Erythropoietin composition |
US5457089A (en) * | 1989-07-20 | 1995-10-10 | Behringwerke Aktiengesellschaft | Muteins of human erythropoietin, the preparation thereof and the use thereof |
US5547933A (en) * | 1983-12-13 | 1996-08-20 | Kirin-Amgen, Inc. | Production of erythropoietin |
US5571787A (en) * | 1993-07-30 | 1996-11-05 | Myelos Corporation | Prosaposin as a neurotrophic factor |
US5614184A (en) * | 1992-07-28 | 1997-03-25 | New England Deaconess Hospital | Recombinant human erythropoietin mutants and therapeutic methods employing them |
US5618698A (en) * | 1983-12-13 | 1997-04-08 | Kirin-Amgen, Inc. | Production of erythropoietin |
US5625035A (en) * | 1992-06-05 | 1997-04-29 | The Regents, University Of California | Erythropoietin binding protein from mammalian serum |
US5661125A (en) * | 1992-08-06 | 1997-08-26 | Amgen, Inc. | Stable and preserved erythropoietin compositions |
US5700909A (en) * | 1993-07-30 | 1997-12-23 | The Regents Of The University Of California | Prosaposin and cytokine-derived peptides |
US5767078A (en) * | 1995-06-07 | 1998-06-16 | Johnson; Dana L. | Agonist peptide dimers |
US5773569A (en) * | 1993-11-19 | 1998-06-30 | Affymax Technologies N.V. | Compounds and peptides that bind to the erythropoietin receptor |
US5830851A (en) * | 1993-11-19 | 1998-11-03 | Affymax Technologies N.V. | Methods of administering peptides that bind to the erythropoietin receptor |
US5835382A (en) * | 1996-04-26 | 1998-11-10 | The Scripps Research Institute | Small molecule mimetics of erythropoietin |
US5856298A (en) * | 1989-10-13 | 1999-01-05 | Amgen Inc. | Erythropoietin isoforms |
US5888772A (en) * | 1993-04-29 | 1999-03-30 | Abbott Laboratories | DNA encoding human a erythropoietin analog |
US6165783A (en) * | 1997-10-24 | 2000-12-26 | Neuro Spheres Holdings Ltd. | Erythropoietin-mediated neurogenesis |
US6730037B2 (en) * | 1990-12-17 | 2004-05-04 | Cardiovascular Imaging Systems, Inc. | Vascular catheter having low-profile distal end |
Family Cites Families (82)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4343782A (en) * | 1978-04-20 | 1982-08-10 | Shapiro Howard M | Cytological assay procedure |
US4658019A (en) * | 1979-04-26 | 1987-04-14 | Ortho Pharmaceutical Corporation | Complement-fixing monoclonal antibody to human T cells |
DE3729863A1 (de) * | 1987-09-05 | 1989-03-16 | Boehringer Mannheim Gmbh | Stabilisierte erythropoietin-lyophilisate |
WO1990008822A1 (en) * | 1989-02-03 | 1990-08-09 | Genetics Institute, Inc. | Erythropoietin receptor |
US5194596A (en) * | 1989-07-27 | 1993-03-16 | California Biotechnology Inc. | Production of vascular endothelial cell growth factor |
US5350836A (en) * | 1989-10-12 | 1994-09-27 | Ohio University | Growth hormone antagonists |
WO1991005867A1 (en) | 1989-10-13 | 1991-05-02 | Amgen Inc. | Erythropoietin isoforms |
US5292654A (en) * | 1990-12-13 | 1994-03-08 | Whitehead Institute For Biomedical Research | Mutant EPO receptor and uses therefor |
US5416071A (en) * | 1991-03-12 | 1995-05-16 | Takeda Chemical Industries, Ltd. | Water-soluble composition for sustained-release containing epo and hyaluronic acid |
US5750376A (en) * | 1991-07-08 | 1998-05-12 | Neurospheres Holdings Ltd. | In vitro growth and proliferation of genetically modified multipotent neural stem cells and their progeny |
US6153407A (en) | 1992-07-28 | 2000-11-28 | Beth Israel Deaconess Medical Center | Erythropoietin DNA having modified 5' and 3' sequences and its use to prepare EPO therapeutics |
DE4228839A1 (de) | 1992-08-29 | 1994-03-03 | Behringwerke Ag | Verfahren zum Nachweis und zur Bestimmung von Mediatoren |
US5354934A (en) * | 1993-02-04 | 1994-10-11 | Amgen Inc. | Pulmonary administration of erythropoietin |
US6071970A (en) * | 1993-02-08 | 2000-06-06 | Nps Pharmaceuticals, Inc. | Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases |
CA2169629C (en) * | 1993-08-16 | 2002-06-11 | Jong Y. Lee | Human erythropoietin receptor fragment and antibodies thereto |
ZA946122B (en) | 1993-08-17 | 1995-03-20 | Amgen Inc | Erythropoietin analogs |
US5859001A (en) * | 1996-01-11 | 1999-01-12 | University Of Florida Research Foundation, Inc. | Neuroprotective effects of polycyclic phenolic compounds |
US5635388A (en) | 1994-04-04 | 1997-06-03 | Genentech, Inc. | Agonist antibodies against the flk2/flt3 receptor and uses thereof |
US5604198A (en) * | 1994-05-12 | 1997-02-18 | Poduslo; Joseph F. | Method to enhance permeability of the blood/brain blood/nerve barriers to therapeutic agents |
US5763198A (en) * | 1994-07-22 | 1998-06-09 | Sugen, Inc. | Screening assays for compounds |
US6121246A (en) | 1995-10-20 | 2000-09-19 | St. Elizabeth's Medical Center Of Boston, Inc. | Method for treating ischemic tissue |
AUPN780096A0 (en) * | 1996-01-30 | 1996-02-22 | Medvet Science Pty. Ltd. | Cytokine antagonists and agonists |
US20020052309A1 (en) * | 1996-09-11 | 2002-05-02 | Athanasius A. Anagnostou | Method of treating endothelial injury |
DE69823046T2 (de) * | 1997-01-16 | 2005-03-31 | Neose Technologies, Inc. | Praktische in vitro sialylierung von rekombinanten glykpproteinen |
EP0885613A1 (de) * | 1997-06-21 | 1998-12-23 | Roche Diagnostics GmbH | Verwendung von modifizierten Hämoglobinen zur Behandlung von Anämien und Kombinationspräparate umfassend Erythropoietin und modifiziertes Hämoglobin |
US6242570B1 (en) * | 1997-07-10 | 2001-06-05 | Beth Israel Deaconess Medical Center | Production and use of recombinant protein multimers with increased biological activity |
US6548296B1 (en) * | 1997-07-23 | 2003-04-15 | Roche Diagnostics Gmbh | Methods for identifying human cell lines useful for endogenous gene activation, isolated human lines identified thereby, and uses thereof |
DE59813187D1 (de) * | 1997-12-03 | 2005-12-15 | Roche Diagnostics Gmbh | Verfahren zur herstellung von polypeptiden mit geeigneter glykosilierung |
US6274158B1 (en) * | 1998-02-04 | 2001-08-14 | Veronica L. Zaharia Czeizler | Treatment with recombinant human erythropoietin of bleeding in patients with normal and abnormal hemostasis |
PT937456E (pt) | 1998-02-23 | 2004-10-29 | Cilag Ag Int | Dispersao lipossomal de eritropoietina |
US6291661B1 (en) * | 1998-07-02 | 2001-09-18 | Immunex Corporation | flt3-L mutants and method of use |
US6103526A (en) * | 1998-10-08 | 2000-08-15 | Protein Sciences Corporation | Spodoptera frugiperda single cell suspension cell line in serum-free media, methods of producing and using |
DE19857609A1 (de) | 1998-12-14 | 2000-06-15 | Hannelore Ehrenreich | Verwendung von Erythropoietin zur Behandlung von cerebralen Ischämien des Menschen |
US6368453B1 (en) * | 1999-03-18 | 2002-04-09 | Andritz Inc. | Chip feeding to a comminuted cellulosic fibrous material treatment vessel |
US7410941B1 (en) * | 1999-04-13 | 2008-08-12 | The Kenneth S. Warren Institute, Inc. | Methods for treatment of neurodegenerative conditions by peripherally administered erythropoietin |
EA004766B1 (ru) * | 1999-04-13 | 2004-08-26 | Дзе Кеннет С. Уоррен Инститьют, Инк. | Модуляция функции возбуждаемых тканей за счет периферического введения эритропоэтина |
US7345019B1 (en) * | 1999-04-13 | 2008-03-18 | The Kenneth S. Warren Institute, Inc. | Modulation of excitable tissue function by peripherally administered erythropoietin |
US6855544B1 (en) * | 1999-04-15 | 2005-02-15 | Crucell Holland B.V. | Recombinant protein production in a human cell |
US20060099685A1 (en) * | 1999-04-15 | 2006-05-11 | Yallop Christopher A | Recombinant expression of factor VIII in human cells |
US8236561B2 (en) * | 1999-04-15 | 2012-08-07 | Crucell Holland B.V. | Efficient production of IgA in recombinant mammalian cells |
US20050170463A1 (en) * | 1999-04-15 | 2005-08-04 | Abraham Bout | Recombinant protein production in permanent amniocytic cells that comprise nucleic acid encoding adenovirus E1A and E1B proteins |
US20050164386A1 (en) * | 1999-04-15 | 2005-07-28 | Uytdehaag Alphonsus G. | Overexpression of enzymes involved in post-translational protein modifications in human cells |
US7297680B2 (en) | 1999-04-15 | 2007-11-20 | Crucell Holland B.V. | Compositions of erythropoietin isoforms comprising Lewis-X structures and high sialic acid content |
PL360581A1 (en) * | 1999-05-11 | 2004-09-06 | Ortho-Mcneil Pharmaceutical, Inc. | Pharmacokinetic and pharmacodynamic modeling of erythropoietin administration |
PE20010288A1 (es) * | 1999-07-02 | 2001-03-07 | Hoffmann La Roche | Derivados de eritropoyetina |
CZ299516B6 (cs) * | 1999-07-02 | 2008-08-20 | F. Hoffmann-La Roche Ag | Konjugát erythropoetinového glykoproteinu, zpusobjeho výroby a použití a farmaceutická kompozice sjeho obsahem |
US20030118547A1 (en) * | 2000-01-27 | 2003-06-26 | Vandenberg Grant William | Composition for intestinal delivery |
US6586398B1 (en) * | 2000-04-07 | 2003-07-01 | Amgen, Inc. | Chemically modified novel erythropoietin stimulating protein compositions and methods |
US20020061849A1 (en) * | 2000-05-02 | 2002-05-23 | Soren Nielsen | Methods for treatment of diseases associated with inflammation under non-ischemic conditions |
NZ522320A (en) * | 2000-05-12 | 2007-03-30 | Neose Technologies Inc | In vitro modification of glycosylation patterns of recombinant glycopeptides |
US7087224B2 (en) * | 2000-10-31 | 2006-08-08 | Amgen Inc. | Method of treating anemia by administering IL-1ra |
KR100401296B1 (ko) * | 2000-12-27 | 2003-10-11 | 드림바이오젠 주식회사 | 수식물질에 의해 수식된 단백질 변이체 및 이것의 제조방법 |
PA8536201A1 (es) * | 2000-12-29 | 2002-08-29 | Kenneth S Warren Inst Inc | Protección y mejoramiento de células, tejidos y órganos que responden a la eritropoyetina |
US7767643B2 (en) * | 2000-12-29 | 2010-08-03 | The Kenneth S. Warren Institute, Inc. | Protection, restoration, and enhancement of erythropoietin-responsive cells, tissues and organs |
US20030072737A1 (en) * | 2000-12-29 | 2003-04-17 | Michael Brines | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs |
US6531121B2 (en) * | 2000-12-29 | 2003-03-11 | The Kenneth S. Warren Institute, Inc. | Protection and enhancement of erythropoietin-responsive cells, tissues and organs |
US7300916B2 (en) | 2001-02-27 | 2007-11-27 | Yoshiko Yasuda | Preventives/remedies for thickened scar, keloid or chronic arthritic diseases |
FR2823220B1 (fr) | 2001-04-04 | 2003-12-12 | Genodyssee | Nouveaux polynucleotides et polypeptides de l'erythropoietine (epo) |
WO2002085940A2 (en) * | 2001-04-04 | 2002-10-31 | Genodyssee | New polynucleotides and polypeptides of the erythropoietin gene |
US6930086B2 (en) * | 2001-09-25 | 2005-08-16 | Hoffmann-La Roche Inc. | Diglycosylated erythropoietin |
CA2756610C (en) | 2001-10-29 | 2015-08-25 | Crucell Holland B.V. | Methods for producing proteins having n-linked glycans comprising (sialyl-) lewis x or lacdinac structures |
US6784154B2 (en) * | 2001-11-01 | 2004-08-31 | University Of Utah Research Foundation | Method of use of erythropoietin to treat ischemic acute renal failure |
KR100467750B1 (ko) * | 2001-11-29 | 2005-01-24 | 씨제이 주식회사 | 생체내 에리스로포이에틴 활성이 증진된 융합단백질 |
KR100467751B1 (ko) * | 2001-12-03 | 2005-01-24 | 씨제이 주식회사 | 생체내 에리스로포이에틴 활성이 증진된 융합단백질 |
CA2468957C (en) * | 2001-12-07 | 2011-07-12 | Crucell Holland B.V. | Methods of propagation of influenza virus in cell lines over expressing sialyl transferases |
US20040009902A1 (en) * | 2002-05-13 | 2004-01-15 | Irving Boime | CTP extended erythropoietin |
US20060135854A9 (en) * | 2002-05-16 | 2006-06-22 | Sleepex Systems, Inc. | Sleep study software architecture |
US7300915B2 (en) | 2002-06-05 | 2007-11-27 | The Regents Of The University Of California | Use of erythropoietin and erythropoietin mimetics for the treatment of neuropathic pain |
MXPA05000063A (es) * | 2002-07-01 | 2005-04-08 | Kenneth S Warren Inst Inc | Citocinas recombinantes protectoras de tejido y acidos nucleicos que las codifican para la proteccion, restauracion y mejora de celulas, tejidos y organos respondedores. |
US20050176627A1 (en) * | 2002-09-09 | 2005-08-11 | Anthony Cerami | Long acting erythropoietins that maintain tissue protective activity of endogenous erythropoietin |
US20040091961A1 (en) * | 2002-11-08 | 2004-05-13 | Evans Glen A. | Enhanced variants of erythropoietin and methods of use |
RU2341284C2 (ru) | 2003-03-27 | 2008-12-20 | Янссен Фармацевтика Нв | Применение эритропоэтина в восстановлении после инсульта |
US20060216757A1 (en) * | 2003-04-25 | 2006-09-28 | The Kenneth S. Warren Institute, Inc. | Tissue protective cytokine receptor complex, assays for identifying tissue protective compounds and uses thereof |
US7718363B2 (en) * | 2003-04-25 | 2010-05-18 | The Kenneth S. Warren Institute, Inc. | Tissue protective cytokine receptor complex and assays for identifying tissue protective compounds |
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 |
MXPA06003234A (es) * | 2003-09-29 | 2006-06-08 | Warren Pharmaceuticals Inc | Citosinas protectoras de los tejidos para el tratamiento y prevencion de la sepsis y la formacion de adhesiones. |
JP2008505184A (ja) | 2004-07-02 | 2008-02-21 | ザ ケネス エス.ウォーレン インスティテュート,インコーポレーテッド | 完全にカルバミル化されたエリトロポイエチンを生成する方法 |
US20060135754A1 (en) | 2004-07-07 | 2006-06-22 | H. Lundbeck A/S | Novel carbamylated EPO and method for its production |
CN102512665A (zh) | 2005-06-01 | 2012-06-27 | 新潟Tlo株式会社 | 含有epo衍生物的血液相关疾病的治疗剂 |
CN101378772B (zh) * | 2005-08-05 | 2013-12-04 | 阿拉伊姆药品公司 | 组织保护性肽及其用途 |
KR100753979B1 (ko) * | 2005-09-07 | 2007-08-31 | 삼성전자주식회사 | Dna 검출 장치 |
US7642078B2 (en) | 2005-12-28 | 2010-01-05 | Crucell Holland B.V. | Methods to obtain recombinant proteins with increased sialylation from cells that express adenovirus E1A protein, and proteins obtained thereby |
-
2002
- 2002-07-03 US US10/188,905 patent/US20030072737A1/en not_active Abandoned
-
2003
- 2003-07-03 EP EP03763353A patent/EP1575528A4/en not_active Withdrawn
- 2003-07-03 EA EA200500149A patent/EA010371B1/ru not_active IP Right Cessation
- 2003-07-03 US US10/520,140 patent/US8404226B2/en not_active Expired - Fee Related
- 2003-07-03 CA CA002491406A patent/CA2491406A1/en not_active Abandoned
- 2003-07-03 ZA ZA200500131A patent/ZA200500131B/en unknown
- 2003-07-03 WO PCT/US2003/021350 patent/WO2004004656A2/en active Search and Examination
- 2003-07-03 PL PL377146A patent/PL377146A1/pl not_active Application Discontinuation
- 2003-07-03 MX MXPA05000060A patent/MXPA05000060A/es unknown
- 2003-07-03 CN CNA038204045A patent/CN1852731A/zh active Pending
- 2003-07-03 KR KR1020057000099A patent/KR20050049467A/ko not_active Application Discontinuation
- 2003-07-03 AU AU2003247934A patent/AU2003247934A1/en not_active Abandoned
- 2003-07-03 BR BRPI0311939-4A patent/BR0311939A/pt not_active IP Right Cessation
- 2003-07-03 JP JP2004520026A patent/JP2006515268A/ja not_active Withdrawn
- 2003-07-04 AR ARP030102422A patent/AR040396A1/es unknown
-
2004
- 2004-12-29 IS IS7619A patent/IS7619A/is unknown
- 2004-12-30 IL IL16606704A patent/IL166067A0/xx unknown
-
2005
- 2005-02-01 NO NO20050550A patent/NO20050550L/no not_active Application Discontinuation
-
2011
- 2011-08-01 US US13/195,757 patent/US20120142589A1/en not_active Abandoned
Patent Citations (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4377513A (en) * | 1980-08-25 | 1983-03-22 | Ken Hayashibara | Process for the production of human erythropoietin |
US5618698A (en) * | 1983-12-13 | 1997-04-08 | Kirin-Amgen, Inc. | Production of erythropoietin |
US5621080A (en) * | 1983-12-13 | 1997-04-15 | Kirin-Amgen, Inc. | Production of erythropoietin |
US5756349A (en) * | 1983-12-13 | 1998-05-26 | Amgen Inc. | Production of erythropoietin |
US5955422A (en) * | 1983-12-13 | 1999-09-21 | Kirin-Amgen, Inc. | Production of erthropoietin |
US5547933A (en) * | 1983-12-13 | 1996-08-20 | Kirin-Amgen, Inc. | Production of erythropoietin |
US4703008A (en) * | 1983-12-13 | 1987-10-27 | Kiren-Amgen, Inc. | DNA sequences encoding erythropoietin |
US4806524A (en) * | 1984-10-18 | 1989-02-21 | Chugai Seiyaku Kabushiki Kaisha | Stable erythropoietin preparation and process for formulating the same |
US4835260A (en) * | 1987-03-20 | 1989-05-30 | Genetics Institute, Inc. | Erythropoietin composition |
US5457089A (en) * | 1989-07-20 | 1995-10-10 | Behringwerke Aktiengesellschaft | Muteins of human erythropoietin, the preparation thereof and the use thereof |
US5856298A (en) * | 1989-10-13 | 1999-01-05 | Amgen Inc. | Erythropoietin isoforms |
US6730037B2 (en) * | 1990-12-17 | 2004-05-04 | Cardiovascular Imaging Systems, Inc. | Vascular catheter having low-profile distal end |
US5625035A (en) * | 1992-06-05 | 1997-04-29 | The Regents, University Of California | Erythropoietin binding protein from mammalian serum |
US5614184A (en) * | 1992-07-28 | 1997-03-25 | New England Deaconess Hospital | Recombinant human erythropoietin mutants and therapeutic methods employing them |
US5661125A (en) * | 1992-08-06 | 1997-08-26 | Amgen, Inc. | Stable and preserved erythropoietin compositions |
US5888772A (en) * | 1993-04-29 | 1999-03-30 | Abbott Laboratories | DNA encoding human a erythropoietin analog |
US5696080A (en) * | 1993-07-30 | 1997-12-09 | Myelos Neurosciences Corporation | Pharmaceutical compositions comprising neurotrophic peptides derived from prosaposin |
US5714459A (en) * | 1993-07-30 | 1998-02-03 | Myelos Neurosciences Corp. | Use of prosaposin and neurotrophic peptides derived therefrom |
US5700909A (en) * | 1993-07-30 | 1997-12-23 | The Regents Of The University Of California | Prosaposin and cytokine-derived peptides |
US5571787A (en) * | 1993-07-30 | 1996-11-05 | Myelos Corporation | Prosaposin as a neurotrophic factor |
US5773569A (en) * | 1993-11-19 | 1998-06-30 | Affymax Technologies N.V. | Compounds and peptides that bind to the erythropoietin receptor |
US5830851A (en) * | 1993-11-19 | 1998-11-03 | Affymax Technologies N.V. | Methods of administering peptides that bind to the erythropoietin receptor |
US5767078A (en) * | 1995-06-07 | 1998-06-16 | Johnson; Dana L. | Agonist peptide dimers |
US5835382A (en) * | 1996-04-26 | 1998-11-10 | The Scripps Research Institute | Small molecule mimetics of erythropoietin |
US6165783A (en) * | 1997-10-24 | 2000-12-26 | Neuro Spheres Holdings Ltd. | Erythropoietin-mediated neurogenesis |
Cited By (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7514072B1 (en) | 1998-12-14 | 2009-04-07 | Hannelore Ehrenreich | Method for the treatment of cerebral ischaemia and use of erythropoietin or erythropoietin derivatives for the treatment of cerebral ischaemia |
US20080014193A1 (en) * | 1999-04-13 | 2008-01-17 | Michael Brines | Modulation of excitable tissue function by peripherally administered erythropoietin |
US20030104988A1 (en) * | 2000-12-29 | 2003-06-05 | Michael Brines | Protection, restoration, and enhancement of erythropoietin-responsive cells, tissues and organs |
US7767643B2 (en) | 2000-12-29 | 2010-08-03 | The Kenneth S. Warren Institute, Inc. | Protection, restoration, and enhancement of erythropoietin-responsive cells, tissues and organs |
US20040122216A1 (en) * | 2002-07-01 | 2004-06-24 | Jacob Nielsen | Recombinant tissue protective cytokines and encoding nucleic acids thereof for protection, restoration, and enhancement of responsive cells, tissues, and organs |
US8404226B2 (en) | 2002-07-03 | 2013-03-26 | The Kenneth S. Warren Institute, Inc. | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs |
US20060034799A1 (en) * | 2002-07-03 | 2006-02-16 | Michael Brines | Tissue protective cytokines for the protection, restoration, and enhancement fo responsive cells, tissues and organs |
US20070254838A1 (en) * | 2002-09-09 | 2007-11-01 | Rene Gantier | Rational evolution of cytokines for higher stability, the cytokines and encoding nucleic acid molecules |
US20090131318A1 (en) * | 2002-09-09 | 2009-05-21 | Rene Gantier | Rational evolution of cytokines for higher stability, the cytokines and encoding nucleic acid molecules |
US8114839B2 (en) | 2002-09-09 | 2012-02-14 | Hanall Biopharma Co., Ltd. | Protease resistant modified erythropoietin polypeptides |
US7718363B2 (en) | 2003-04-25 | 2010-05-18 | The Kenneth S. Warren Institute, Inc. | Tissue protective cytokine receptor complex and assays for identifying tissue protective compounds |
US20060216757A1 (en) * | 2003-04-25 | 2006-09-28 | The Kenneth S. Warren Institute, Inc. | Tissue protective cytokine receptor complex, assays for identifying tissue protective compounds and uses thereof |
US20090258821A1 (en) * | 2003-05-19 | 2009-10-15 | The Kenneth S. Warren Institute, In | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs with an extended therapeutic window |
US20070129293A1 (en) * | 2003-09-29 | 2007-06-07 | The Kenneth S. Warren Institute, Inc. | Tissue protective cytokines for the treatment and prevention of sepsis and the formation of adhesions |
US7645733B2 (en) | 2003-09-29 | 2010-01-12 | The Kenneth S. Warren Institute, Inc. | Tissue protective cytokines for the treatment and prevention of sepsis and the formation of adhesions |
US8524508B2 (en) | 2003-11-25 | 2013-09-03 | Mayo Foundation For Medical Education And Research | Methods of treating neuromyelitis optica (NMO) |
US20060135754A1 (en) * | 2004-07-07 | 2006-06-22 | H. Lundbeck A/S | Novel carbamylated EPO and method for its production |
EP2540309A2 (en) | 2005-08-05 | 2013-01-02 | Araim Pharmaceuticals, Inc. | Tissue protective peptides and uses thereof |
EP2371855A1 (en) | 2005-08-05 | 2011-10-05 | Araim Pharmaceuticals, Inc. | Tissue protective peptides and uses thereof |
EP2594279A1 (en) | 2005-08-05 | 2013-05-22 | Araim Pharmaceuticals, Inc. | Tissue protective peptides and uses thereof |
US20070072795A1 (en) * | 2005-09-28 | 2007-03-29 | Anton Haselbeck | Treatment of neurodegenerative disorders |
US8252743B2 (en) | 2006-11-28 | 2012-08-28 | Hanall Biopharma Co., Ltd. | Modified erythropoietin polypeptides and uses thereof for treatment |
US10792338B2 (en) | 2007-08-16 | 2020-10-06 | Remedor Biomed Ltd. | Erythropoietin and fibronectin compositions for therapeutic and cosmetic applications |
EP2933264A2 (en) | 2008-01-22 | 2015-10-21 | Araim Pharmaceuticals, Inc. | Tissue protective peptides and peptide analogs for preventing and treating diseases and disorders associated with tissue damage |
US20100310626A1 (en) * | 2008-01-24 | 2010-12-09 | Remedor Biomed Ltd. | Erythropoietin and fibronectin compositions for bone regeneration |
WO2012069474A2 (en) | 2010-11-24 | 2012-05-31 | H. Lundbeck A/S | A method for reducing potential virus burden in a sample by cyanate treatment |
US20140178335A1 (en) * | 2011-07-27 | 2014-06-26 | Neumedicines, Inc. | Use of il-12 to generate endogenous erythropoietin |
US10864253B2 (en) | 2016-04-29 | 2020-12-15 | Araim Pharmaceuticals, Inc. | Tissue protective peptides for preventing and treating diseases and disorders associated with tissue damage |
US11129906B1 (en) | 2016-12-07 | 2021-09-28 | David Gordon Bermudes | Chimeric protein toxins for expression by therapeutic bacteria |
Also Published As
Publication number | Publication date |
---|---|
ZA200500131B (en) | 2008-02-27 |
WO2004004656A2 (en) | 2004-01-15 |
EP1575528A4 (en) | 2009-06-24 |
IL166067A0 (en) | 2006-01-15 |
IS7619A (is) | 2004-12-29 |
AR040396A1 (es) | 2005-03-30 |
BR0311939A (pt) | 2007-05-08 |
WO2004004656A3 (en) | 2006-06-01 |
CN1852731A (zh) | 2006-10-25 |
KR20050049467A (ko) | 2005-05-25 |
PL377146A1 (pl) | 2006-01-23 |
EA010371B1 (ru) | 2008-08-29 |
MXPA05000060A (es) | 2005-04-08 |
US20060034799A1 (en) | 2006-02-16 |
US8404226B2 (en) | 2013-03-26 |
US20120142589A1 (en) | 2012-06-07 |
EP1575528A2 (en) | 2005-09-21 |
AU2003247934A1 (en) | 2004-01-23 |
JP2006515268A (ja) | 2006-05-25 |
CA2491406A1 (en) | 2004-01-15 |
NO20050550L (no) | 2005-03-22 |
EA200500149A1 (ru) | 2006-08-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20030072737A1 (en) | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs | |
AU2003251770B2 (en) | Recombinant tissue protective cytokines and encoding nucleic acids thereof for protection, restoration, and enhancement of responsive cells, tissues, and organs | |
EP1406922B1 (en) | Protection, restoration, and enhancement of erythropoietin-responsive cells, tissues and organs | |
US7767643B2 (en) | Protection, restoration, and enhancement of erythropoietin-responsive cells, tissues and organs | |
AU2002239665A1 (en) | Protection, restoration, and enhancement of erythropoietin-responsive cells, tissues and organs | |
WO2005084364A2 (en) | Long acting tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs | |
ZA200410387B (en) | Recombinant tissue protective cytokines and encoding nucleic acids thereof for protection, restoration and enhancement of responsive cells, tissues and organs | |
AU2007200697A1 (en) | Protection, restoration, and enhancement of erythropoietin-responsive cells, tissues and organs |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: KENNETH S. WARREN INSTITUTE, INC., THE, NEW YORK Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BRINES, MICHAEL;CERAMI, ANTHONY;CERAMI, CARLA;REEL/FRAME:014362/0014 Effective date: 20030626 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |