WO1995013823A1 - Method of treating neurological disorders - Google Patents
Method of treating neurological disorders Download PDFInfo
- Publication number
- WO1995013823A1 WO1995013823A1 PCT/US1994/013177 US9413177W WO9513823A1 WO 1995013823 A1 WO1995013823 A1 WO 1995013823A1 US 9413177 W US9413177 W US 9413177W WO 9513823 A1 WO9513823 A1 WO 9513823A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- igf
- igfbp
- complex
- insulin
- growth factor
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 41
- 208000012902 Nervous system disease Diseases 0.000 title abstract description 7
- 208000025966 Neurological disease Diseases 0.000 title abstract description 6
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims abstract description 170
- 102000013275 Somatomedins Human genes 0.000 claims abstract description 95
- 102000004374 Insulin-like growth factor binding protein 3 Human genes 0.000 claims abstract description 86
- 108090000965 Insulin-like growth factor binding protein 3 Proteins 0.000 claims abstract description 85
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 claims description 35
- 102000048143 Insulin-Like Growth Factor II Human genes 0.000 claims description 34
- 102000028416 insulin-like growth factor binding Human genes 0.000 claims description 34
- 108091022911 insulin-like growth factor binding Proteins 0.000 claims description 34
- 230000001537 neural effect Effects 0.000 claims description 17
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 claims description 10
- 210000000653 nervous system Anatomy 0.000 claims description 10
- 208000024827 Alzheimer disease Diseases 0.000 claims description 7
- 208000032843 Hemorrhage Diseases 0.000 claims description 6
- 201000009906 Meningitis Diseases 0.000 claims description 6
- 230000037396 body weight Effects 0.000 claims description 6
- 230000006872 improvement Effects 0.000 claims description 6
- 201000006417 multiple sclerosis Diseases 0.000 claims description 6
- 208000023105 Huntington disease Diseases 0.000 claims description 5
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 238000010254 subcutaneous injection Methods 0.000 claims description 5
- 239000007929 subcutaneous injection Substances 0.000 claims description 5
- 208000010693 Charcot-Marie-Tooth Disease Diseases 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 4
- 238000010504 bond cleavage reaction Methods 0.000 claims description 4
- 238000007917 intracranial administration Methods 0.000 claims description 4
- 239000002581 neurotoxin Substances 0.000 claims description 4
- 231100000618 neurotoxin Toxicity 0.000 claims description 4
- 230000007017 scission Effects 0.000 claims description 4
- 238000001356 surgical procedure Methods 0.000 claims description 4
- 101001044927 Homo sapiens Insulin-like growth factor-binding protein 3 Proteins 0.000 claims description 3
- 102000044162 human IGF1 Human genes 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 102000057148 human IGFBP3 Human genes 0.000 claims 2
- 101001076292 Homo sapiens Insulin-like growth factor II Proteins 0.000 claims 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 claims 1
- 102000057877 human IGF2 Human genes 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 9
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 74
- 241000700159 Rattus Species 0.000 description 34
- 210000004556 brain Anatomy 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 29
- 210000001519 tissue Anatomy 0.000 description 27
- 238000011282 treatment Methods 0.000 description 21
- 210000002569 neuron Anatomy 0.000 description 20
- 108020003175 receptors Proteins 0.000 description 15
- 102000005962 receptors Human genes 0.000 description 15
- 108020004999 messenger RNA Proteins 0.000 description 13
- 241000282414 Homo sapiens Species 0.000 description 12
- 210000005036 nerve Anatomy 0.000 description 12
- 230000012010 growth Effects 0.000 description 11
- 210000003169 central nervous system Anatomy 0.000 description 10
- 230000006870 function Effects 0.000 description 10
- 210000002241 neurite Anatomy 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 230000001976 improved effect Effects 0.000 description 9
- 102000004372 Insulin-like growth factor binding protein 2 Human genes 0.000 description 8
- 108090000964 Insulin-like growth factor binding protein 2 Proteins 0.000 description 8
- 101001055320 Myxine glutinosa Insulin-like growth factor Proteins 0.000 description 8
- 230000001605 fetal effect Effects 0.000 description 8
- 210000004498 neuroglial cell Anatomy 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 210000000278 spinal cord Anatomy 0.000 description 8
- 241000282412 Homo Species 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000002297 mitogenic effect Effects 0.000 description 7
- 210000003205 muscle Anatomy 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 6
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 230000037444 atrophy Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000002218 hypoglycaemic effect Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 230000008929 regeneration Effects 0.000 description 6
- 238000011069 regeneration method Methods 0.000 description 6
- 230000028327 secretion Effects 0.000 description 6
- 206010003694 Atrophy Diseases 0.000 description 5
- 208000016192 Demyelinating disease Diseases 0.000 description 5
- 206010012305 Demyelination Diseases 0.000 description 5
- 206010018338 Glioma Diseases 0.000 description 5
- 208000013016 Hypoglycemia Diseases 0.000 description 5
- 210000002987 choroid plexus Anatomy 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 230000002518 glial effect Effects 0.000 description 5
- 239000003102 growth factor Substances 0.000 description 5
- 210000002161 motor neuron Anatomy 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 102000006386 Myelin Proteins Human genes 0.000 description 4
- 108010083674 Myelin Proteins Proteins 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 210000003710 cerebral cortex Anatomy 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 230000001771 impaired effect Effects 0.000 description 4
- 210000005012 myelin Anatomy 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 230000037152 sensory function Effects 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 208000000044 Amnesia Diseases 0.000 description 3
- 102000014914 Carrier Proteins Human genes 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 108010051696 Growth Hormone Proteins 0.000 description 3
- 208000010428 Muscle Weakness Diseases 0.000 description 3
- 206010028372 Muscular weakness Diseases 0.000 description 3
- -1 N-methyl-D-aspartate subclass of glutamate Chemical class 0.000 description 3
- 206010029260 Neuroblastoma Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 102000005157 Somatostatin Human genes 0.000 description 3
- 108010056088 Somatostatin Proteins 0.000 description 3
- 102100038803 Somatotropin Human genes 0.000 description 3
- 108091008324 binding proteins Proteins 0.000 description 3
- 230000032823 cell division Effects 0.000 description 3
- 210000001638 cerebellum Anatomy 0.000 description 3
- 210000004720 cerebrum Anatomy 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 3
- 239000000122 growth hormone Substances 0.000 description 3
- 210000001320 hippocampus Anatomy 0.000 description 3
- 230000002608 insulinlike Effects 0.000 description 3
- 230000033001 locomotion Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000014511 neuron projection development Effects 0.000 description 3
- 210000004248 oligodendroglia Anatomy 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 230000000750 progressive effect Effects 0.000 description 3
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 3
- 229960000553 somatostatin Drugs 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 108090000144 Human Proteins Proteins 0.000 description 2
- 102000003839 Human Proteins Human genes 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000004375 Insulin-like growth factor-binding protein 1 Human genes 0.000 description 2
- 108090000957 Insulin-like growth factor-binding protein 1 Proteins 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
- 208000026139 Memory disease Diseases 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 208000008457 Neurologic Manifestations Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 206010036105 Polyneuropathy Diseases 0.000 description 2
- 108010071390 Serum Albumin Proteins 0.000 description 2
- 102000007562 Serum Albumin Human genes 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 210000001130 astrocyte Anatomy 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 210000000133 brain stem Anatomy 0.000 description 2
- 210000001159 caudate nucleus Anatomy 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 208000015114 central nervous system disease Diseases 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 238000002405 diagnostic procedure Methods 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 231100000317 environmental toxin Toxicity 0.000 description 2
- 229940126864 fibroblast growth factor Drugs 0.000 description 2
- 239000012737 fresh medium Substances 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 230000002363 herbicidal effect Effects 0.000 description 2
- 239000004009 herbicide Substances 0.000 description 2
- 230000000971 hippocampal effect Effects 0.000 description 2
- 210000003016 hypothalamus Anatomy 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000006984 memory degeneration Effects 0.000 description 2
- 208000023060 memory loss Diseases 0.000 description 2
- 210000001259 mesencephalon Anatomy 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- 230000023105 myelination Effects 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 210000000956 olfactory bulb Anatomy 0.000 description 2
- 210000000535 oligodendrocyte precursor cell Anatomy 0.000 description 2
- 230000009984 peri-natal effect Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 210000000578 peripheral nerve Anatomy 0.000 description 2
- 210000001428 peripheral nervous system Anatomy 0.000 description 2
- 208000027232 peripheral nervous system disease Diseases 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000001817 pituitary effect Effects 0.000 description 2
- 230000007824 polyneuropathy Effects 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000011514 reflex Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 238000011830 transgenic mouse model Methods 0.000 description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 1
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 description 1
- MTPJEFOSTIKRSS-UHFFFAOYSA-N 3-(dimethylamino)propanenitrile Chemical compound CN(C)CCC#N MTPJEFOSTIKRSS-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000000412 Avitaminosis Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- 206010008748 Chorea Diseases 0.000 description 1
- 102000012289 Corticotropin-Releasing Hormone Human genes 0.000 description 1
- 108010022152 Corticotropin-Releasing Hormone Proteins 0.000 description 1
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 208000003870 Drug Overdose Diseases 0.000 description 1
- 206010013883 Dwarfism Diseases 0.000 description 1
- 108010065372 Dynorphins Proteins 0.000 description 1
- 206010014612 Encephalitis viral Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000001308 Fasciculation Diseases 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- 206010016803 Fluid overload Diseases 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 108091052347 Glucose transporter family Proteins 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 206010056438 Growth hormone deficiency Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 102000004371 Insulin-like growth factor binding protein 5 Human genes 0.000 description 1
- 108090000961 Insulin-like growth factor binding protein 5 Proteins 0.000 description 1
- 102000004369 Insulin-like growth factor-binding protein 4 Human genes 0.000 description 1
- 108090000969 Insulin-like growth factor-binding protein 4 Proteins 0.000 description 1
- 102000004883 Insulin-like growth factor-binding protein 6 Human genes 0.000 description 1
- 108090001014 Insulin-like growth factor-binding protein 6 Proteins 0.000 description 1
- 208000032984 Intraoperative Complications Diseases 0.000 description 1
- 101710151321 Melanostatin Proteins 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 102000008934 Muscle Proteins Human genes 0.000 description 1
- 108010074084 Muscle Proteins Proteins 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- 206010060860 Neurological symptom Diseases 0.000 description 1
- 102400000064 Neuropeptide Y Human genes 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010034701 Peroneal nerve palsy Diseases 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 108010051508 Preconativ Proteins 0.000 description 1
- 102100024622 Proenkephalin-B Human genes 0.000 description 1
- 101000746366 Rattus norvegicus Granulocyte-macrophage colony-stimulating factor Proteins 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 241000219100 Rhamnaceae Species 0.000 description 1
- 241000239226 Scorpiones Species 0.000 description 1
- 241000270295 Serpentes Species 0.000 description 1
- 102400000096 Substance P Human genes 0.000 description 1
- 101800003906 Substance P Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 108010055044 Tetanus Toxin Proteins 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 206010047627 Vitamin deficiencies Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 101001034661 Xenopus laevis Insulin-like growth factor I-A Proteins 0.000 description 1
- YOWZJZJLXUQHGF-UHFFFAOYSA-M [7-(dimethylamino)phenothiazin-3-ylidene]-dimethylazanium;dimethyl-[7-(methylamino)phenothiazin-3-ylidene]azanium;dichloride Chemical compound [Cl-].[Cl-].C1=CC(=[N+](C)C)C=C2SC3=CC(NC)=CC=C3N=C21.C1=CC(=[N+](C)C)C=C2SC3=CC(N(C)C)=CC=C3N=C21 YOWZJZJLXUQHGF-UHFFFAOYSA-M 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000002552 acute disseminated encephalomyelitis Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 210000004727 amygdala Anatomy 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 231100000659 animal toxin Toxicity 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 230000004641 brain development Effects 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- FFSAXUULYPJSKH-UHFFFAOYSA-N butyrophenone Chemical compound CCCC(=O)C1=CC=CC=C1 FFSAXUULYPJSKH-UHFFFAOYSA-N 0.000 description 1
- 230000004094 calcium homeostasis Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 1
- 230000000768 catecholaminergic effect Effects 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 208000004209 confusion Diseases 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 210000001653 corpus striatum Anatomy 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000003210 demyelinating effect Effects 0.000 description 1
- 210000001947 dentate gyrus Anatomy 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 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 1
- 206010013023 diphtheria Diseases 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 206010013395 disorientation Diseases 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 231100000725 drug overdose Toxicity 0.000 description 1
- 238000000537 electroencephalography Methods 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 230000004578 fetal growth Effects 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000011990 functional testing Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003823 glutamate receptor agonist Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 239000011440 grout Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 208000034783 hypoesthesia Diseases 0.000 description 1
- 238000003365 immunocytochemistry Methods 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 208000018879 impaired coordination Diseases 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000030214 innervation Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 231100000863 loss of memory Toxicity 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 238000013160 medical therapy Methods 0.000 description 1
- 210000002418 meninge Anatomy 0.000 description 1
- 208000011645 metastatic carcinoma Diseases 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 230000004220 muscle function Effects 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000008035 nerve activity Effects 0.000 description 1
- 210000003061 neural cell Anatomy 0.000 description 1
- 210000003757 neuroblast Anatomy 0.000 description 1
- 210000000461 neuroepithelial cell Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 210000000715 neuromuscular junction Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000002536 noncholinergic effect Effects 0.000 description 1
- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 1
- 210000001009 nucleus accumben Anatomy 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 210000002951 peptidergic neuron Anatomy 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 150000004633 phorbol derivatives Chemical class 0.000 description 1
- 239000002644 phorbol ester Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 210000004129 prosencephalon Anatomy 0.000 description 1
- 210000002637 putamen Anatomy 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 239000003128 rodenticide Substances 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000003497 sciatic nerve Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 210000003594 spinal ganglia Anatomy 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000008939 stimulatory process Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 238000009120 supportive therapy Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 210000004377 supraoptic nucleus Anatomy 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 208000006379 syphilis Diseases 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940118376 tetanus toxin Drugs 0.000 description 1
- 210000004001 thalamic nuclei Anatomy 0.000 description 1
- 229910052716 thallium Inorganic materials 0.000 description 1
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 201000002498 viral encephalitis Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—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
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- 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
- A61K38/22—Hormones
- A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
-
- 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
- A61P25/28—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
- A61P37/00—Drugs for immunological or allergic disorders
Definitions
- This process relates generally to the field of medical therapy and particularly to the treatment of neurological disorders by administering a therapeutic composition containing a complex of an insulin-like growth factor (IGF) and an insulin-like growth factor binding protein (IGFBP) .
- IGF insulin-like growth factor
- IGFBP insulin-like growth factor binding protein
- Growth factors are polypeptides which stimulate a wide variety of biological responses (eg. DNA synthesis, cell division, expression of specific genes, etc.) in a defined population of target cells.
- a variety of growth factors have been identified including transforming growth factor-. ⁇ (TGF- / 8-) , TGF-j ⁇ 2 , TGF-jS 3 , epidermal growth factor (EGF) , platelet-derived growth factor (PDGF) , fibroblast growth factor (FGF) , insulin- like growth factor-I (IGF-I) , and IGF-II.
- IGF-I and IGF-II are related in amino acid sequence and structure, with each polypeptide having a molecular weight of approximately 7500 daltons. IGF-I mediates the major effects of growth hormone, and thus is the primary mediator of growth after birth. IGF-I has also been implicated in the actions of various other growth factors, since treatment of cells with such growth factors leads to increased production of IGF-I. In contrast, IGF-II is believed to have a major role in fetal growth. Both IGF-I and IGF-II have insulin-like activities (hence the name) , and are mitogenic (stimulating cell division) for the cells in neural tissue, muscle, reproductive tissue, skeletal tissue and a wide variety of other tissues.
- IGFs are present in substantial quantity in the circulation, but only a very small fraction of this IGF is free in the circulation or in other body fluids. Most circulating IGF is bound to an IGF-binding protein called IGFBP-3. IGF-I may be measured in blood serum to diagnose abnormal growth-related conditions, e.g., pituitary gigantis , acro videy, dwarfism, various growth hormone deficiencies, etc. Although IGF-I is produced in many tissues, most circulating IGF-I is believed to be synthesized in the liver.
- IGF IGF-I or -II
- IGFBP-3 IGF specific binding protein termed IGFBP-3
- ALS acid labile subunit
- This ternary complex is composed of equimolar amounts of each of the three components.
- the ALS has no direct IGF binding activity and appears to bind only a preformed IGF-I/IGFBP-3 complex.
- the ternary complex of IGF + IGFBP-3 + ALS has a molecular weight of approximately 150,000 daltons.
- IGFBP-3 is the most abundant IGF binding protein in the circulation, but at least five other distinct IGF binding proteins (IGFBPs) have been identified in various tissues and body fluids.
- IGF binding proteins bind IGFs, they each originate from separate genes and have distinct a ino acid sequences. Thus, the binding proteins are not merely analogs of a common precursor. Unlike IGFBP-3, the other IGFBPs in the circulation are not saturated with IGFs. None of the IGF binding proteins other than IGFBP-3 can form the 150 Kd circulating ternary complex.
- IGF-I and IGFBP-3 may be purified from natural sources or produced by recombinant means.
- IGF-I has been purified from human serum for a number of years. See, Rinderknecht, E.W. , et al., Proc Natl Acad Sci (USA) 21, 2365-2369 (1976) . Recombinant IGF-I processes are shown in EPA 0,128,733, published in December of 1984.
- IGFBP-3 may be purified from natural sources using a process such as that shown in Baxter et al., "Growth Hormone-Dependent Insulin-Like Growth
- IGFBP-3 may be synthesized by recombinant organisms as discussed in Sommer, A. S., et. al. , In Modern Concepts of Insulin- Like Growth Factors (E. M. Spencer, ed. , Elsevier, New York) 715-728 (1991) . This recombinant IGFBP-3 binds IGF-I in a 1:1 molar ratio. The topical administration of the IGF-I/IGFBP-3 complex to rat and pig wounds was significantly more effective than IGF-I alone. Sommer et.
- Patent Cooperation Treaty Publication No. WO 92/19256 published on November 12, 1992 and applied for by Kabi Pharmacia AB, discloses a method for inducing nerve regeneration by treating subjects suffering from neuropathy or degenerative neural disorders with IGF-II or IGF-II + IGF-I. The use of any IGF binding protein in these treatments is not disclosed.
- European Patent Application EP 0 308 386 Al published on March 22, 1989 and applied for by KabiVitrum AB, discloses a method for improving the regeneration of transected peripheral nerves by treating subjects with an effective amount of IGF-I.
- the use of any IGF binding protein in these treatments is not disclosed.
- All of the important elements of the IGF system are found in the central and peripheral nervous systems of humans and other mammals, including IGF-I and -II and the IGF binding proteins and receptors. IGF-I and IGF-II have been implicated in the growth, survival and differentiated function of several classes of neurons and glial cells.
- IGF-I and IGF-II mRNAs have characteristic regional distributions in fetal and adult rat and human brain. IGF-I mRNA is present at high levels in the olfactory bulb and cervical thoracic spinal cord and at moderate levels in the midbrain and cerebellum of adult rats. IGF-I mRNA is also synthesized by primary cultures of embryonic astroglial and neuronal cells. IGF-II mRNA is both more abundant in brain than IGF-I mRNA and is much more uniformly distributed.
- IGF-II mRNA is somewhat elevated in the choroid plexus, cerebellum and medulla- pons, and somewhat reduced in midbrain and corpus striatum.
- IGF-II mRNA is synthesized by cultured embryonic astroglial but not neuronal cells. Both mRNAs are highest at embryonic day 8-14 in rat brain, and decline from this peak to the adult level by the time of birth.
- IGF-I and IGF-II have also been detected in cerebrospinal fluid (CSF) and by immunohistochemistry in human, rat and cat brain. IGF-II immunoreactivity in the brain is higher than that of IGF-I.
- CSF cerebrospinal fluid
- IGF-II immunoreactivity in the brain is higher than that of IGF-I.
- Adult and fetal human brain contain both the normal form of IGF-I and a truncated form of IGF-I missing three N-terminal amino acids.
- IGF-I peptide is also secreted by cultured rat glioma cells. IGF-II immunoreactivity is highest in the anterior pituitary, dorsomedial hypothalamus and supraoptic nucleus of the brain.
- IGF-II Intraleukin-II peptides
- IGF-II Intraleukin-II peptides
- IGF-I genes in neural tissue is under complex hormonal control.
- basic fibroblast growth factor bFGF
- dexamethasone and retinoic acid which inhibit the growth of rat glioma cells, reduce the accumulation of IGF-I mRNA and inhibit the secretion of IGF-I peptide by these cells.
- Type I IGF receptors which transduce mitogenic and differentiation signals provided by the IGFs, are also present in the brain.
- concentration and distribution of this receptor varies during development.
- brain Type I receptor levels are quite high (4-10 times higher than in the adult) , and the receptor is especially abundant in the superficial cortical layers, nucleus accumbens and hippocampus.
- Type I receptor levels are reduced and the receptor is more evenly distributed. There is some receptor enrichment in adult superficial and deep cortical layers, olfactory bulb, endopiriform nucleus, basomedial nucleus of the amygdala, thalamic nuclei and hippocampus.
- Brain Type I IGF receptor is present in two forms, a normal sized form and a somewhat smaller form than that found in peripheral tissues. Hence this size difference is largely due to reduced glycosylation of the smaller of the brain species.
- bFGF increases the synthesis of Type I IGF- receptors in cultured neuronal and glial cells.
- Type II IGF receptor Substantial quantities of the Type II IGF receptor are also found in the brain, but the function of this receptor is obscure. In fetal and early postnatal rats, the Type II IGF receptor is abundant throughout the brain, whereas it is restricted to neurons in the forebrain (eg. hippocampus and dentate gyrus) in adult rats.
- forebrain eg. hippocampus and dentate gyrus
- the third element of the IGF system is also synthesized by cells of the nervous system and are found in CSF and neural tissue.
- IGFBP-2 mRNA is abundant in fetal rat brain stem, cerebral cortex, hypothalamus and choroid plexus and persists in adult brain. It is important to note that IGF-II mRNA is also abundant in the choroid plexus, and that this region of the brain is important in generating CSF.
- IGFBP-2 is the most abundant IGF binding protein, with substantially higher IGFBP-2 levels in neonatal CSF than in adult CSF. Lower levels of IGFBP-3 are also present, as well as traces of lower molecular weight IGFBP species. Using immunocytochemistry with human fetal tissues, IGFBP-3 was localized to neuronal cell bodies in the upper region of the cerebral cortex, while IGFBP-1 and -2 were not detected in the cerebral cortex. IGFBP-3 was not detectable in the meninges.
- IGFBP KDa IGFBP.
- the glial cultures secreted approximately 5 times as much IGFBP-2 as did the embryonic neuronal cultures, and IGFBP-2 was the only IGFBP secreted by choroid plexus cultures. In contrast, gliomas and astrocytes synthesized predominantly IGFBP-3.
- the regulation of IGFBP synthesis has not been extensively studied, but it is known that bFGF treatment greatly increases IGFBP secretion by neuronal cultures and inhibits IGFBP secretion in glial cultures. IGF-I stimulated IGFBP secretion in both cultures and in the rat neuroblastoma cell line B104.
- IGF-I and IGF-II are mitogenic (ie. stimulate cell division) for oligodendrocyte precursor cells from cultured perinatal rat cerebrum explants, embryonic rat sympathetic neuroblasts, human neuroblastoma cells, newborn rat astroglial cells, and neonatal rat cerebral cortex astrocytes.
- IGF-I has been shown to promote the survival of various types of cultured nervous system cells.
- IGF-I acts as a survival factor in cultured embryonic mouse neuroepithelial cells.
- bFGF which is mitogenic for these cells, induces endogenous production of IGF-I, which is required for the expression of the mitogenic effect of bFGF.
- autocrine production of IGF-I has been implicated as the mediator of at least part of the mitogenic effect of epidermal growth factor (EGF) on cultured newborn rat astroglial cells.
- EGF-I epidermal growth factor
- IGF-I has also been shown to protect rat hippocampal and septal neuronal cell cultures from hypoglycemia-induced damage by stabilizing neuronal calcium homeostasis.
- IGF-I In cultures of undifferentiated neural cells, IGF-I promotes the differentiation of oligodendrocyte precursor cells in explant cultures of perinatal rat cerebrum, catecholaminergic precursor cells in cultured chick dorsal root ganglia, and cultured SH-SY5Y human neuroblastoma cells in synergy with the phorbol esters. IGF-I also induces the synthesis of the rat brain glucose transporter gene in primary rat neuronal and glial cell cultures. Finally, IGF-I, but not IGF-II, significantly increases the potassium-evoked release of acetylcholine (a major neurotransmitter) from adult rat hippocampal tissue slices.
- acetylcholine a major neurotransmitter
- IGF-II nerve growth factor
- IGF-II substantially stimulate rapid neurite outgrowth in embryonic chick spinal cord motor neurons in culture.
- IGF-II administered daily to mouse gluteus muscle caused rapid, marked terminal and nodal neuronal sprouting of neurites. This effect was detectable after as little as 3 days of treatment and produced 10 fold more neurite sprouts in IGF-II treated than control muscle after one week of treatment.
- IGF-II treatment also caused a nearly 5-fold increase in the number of endplates that had formed neurite sprouts.
- transgenic mice expressing a human IGF-IA transgene developed substantially larger brains than their control littermates.
- the brains of the transgenic mice expressing hIGF-I also contained substantially more myelin than did the brains of their control littermates.
- IGF insulin-like growth factor
- IGFBP-3) in an amount sufficient to alleviate said condition.
- the IGF used in the complex is provided as IGF-I.
- IGF and IGF are provided as IGF-I.
- IGFBP are present in equimolar amounts.
- both IGF and IGFBP-3 are human proteins obtained from recombinant sources.
- the complex of IGF and IGFBP-3 is administered parenterally. In a further embodiment, the complex is administered by subcutaneous injection.
- the subject to whom the complex is administered is a mammal.
- the method provides for treating a subject for exposure to neurotoxins, cerebrovascular hemorrhage, neuronal scission during surgery, meningitis or other infection of tissues of the nervous system.
- the method includes administration of the IGF/IGFBP-3 complex in an amount sufficient to alleviate the condition.
- the method provides a treatment for multiple sclerosis, amyotrophic lateral sclerosis or Charcot-Marie-Tooth disease, in which the subject is parenterally administered a complex of IGF/IGFBP-3 in an amount sufficient to alleviate said condition.
- the IGF/IGFBP complex can be administered using normal parenteral routes for the treatment of peripheral nervous system disorders or for the treatment of central nervous system disorders in which the blood brain barrier is compromised (eg. multiple sclerosis) , thus allowing the passage of complex into the brain.
- the IGF/IGFBP complex can be administered directly to the CNS by intracranial administration, such as by an implanted shunt into the ventricles of the brain.
- the Inventors propose that the administered complex of IGF and IGFBP-3 results in the gradual release of free IGF in elevated levels. This graded, long lasting increase in bioavailable IGF stimulates the growth, survival and maturation of neuronal tissue cells without causing the local or systemic side effects commonly observed in treatments with free IGF (eg. hypoglycemia, receptor down regulation, growth hormone suppression) .
- Subjects are defined as humans and mammalian farm animals, sport animals and pets. Farm animals include, but are not limited to, cows, hogs and sheep. Sport animals include, but are not limited to, dogs and horses. The category pets includes, but is not limited to, cats and dogs.
- IGF insulin-like growth factor
- IGF-I comprises a family of factors, including, but not limited to, IGF-I and IGF-II.
- IGF is a polypeptide having a molecular weight of about 7500 daltons. IGF may be obtained from natural sources or prepared by recombinant means.
- IGFBPs Insulin-like growth factor binding proteins
- IGFBPs comprises a family of binding proteins, including but not limited to IGFBP-1, IGFBP-2, IGFBP-3,
- IGFBP-4, IGFBP-5 and IGFBP-6 IGFBP may be obtained from natural sources or prepared by recombinant means. At least one form of IGFBP (for example, IGFBP-3) complexes with IGF and with a third molecule known as ALS.
- a "therapeutic composition” as used herein is defined as comprising IGF complexed with its binding protein IGFBP-3. The therapeutic composition also contains other substances such as water, minerals and carriers such as proteins. "Alleviation of the condition" is said to occur when the subject to whom the IGF/IGFBP-3 complex is administered exhibits improved function of affected nervous tissue.
- improvements include, but are not limited to, improved coordination of movement, improved muscle function and strength, decreased pain, reduced numbness of extremities, and increased sensory function (eg. touch) .
- improvements include, but are not limited to, improved ability to reason, improved memory, improved speech, improved coordination or movement, reduced pain and improved sensory function (eg. sight, hearing) .
- the method of the present invention contemplates treating neurological disorders by administering a complex of IGF and IGFBP-3.
- IGFBP-3 IGF/IGFBP-3 normally circulates in the form of a complex in humans and other mammals. This complex associates with a third protein (ALS) , which is present in excess over the concentration of IGF and IGFBP-3. Therefore, ALS is found both associated with the IGF/IGFBP-3 complex and in the free form.
- the resultant ternary complex has a size of about 150 kd.
- Conditions which are treated by the method of the present invention include Huntington's disease, Alzheimer's disease, exposure to neurotoxins, cerebrovascular hemorrhage, neuronal scission during surgery, meningitis, other infection of the tissues of the nervous system, multiple sclerosis, amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease.
- Huntington's disease is defined as an autosomal dominant disorder usually beginning in middle age and characterized by choreif ⁇ rm movements and progressive intellectual deterioration. There are estimated to be about 25,000 cases in the United States. It is diagnosed on CT scans by characteristic "boxcar ventricles" which result from atrophy of the caudate nucleus.
- GABA neurotransmitters
- substance P an 11-amino acid peptide
- somatostatin and neuropeptide y may be relatively increased in the caudate nucleus and putamen.
- glutamate receptor agonists that act on the N-methyl-D-aspartate subclass of glutamate receptors.
- IGF/IGFBP-3 Intracellular neurotrophic factor/IGFBP-3 helps this condition through its trophic effects on nerve growth and maintenance.
- Alzheimer's disease is a form of progressive atrophy of the brain. It is the commonest cause of dementia in the elderly and has a frequency of almost 20% in those over 80 years old. The primary feature is death and disappearance of cells from the brain, resulting in extensive convolutional atrophy. Acetylcholine- transmitting neurons are particularly affected. Loss of peptidergic neurons in the cerebrum is associated with reduced somatostatin and corticotropin releasing factor concentrations.
- Somatostatin is also abnormally low in the CSF.
- An early symptom is memory loss, followed by slow disintegration of judgment and affect.
- the clinician must rule out organic causes, such as drug overdoses, vitamin deficiencies, alcohol, ischemic conditions, etc.
- IGF/IGFBP-3 complex administration such as with an improved sense of well-being, affect and/or memory.
- Another condition in which the IGF/IGFBP complex promotes healing is exposure to neurotoxins.
- Polyneuropathy can result from exposure to the following environmental toxins: acrylamide (herbicide, grout), arsenic (herbicide, insecticide) , buckthorn, carbon disulfide, diphtheria, dimethylamino propionitrile, y- diketone hexacarbon solvents, inorganic lead, organophosphates and thallium (rat poison) .
- Many drugs have neurologic adverse reactions. See, for example, Tables 363-1-3, which list polyneuropathies associated with systemic disease, drugs or environmental toxins, and genetically determined conditions, respectively (Harrison's Principles of Internal Medicine. 12th ed. McGraw-Hill, New York City, 1991, pp. 2099-2103).
- animal toxins such as the tetanus- toxin and the toxins of various snakes and scorpions, damage the nervous system and interfere with respiration, heart rate, etc.
- the specific or underlying disorder must be treated, and vital functions may need to be supported.
- the administration of the IGF/IGFBP-3 complex speeds healing and encourages the sprouting of new neurites.
- Cerebrovascular hemorrhage is characterized by rupture of a cerebral blood vessel and bleeding into the intracranial space, which compresses and may damage cerebral nerve and glial cells. Similarly, during surgery, nerves may be inadvertently or necessarily compressed or severed (scission) . In both situations, the administration of IGF/IGFBP-3 will help nervous tissue recover.
- Acute viral encephalitis is an acute inflammation of the brain due to virus or hypersensitivity caused by a virus or other foreign protein. If the spinal cord structures also are affected, the condition is called encephalomyelitis. It is frequently called “aseptic” because no organisms are found. Cerebral edema is present, along with numerous small hemorrhages which are scattered throughout the brain, brainstem, cerebellum and sometimes the spinal cord. Viral invasion may cause nerve necrosis and/or inclusion bodies. Demyelinating lesions sometimes are seen around veins. Therapy of the underlying infection is the primary concern.
- General therapy includes antiviral and/or antibacterial therapy, fluid therapy without overhydration, and if indicated steroid therapy to counteract the swelling associated with meningitis.
- IGF/IGFBP-3 administration helps restore nerve and glial cells.
- IGF/IGFBP can be administered intracranially with other therapies. Meningitis also is associated with a number of non-bacterial/viral conditions, such as fungal infections (especially with AIDS or immunosuppressive therapy) , TB, dissemination of malignant cells as in leukemia, metastatic carcinoma (especially of lung and breast) , gliomas, syphilis and sarcoidosis.
- Current therapy includes treatment of the underlying disorder, as well as steroids (such as prednisone) to reduce inflammation.
- administration of IGF/IGFBP-3 enhances recovery of injured nervous and glial tissue.
- Multiple sclerosis has been characterized as "a slowly progressive CNS disease characterized by disseminated patches of demyelination in the brain and spinal cord, resulting in multiple and varied neurologic symptoms and signs, usually with remissions and exacerbations.”
- THE MERCK MANUAL 15th ed., Merck & Co., Rahway, N.J., 1987, pp. 1414-17.
- the administration of IGF/IGFBP-3 will encourage the replacement of neurites and glial cells.
- amyotrophic lateral sclerosis primarily affects motor neurons, producing muscular weakness and atrophy. Cramps are an early sign. Later fasciculations, spasticity and hyperactive reflexes are observed. IGF/IGFBP-3 administration will encourage the formation of new neurites.
- Charcot-Marie-Tooth disease is an autosomally dominant disorder of the peripheral nervous system in which weakness and atrophy, particularly of the peroneal and distal leg muscles, gradually develops over years. Biopsy may show segmental demyelination and remyelination. At present there is no specific treatment, aside from bracing weak muscles such as to limit foot drop. The administration of IGF/IGFBP-3 is supportive therapy, intended to enhance remyelination.
- IGF and IGFBP-3 Systemic administration of IGF and IGFBP-3, either from natural or recombinant sources, as a preformed complex results in the formation of the normal ternary complex with the excess ALS.
- This type of treatment produces a prolonged increase in the level of circulating IGF, which is gradually released from the ternary complex.
- This mode of administration avoids the detrimental side effects associated with administration of free IGF-I, namely, hypoglycemia, suppression of growth hormone and ALS production, and release of endogenous IGF-II since administered exogenous free IGF-I replaces endogenous IGF-II in normally circulating IGF-11/IGFBP-3 complexes.
- the formulation, method of administration and dosage will depend upon the disorder to be treated and the medical history of the patient. These factors are readily determined in the course of therapy. Suitable patients with neurological disorders can be identified by medical history, physical findings and laboratory tests. The medical history may reveal such facts as loss of coordination, muscle weakness, tremors, dizziness, headache, loss of memory, impaired speech, cognitive difficulties and the specific findings associated with the individual conditions discussed above. Patients may have physical findings such as muscle weakness, impaired reflexes, impaired coordination, disorientation, memory loss, impaired language function, impaired sensory function as well as specific findings associated with the individual conditions discussed above.
- the formulation comprises a complex of IGF and IGFBP-3.
- the IGF is IGF-I, although IGF-II also is useful.
- IGF and IGFBP-3 naturally complex in a 1:1 molar ratio, a composition of equimolar amounts of IGF and IGFBP-3 is preferred.
- the product can be formulated with IGF:IGFBP-3 molar ratios ranging from about 0.5 to 1.5. More preferably, the molar ratio is about 0.9 to 1.3; and most preferably, the product is formulated with approximately a 1:1 molar ratio.
- the IGF and IGFBP-3 are human proteins obtained from natural or recombinant sources. Most preferably, IGF and IGFBP-3 are human IGF-I and IGFBP-3 made by recombinant means and designated rhIGF-I and rhIGFBP-3, respectively. rhIGFBP-3 may be in glycosylated or non-glycosylated form. E. coli is a source of the non-glycosylated IGFBP-3. Glycosylated IGFB -3 may be obtained from Chinese hamster ovary (CHO) cells.
- CHO Chinese hamster ovary
- the method of the present invention provides for formulating the complex in modes which are readily apparent to those skilled in the art.
- the IGF and IGFBP-3 are complexed prior to administration to the treated subject.
- the complex is formed by mixing approximately equimolar amounts of IGF-I and IGFBP-3 dissolved in physiologically compatible carriers such as normal saline solution or phosphate buffered saline solution.
- physiologically compatible carriers such as normal saline solution or phosphate buffered saline solution.
- a concentrated solution of rhIGF-I and a concentrated solution of rhIGFBP-3 are mixed together for a sufficient time to form an equimolar complex.
- compositions of the complex may be in the form of solid, semi-solid or liquid dosage preparations, such as for example, tablets, pills, powders, capsules, liquids, suspensions or the like.
- Physiologically compatible carriers include intravenous solutions, such as normal saline, serum albumin, 5% dextrose, plasma preparations, and other protein-containing solutions.
- the preferred carrier for parenteral administration of the complex is a sterile, isotonic aqueous solution, such as normal saline or 5% dextrose.
- a solution of the complex may be placed, into an implant, such as an osmotic pump, for the slow release of the complex over an extended period of time.
- the complex may be provided in sustained release carrier formulations such as semi-permeable polymer carriers in the form of suppositories or microcapsules.
- sustained release carrier formulations such as semi-permeable polymer carriers in the form of suppositories or microcapsules. See, for instance, U.S. Patent No. 3,773,919 for Microcapsular Sustained Release Matrices Including Polylactides; Sidman et al., Biopolymers 22 (1) : 547-556 (1983) for copolymers of L- glutamic acid and 7-ethyl-L-glutamate; Langer et al. , J Biomed Res 15: 267-277 (1981) for poly(2-hydroxyethylmethacrylate) or the like.
- the mode of administration delivers the complex to the subject in a safe, physiologically effective manner.
- the complex may be given by intranasal, subcutaneous, intravenous, intramuscular, intraperitoneal, intracranial or other conventional routes of administration.
- the complex is injected subcutaneously, intravenously or intramuscularly.
- the complex is administered by subcutaneous injection. By subcutaneous injection, the complex appears not to be toxic or mitogenic at the injection site.
- the dose of complex to be administered can be readily determined by those skilled in the art, based on the usual patient symptoms discussed above.
- the dosage of complex is about 0.01 to 10 mg of IGF-I or IGF- Il/kg of body weight/day, complexed to an equimolar amount of IGFBP-3.
- the daily dosage of the complex for humans is about 0.05 to 7.5 mg IGF/kg/day, complexed to an equimolar amount of IGFBP-3.
- the daily dosage of the complex for humans is about 0.1 to 5 mg IGF/kg/day, complexed to an equimolar amount of IGFBP-3.
- each dose of complex is preferably about 0.05 to 10 mg IGF/kg of body weight, complexed to an equimolar amount of IGFBP-3. More preferably, for twice weekly administration, the dose of the complex is about 0.1 to 7.5 mg IGF/kg, complexed to an equimolar amount of IGFBP-3. Most preferably, for twice weekly administration, the dose of the complex is about 0.5 to 5 mg IGF/kg, complexed to an equimolar amount of IGFBP-3.
- the patient is started with a relatively low dose of the complex, such as 0.05 mg IGF/kg of body weight/day.
- a relatively low dose of the complex such as 0.05 mg IGF/kg of body weight/day.
- Physical examinations, functional tests and diagnostic procedures such as those outlined above should be performed on the treated patients to determine if there is improvement.
- the patient shows improvements in the structure and/or function of the peripheral or central nervous tissue affected by the neurological disorder following such treatment. If the patient improves with the low dose, the low dose preferably should be continued until acceptable clinical endpoints have been achieved. If the patient does not respond to low dose IGF/IGFBP-3 complex with sufficient clinical improvement, the dose of complex should be increased gradually until such an outcome is achieved.
- the invention has been disclosed by direct description. Following are examples showing the efficacy of the IGF/IGFBP-3 complex in stimulating processes critical to the growth, survival and functioning of neurological tissue. The examples are only examples and should not be taken in any way as limiting to the scope of the process.
- Example 1 This example is designed to demonstrate the ability of the rhIGF-I/IGFBP-3 complex to stimulate the sprouting of neurites (nerve processes) in cultured embryonic chick spinal cord motor neurons.
- the sprouting of neurites leads to the re-establishment of innervation and consequently full function of partially denervated neuromuscular junctions and disrupted central nervous system neural connections.
- cultures of motor neuron cells are prepared from embryonic chick spinal cord tissue. Dissociated lumbar and brachial spinal cord cells are purified by differential Ficoll gradient centrifugation, and the motor neuron fraction is isolated. Primary cultures of these cells are plated in laminin coated tissue culture dish wells in enriched L15 medium containing 20% horse serum and 20 ⁇ g/ml embryonic chick hind limb muscle protein extract. The majority of the cells in this culture are neurons with large multipolar cell bodies, and non-neuronal cells represent only a few percent of the total. Cells are plated in either the above medium alone, or in medium containing 1 to 100 ng/ml rhIGF-I complexed to an equimolar amount of rhIGFBP-3. The extent of neurite outgrowth in each set of cultures is assessed by light microscopy daily for up to 7 days. The effect of each treatment is determined by measuring the total- length of the neurite tree for each neuron at each time point.
- Example 2 This example is designed to demonstrate the ability of the IGF-I/IGFBP-3 complex to stimulate regeneration of severed neurons. Traumatic or surgical injury to peripheral nerves is troublesome since the regeneration of damaged nerves is often slow and functionally incomplete. There is a clinical need for agents that can promote more rapid and completely functional regeneration of such damaged nerves.
- groups of rats have the osmotic pump filled with various concentrations rhlGF- 1/IGFBP-3 complex (0.1-1 mg/ml of rhIGF-I complexed to an equimolar amount of rhIGFBP-3) in physiological saline plus 1% rat serum albumin (RSA) .
- the pump is filled with physiological saline plus 1% RSA only.
- the pumps are left in place to pump at a rate of approximately 0.5 ⁇ l/hr for approximately 3-4 weeks to allow nerve regeneration. At the end of the 3-4 week treatment period, the animals are sacrificed and the silicone blocks recovered.
- the pumps are removed from the block and any tissue in the block is fixed by immersing the opened block in standard glutaraldehyde fixative. The fixed tissue is then stained with osmium tetroxide and dehydrated. Each channel in the block is cut into short lengths numbered starting from the severed nerve stump. Thin sections are cut from each short length of channel and are stained with methylene blue and azur II. Light microscopy is used to evaluate the presence of myelinated axons from the regenerated nerve in each short length of each channel.
- Example 3 This example is designed to demonstrate the ability of the rhIGF-I/IGFBP-3 complex to stimulate the growth and myelination of nervous tissue in the central nervous system.
- a variety of illnesses result in the demyelination of central nervous system neurons (eg. multiple sclerosis, acute disseminated encephalomyelitis) .
- This demyelination results in defective nerve transmission and loss of sensory and motor function.
- An agent that would stimulate myelin production in such cases would be a useful therapeutic.
- myelin production is assessed in fetal rat brain aggregate cultures. Whole fetal rat brain cells are dissociated into single cells, filtered, and then placed into aggregate culture medium (Almazan et. al . , Dev.
- oligodendrocytes are also quantitated by measuring the activity of the oligodendrocyte marker 2' -3' -cyclic nucleotide 3'- phosphohydrolase (CNP) in cell homogenates.
- CNP oligodendrocyte marker 2' -3' -cyclic nucleotide 3'- phosphohydrolase
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Marine Sciences & Fisheries (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Plant Substances (AREA)
- Steroid Compounds (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95901254A EP0729361A4 (en) | 1993-11-15 | 1994-11-15 | Method of treating neurological disorders |
AU10570/95A AU693489B2 (en) | 1993-11-15 | 1994-11-15 | Method of treating neurological disorders |
JP7514567A JPH09509140A (en) | 1993-11-15 | 1994-11-15 | How to treat neurological disorders |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15286893A | 1993-11-15 | 1993-11-15 | |
US08/152,868 | 1993-11-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995013823A1 true WO1995013823A1 (en) | 1995-05-26 |
Family
ID=22544799
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1994/013177 WO1995013823A1 (en) | 1993-11-15 | 1994-11-15 | Method of treating neurological disorders |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0729361A4 (en) |
JP (1) | JPH09509140A (en) |
AU (1) | AU693489B2 (en) |
CA (1) | CA2176708A1 (en) |
WO (1) | WO1995013823A1 (en) |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997021449A1 (en) * | 1995-12-13 | 1997-06-19 | Aurogen Incorporated | Method for effecting changes in the central nervous system by administration of igf-i or igf-ii |
WO1998036764A2 (en) * | 1997-02-25 | 1998-08-27 | Celtrix Pharmaceuticals, Inc. | Method of treating psychological and metabolic disorders using igf or igf/igfbp-3 |
WO1998039967A1 (en) * | 1997-03-12 | 1998-09-17 | The General Hospital Corporation | A method for treating or preventing alzheimer's disease |
WO1999062536A2 (en) * | 1998-06-01 | 1999-12-09 | Celtrix Pharmaceuticals, Inc. | Pharmaceutical formulations for igf/igfbp |
US6025368A (en) * | 1997-02-25 | 2000-02-15 | Celtrix Pharmaceuticals, Inc. | Method for treating the symptoms of chronic stress-related disorders using IGF |
US6040292A (en) * | 1999-06-04 | 2000-03-21 | Celtrix Pharmaceuticals, Inc. | Methods for treating diabetes |
US6417330B1 (en) | 1998-06-01 | 2002-07-09 | Celtrix Pharmaceuticals, Inc. | Insulin-like growth factor binding protein variants |
US6440928B1 (en) | 1988-12-06 | 2002-08-27 | Colorado State University Research Foundation | Method for treating diabetic neuropathy with NGF |
US6514937B1 (en) | 1997-02-25 | 2003-02-04 | Celtrix Pharmaceuticals, Inc. | Method of treating psychological and metabolic disorders using IGF or IGF/IGFBP-3 |
US6861406B2 (en) | 2001-09-18 | 2005-03-01 | Bioexpertise, Llc | IGF-binding protein-derived peptide |
US6887851B2 (en) | 2001-09-18 | 2005-05-03 | Bioexpertise, Llc | IGF-binding protein-derived peptide |
US6914049B2 (en) | 2001-09-18 | 2005-07-05 | Bioexpertise, Llc | IGF-binding protein-derived peptide or small molecule |
EP1560933A2 (en) * | 2002-11-14 | 2005-08-10 | Wyeth | Methods and compositions for treating neurological disorders |
US7041314B2 (en) | 2001-05-24 | 2006-05-09 | Neuren Pharmaceuticals Ltd. | GPE analogs and peptidominetics |
US7288516B1 (en) | 1999-09-20 | 2007-10-30 | Celtrix Pharmaceuticals, Inc. | Null IGF for the treatment of cancer |
WO2007123723A2 (en) | 2006-03-31 | 2007-11-01 | Rhode Island Hospital | Diagnosis and treatment of alzheimer's disease |
US7371813B2 (en) | 2000-09-19 | 2008-05-13 | Bioexpertise Llc | Method for use of IGF-binding protein for selective sensitization of target cells in vivo |
US7605177B2 (en) | 2001-05-24 | 2009-10-20 | Neuren Pharmaceuticals Limited | Effects of glycyl-2 methyl prolyl glutamate on neurodegeneration |
US7714020B2 (en) | 2001-05-24 | 2010-05-11 | Neuren Pharmaceuticals Limited | Treatment of non-convulsive seizures in brain injury using G-2-methyl-prolyl glutamate |
RU2669692C1 (en) * | 2017-08-14 | 2018-10-15 | Павел Андреевич Канаев | Method for producing complex of biologically active peptides with neurotropic activity |
WO2023242442A1 (en) * | 2022-06-17 | 2023-12-21 | Oak Hill Bio Limited | Method of maturing/differentiating neurons and/or modulating the vagus nerve |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5068224A (en) * | 1987-09-18 | 1991-11-26 | Kabivitrum Ab | Method of improving regeneration of transfected peripheral nerves using igf-1 |
US5093317A (en) * | 1989-06-05 | 1992-03-03 | Cephalon, Inc. | Treating disorders by application of insulin-like growth factor |
WO1992019256A1 (en) * | 1991-05-03 | 1992-11-12 | Kabi Pharmacia Ab | New medicinal use |
US5187151A (en) * | 1991-02-12 | 1993-02-16 | Genentech, Inc. | Use of binding protein with igf-i as an anabolic growth promoting agent |
WO1993002695A1 (en) * | 1991-08-01 | 1993-02-18 | Genentech, Inc. | Igf-1 to improve the neural condition |
US5258287A (en) * | 1988-03-22 | 1993-11-02 | Genentech, Inc. | DNA encoding and methods of production of insulin-like growth factor binding protein BP53 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE8505920D0 (en) * | 1985-12-13 | 1985-12-13 | Kabigen Ab | NEW PROTEIN AND ITS USE |
US5652214A (en) * | 1989-06-05 | 1997-07-29 | Cephalon, Inc. | Treating disorders by application of insulin-like growth factors and analogs |
US6310040B1 (en) * | 1991-11-08 | 2001-10-30 | Cephalon, Inc. | Treating retinal neuronal disorders by the application of insulin-like growth factors and analogs |
HU217543B (en) * | 1992-06-12 | 2000-02-28 | Albert Einstein College Of Medicine Of Yeshiva University | Process for producing pharmaceutical compositions prevention and treatment of peripherial neuropathy and pharmaceutical compositions containing insulin-like growth factor i and chemotherapeutic agent |
-
1994
- 1994-11-15 CA CA002176708A patent/CA2176708A1/en not_active Abandoned
- 1994-11-15 JP JP7514567A patent/JPH09509140A/en active Pending
- 1994-11-15 EP EP95901254A patent/EP0729361A4/en not_active Withdrawn
- 1994-11-15 WO PCT/US1994/013177 patent/WO1995013823A1/en not_active Application Discontinuation
- 1994-11-15 AU AU10570/95A patent/AU693489B2/en not_active Ceased
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5068224A (en) * | 1987-09-18 | 1991-11-26 | Kabivitrum Ab | Method of improving regeneration of transfected peripheral nerves using igf-1 |
US5258287A (en) * | 1988-03-22 | 1993-11-02 | Genentech, Inc. | DNA encoding and methods of production of insulin-like growth factor binding protein BP53 |
US5093317A (en) * | 1989-06-05 | 1992-03-03 | Cephalon, Inc. | Treating disorders by application of insulin-like growth factor |
US5187151A (en) * | 1991-02-12 | 1993-02-16 | Genentech, Inc. | Use of binding protein with igf-i as an anabolic growth promoting agent |
WO1992019256A1 (en) * | 1991-05-03 | 1992-11-12 | Kabi Pharmacia Ab | New medicinal use |
WO1993002695A1 (en) * | 1991-08-01 | 1993-02-18 | Genentech, Inc. | Igf-1 to improve the neural condition |
Non-Patent Citations (6)
Title |
---|
E.M. SPENCER, "Modern Concepts of Insulin-Like Growth Factors", published 1991, by ELSEVIER (N.Y.), pages 715-728. * |
JOURNAL OF CELL BIOLOGY, Volume 111, issued September 1990, R. ARMSTRONG, "In Vitro Analysis of the Oligodendrocyte Lineage in Mice During Demyelination and Remyelination", pages 1183-1195. * |
JOURNAL OF NEUROCHEMISTRY, Vol. 58, Number 4, issued 1992, F.T. CREWS et al., "Insulin-Like Growth Factor I Receptor Binding in Brains of Alzheimer's and Alcoholic Patients", pages 1205-1210. * |
JOURNAL OF NEUROSCIENCE, Vol. 12, Number 4, issued April 1992, R.C. ARMSTRONG et al., "Pre-Oligodendrocytes from Adult Human CNS", pages 1538-1547. * |
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA, Volume 83, issued February 1986, F.A. MCMORRIS et al., "Insulin-Like Growth Factor I/Somatomedin C: A Potent Inducer of Oligodendrocyte Development", pages 822-826. * |
See also references of EP0729361A4 * |
Cited By (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6440928B1 (en) | 1988-12-06 | 2002-08-27 | Colorado State University Research Foundation | Method for treating diabetic neuropathy with NGF |
WO1997021449A1 (en) * | 1995-12-13 | 1997-06-19 | Aurogen Incorporated | Method for effecting changes in the central nervous system by administration of igf-i or igf-ii |
US6518238B1 (en) | 1997-02-25 | 2003-02-11 | Celtrix Pharmaceuticals, Inc. | Method of treating psychological and metabolic disorders using IGF or IGF/IGFBP-3 |
WO1998036764A2 (en) * | 1997-02-25 | 1998-08-27 | Celtrix Pharmaceuticals, Inc. | Method of treating psychological and metabolic disorders using igf or igf/igfbp-3 |
US6015786A (en) * | 1997-02-25 | 2000-01-18 | Celtrix Pharmaceuticals, Inc. | Method for increasing sex steroid levels using IGF or IGF/IGFBP-3 |
US6025368A (en) * | 1997-02-25 | 2000-02-15 | Celtrix Pharmaceuticals, Inc. | Method for treating the symptoms of chronic stress-related disorders using IGF |
US6025332A (en) * | 1997-02-25 | 2000-02-15 | Celtrix Pharmaceuticals, Inc. | Method for treating low circulating levels of sex hormone steroids associated with aging using IGF or IGF/IGFBP-3 |
WO1998036764A3 (en) * | 1997-02-25 | 1999-02-18 | Celtrix Pharma | Method of treating psychological and metabolic disorders using igf or igf/igfbp-3 |
US6514937B1 (en) | 1997-02-25 | 2003-02-04 | Celtrix Pharmaceuticals, Inc. | Method of treating psychological and metabolic disorders using IGF or IGF/IGFBP-3 |
US7300927B2 (en) | 1997-03-12 | 2007-11-27 | Robert W. Esmond | Method for treating or preventing Alzheimer's disease |
WO1998039967A1 (en) * | 1997-03-12 | 1998-09-17 | The General Hospital Corporation | A method for treating or preventing alzheimer's disease |
WO1999062536A3 (en) * | 1998-06-01 | 2000-03-30 | Celtrix Pharma | Pharmaceutical formulations for igf/igfbp |
US6417330B1 (en) | 1998-06-01 | 2002-07-09 | Celtrix Pharmaceuticals, Inc. | Insulin-like growth factor binding protein variants |
US6436897B2 (en) | 1998-06-01 | 2002-08-20 | Celtrix Pharmaceuticals, Inc. | Pharmaceutical formulations for IGF/IGFBP |
WO1999062536A2 (en) * | 1998-06-01 | 1999-12-09 | Celtrix Pharmaceuticals, Inc. | Pharmaceutical formulations for igf/igfbp |
US6040292A (en) * | 1999-06-04 | 2000-03-21 | Celtrix Pharmaceuticals, Inc. | Methods for treating diabetes |
US7288516B1 (en) | 1999-09-20 | 2007-10-30 | Celtrix Pharmaceuticals, Inc. | Null IGF for the treatment of cancer |
US7371813B2 (en) | 2000-09-19 | 2008-05-13 | Bioexpertise Llc | Method for use of IGF-binding protein for selective sensitization of target cells in vivo |
US7041314B2 (en) | 2001-05-24 | 2006-05-09 | Neuren Pharmaceuticals Ltd. | GPE analogs and peptidominetics |
US7714020B2 (en) | 2001-05-24 | 2010-05-11 | Neuren Pharmaceuticals Limited | Treatment of non-convulsive seizures in brain injury using G-2-methyl-prolyl glutamate |
US7605177B2 (en) | 2001-05-24 | 2009-10-20 | Neuren Pharmaceuticals Limited | Effects of glycyl-2 methyl prolyl glutamate on neurodegeneration |
US6861406B2 (en) | 2001-09-18 | 2005-03-01 | Bioexpertise, Llc | IGF-binding protein-derived peptide |
US6914049B2 (en) | 2001-09-18 | 2005-07-05 | Bioexpertise, Llc | IGF-binding protein-derived peptide or small molecule |
US6887851B2 (en) | 2001-09-18 | 2005-05-03 | Bioexpertise, Llc | IGF-binding protein-derived peptide |
EP1560933A2 (en) * | 2002-11-14 | 2005-08-10 | Wyeth | Methods and compositions for treating neurological disorders |
EP1560933A4 (en) * | 2002-11-14 | 2007-11-21 | Wyeth Corp | Methods and compositions for treating neurological disorders |
WO2007123723A2 (en) | 2006-03-31 | 2007-11-01 | Rhode Island Hospital | Diagnosis and treatment of alzheimer's disease |
RU2669692C1 (en) * | 2017-08-14 | 2018-10-15 | Павел Андреевич Канаев | Method for producing complex of biologically active peptides with neurotropic activity |
WO2023242442A1 (en) * | 2022-06-17 | 2023-12-21 | Oak Hill Bio Limited | Method of maturing/differentiating neurons and/or modulating the vagus nerve |
Also Published As
Publication number | Publication date |
---|---|
AU693489B2 (en) | 1998-07-02 |
JPH09509140A (en) | 1997-09-16 |
AU1057095A (en) | 1995-06-06 |
EP0729361A1 (en) | 1996-09-04 |
CA2176708A1 (en) | 1995-05-26 |
EP0729361A4 (en) | 1996-11-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU693489B2 (en) | Method of treating neurological disorders | |
US5624898A (en) | Method for administering neurologic agents to the brain | |
US8946151B2 (en) | Method of treating Parkinson's disease in humans by convection-enhanced infusion of glial cell-line derived neurotrophic factor to the putamen | |
AU2007229301B2 (en) | Continuous dosing regimens for neural stem cell proliferating agents and neural stem cell differentiating agents | |
KR20080074108A (en) | Oligodendrocyte precursor cell proliferation regulated by prolactin | |
US20020072498A1 (en) | Method for administering ciliary neurotrophic factor to the brain | |
Day-Lollini et al. | Hyperplastic changes within the leptomeninges of the rat and monkey in response to chronic intracerebroventricular infusion of nerve growth factor | |
US6680295B1 (en) | Method and pharmaceutical composition for prevention and treatment of brain damage | |
US20040209810A1 (en) | Method of treating Parkinson's disease in humans by intraputaminal infusion of glial cell-line derived neurotrophic factor | |
EP0388226B1 (en) | Means for the treatment of senile dementia, memory disorders and related conditions | |
US20030027755A1 (en) | Compositions and methods for the rescue of white matter | |
Festoff et al. | The insulin-like growth factor signaling system and ALS neurotrophic factor treatment strategies | |
Vaught et al. | Potential utility of rhIGF‐1 in neuromuscular and/or degenerative disease | |
AU9185198A (en) | Preventives or remedies for ischemic diseases | |
DE60110247T2 (en) | Angiogenic tri- or tetrapeptides derived from AcSDKP | |
EP0874641B1 (en) | Igf-i and -ii for the treatment of diseases of the central nervous system | |
US20070078089A1 (en) | Method for effecting changes in the central nervous system by administration of IGF-I or IGF-II | |
WO1997003689A1 (en) | Method of treating epilepsy with brain derived neurotrophic factor | |
US8106009B2 (en) | Pharmaceutical composition for preventing or treating ischemic diseases | |
Vaught et al. | Potential utility of rhlGF-1 in neuromuscular and/or degenerative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA JP |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2176708 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1995901254 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1995901254 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1995901254 Country of ref document: EP |