JP2016065064A - 末梢神経損傷を処置するためのニューレグリンの使用 - Google Patents
末梢神経損傷を処置するためのニューレグリンの使用 Download PDFInfo
- Publication number
- JP2016065064A JP2016065064A JP2015210351A JP2015210351A JP2016065064A JP 2016065064 A JP2016065064 A JP 2016065064A JP 2015210351 A JP2015210351 A JP 2015210351A JP 2015210351 A JP2015210351 A JP 2015210351A JP 2016065064 A JP2016065064 A JP 2016065064A
- Authority
- JP
- Japan
- Prior art keywords
- neuregulin
- nerve
- injury
- peripheral nerve
- nerve injury
- 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.)
- Granted
Links
- 108050003475 Neuregulin Proteins 0.000 title claims abstract description 76
- 102000014413 Neuregulin Human genes 0.000 title claims abstract description 74
- 208000010886 Peripheral nerve injury Diseases 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 40
- 238000001356 surgical procedure Methods 0.000 claims abstract description 35
- 208000028389 Nerve injury Diseases 0.000 claims description 49
- 230000008764 nerve damage Effects 0.000 claims description 49
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 31
- 201000001881 impotence Diseases 0.000 claims description 31
- 210000000578 peripheral nerve Anatomy 0.000 claims description 24
- 238000011471 prostatectomy Methods 0.000 claims description 8
- 206010060862 Prostate cancer Diseases 0.000 claims description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 7
- 230000002829 reductive effect Effects 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 230000036961 partial effect Effects 0.000 claims description 2
- 210000005036 nerve Anatomy 0.000 abstract description 64
- 230000006378 damage Effects 0.000 abstract description 50
- 208000014674 injury Diseases 0.000 abstract description 38
- 208000027418 Wounds and injury Diseases 0.000 abstract description 31
- 230000008733 trauma Effects 0.000 abstract description 9
- 238000010186 staining Methods 0.000 description 54
- 108090000765 processed proteins & peptides Proteins 0.000 description 42
- 239000000203 mixture Substances 0.000 description 27
- 210000001519 tissue Anatomy 0.000 description 23
- 150000001413 amino acids Chemical group 0.000 description 22
- 230000037396 body weight Effects 0.000 description 22
- 108091000117 Tyrosine 3-Monooxygenase Proteins 0.000 description 21
- 102000048218 Tyrosine 3-monooxygenases Human genes 0.000 description 21
- 208000025962 Crush injury Diseases 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 19
- 108091006774 SLC18A3 Proteins 0.000 description 19
- 102000045965 Vesicular Acetylcholine Transport Proteins Human genes 0.000 description 19
- DVGHHMFBFOTGLM-UHFFFAOYSA-L fluorogold Chemical compound F[Au][Au]F DVGHHMFBFOTGLM-UHFFFAOYSA-L 0.000 description 19
- 102000004196 processed proteins & peptides Human genes 0.000 description 18
- 108090000623 proteins and genes Proteins 0.000 description 18
- 230000006870 function Effects 0.000 description 17
- 229940024606 amino acid Drugs 0.000 description 16
- 235000001014 amino acid Nutrition 0.000 description 15
- 229920001184 polypeptide Polymers 0.000 description 15
- 238000004321 preservation Methods 0.000 description 15
- 210000003050 axon Anatomy 0.000 description 14
- 210000003899 penis Anatomy 0.000 description 13
- 235000018102 proteins Nutrition 0.000 description 13
- 102000004169 proteins and genes Human genes 0.000 description 13
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 12
- 210000004126 nerve fiber Anatomy 0.000 description 12
- 102100022397 Nitric oxide synthase, brain Human genes 0.000 description 11
- 101710111444 Nitric oxide synthase, brain Proteins 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 230000008929 regeneration Effects 0.000 description 10
- 238000011069 regeneration method Methods 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 238000011084 recovery Methods 0.000 description 8
- 102000048238 Neuregulin-1 Human genes 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 230000009986 erectile function Effects 0.000 description 7
- 230000030214 innervation Effects 0.000 description 7
- 210000001640 nerve ending Anatomy 0.000 description 7
- 230000001537 neural effect Effects 0.000 description 7
- 102000012545 EGF-like domains Human genes 0.000 description 6
- 108050002150 EGF-like domains Proteins 0.000 description 6
- 108090000556 Neuregulin-1 Proteins 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 6
- 230000004064 dysfunction Effects 0.000 description 6
- 210000003414 extremity Anatomy 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 230000033001 locomotion Effects 0.000 description 6
- 108091005601 modified peptides Proteins 0.000 description 6
- 210000002569 neuron Anatomy 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 210000004116 schwann cell Anatomy 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 210000005056 cell body Anatomy 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002372 labelling Methods 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 210000002460 smooth muscle Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 102000001301 EGF receptor Human genes 0.000 description 4
- 108060006698 EGF receptor Proteins 0.000 description 4
- 208000003098 Ganglion Cysts Diseases 0.000 description 4
- 208000004454 Hyperalgesia Diseases 0.000 description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 4
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 4
- 208000005400 Synovial Cyst Diseases 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 210000003461 brachial plexus Anatomy 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- -1 carrier Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 210000005226 corpus cavernosum Anatomy 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 238000003780 insertion Methods 0.000 description 4
- 230000037431 insertion Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000036407 pain Effects 0.000 description 4
- 230000018052 penile erection Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 3
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 3
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 229960001230 asparagine Drugs 0.000 description 3
- 235000009582 asparagine Nutrition 0.000 description 3
- 230000003376 axonal effect Effects 0.000 description 3
- 230000002146 bilateral effect Effects 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000008033 biological extinction Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 230000007850 degeneration Effects 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 239000002612 dispersion medium Substances 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 230000007849 functional defect Effects 0.000 description 3
- 210000000609 ganglia Anatomy 0.000 description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 229960000310 isoleucine Drugs 0.000 description 3
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 230000007659 motor function Effects 0.000 description 3
- 230000004112 neuroprotection Effects 0.000 description 3
- 230000000324 neuroprotective effect Effects 0.000 description 3
- 150000007523 nucleic acids Chemical group 0.000 description 3
- 230000008447 perception Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000011514 reflex Effects 0.000 description 3
- 230000001172 regenerating effect Effects 0.000 description 3
- 238000002271 resection Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 230000007441 retrograde transport Effects 0.000 description 3
- 230000037152 sensory function Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 210000001364 upper extremity Anatomy 0.000 description 3
- 239000004474 valine Substances 0.000 description 3
- 101150028074 2 gene Proteins 0.000 description 2
- 101150090724 3 gene Proteins 0.000 description 2
- 101150033839 4 gene Proteins 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
- 239000004475 Arginine Substances 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 208000000094 Chronic Pain Diseases 0.000 description 2
- 108091026890 Coding region Proteins 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102100040896 Growth/differentiation factor 15 Human genes 0.000 description 2
- 101000893549 Homo sapiens Growth/differentiation factor 15 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 208000035154 Hyperesthesia Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-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
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- 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 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-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
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 108010083674 Myelin Proteins Proteins 0.000 description 2
- 102000006386 Myelin Proteins Human genes 0.000 description 2
- 101150038921 NRG1 gene Proteins 0.000 description 2
- 206010029174 Nerve compression Diseases 0.000 description 2
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 2
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 101000653754 Rattus norvegicus Sphingosine 1-phosphate receptor 5 Proteins 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000001800 adrenalinergic effect Effects 0.000 description 2
- 206010053552 allodynia Diseases 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 238000002659 cell therapy Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 238000011990 functional testing Methods 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000003601 intercostal effect Effects 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 210000002414 leg Anatomy 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 210000005012 myelin Anatomy 0.000 description 2
- 230000000926 neurological effect Effects 0.000 description 2
- 231100000862 numbness Toxicity 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 238000011472 radical prostatectomy Methods 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000007832 reinnervation Effects 0.000 description 2
- 230000004648 relaxation of smooth muscle Effects 0.000 description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 2
- 229940081974 saccharin Drugs 0.000 description 2
- 235000019204 saccharin Nutrition 0.000 description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- 235000019615 sensations Nutrition 0.000 description 2
- 230000001953 sensory effect Effects 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 210000003594 spinal ganglia Anatomy 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 230000002889 sympathetic effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 230000000472 traumatic effect Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- RGOIEYAZJSYLJT-BHFSHLQUSA-N (2s)-2-aminobutanedioic acid;(2s)-2,5-diamino-5-oxopentanoic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O.OC(=O)[C@@H](N)CCC(N)=O RGOIEYAZJSYLJT-BHFSHLQUSA-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
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- LCSKNASZPVZHEG-UHFFFAOYSA-N 3,6-dimethyl-1,4-dioxane-2,5-dione;1,4-dioxane-2,5-dione Chemical group O=C1COC(=O)CO1.CC1OC(=O)C(C)OC1=O LCSKNASZPVZHEG-UHFFFAOYSA-N 0.000 description 1
- ZOXZWYWOECCBSH-UHFFFAOYSA-N 4 Methyl N-ethylcathinone Chemical compound CCNC(C)C(=O)C1=CC=C(C)C=C1 ZOXZWYWOECCBSH-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000025978 Athletic injury Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010004954 Birth trauma Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 102000056372 ErbB-3 Receptor Human genes 0.000 description 1
- 102000044591 ErbB-4 Receptor Human genes 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000036119 Frailty Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 102000034615 Glial cell line-derived neurotrophic factor Human genes 0.000 description 1
- 108091010837 Glial cell line-derived neurotrophic factor Proteins 0.000 description 1
- 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 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 102000003693 Hedgehog Proteins Human genes 0.000 description 1
- 108090000031 Hedgehog Proteins Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000979249 Homo sapiens Neuromodulin Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 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 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-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
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-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
- 229930195725 Mannitol Natural products 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 206010062575 Muscle contracture Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- 208000001738 Nervous System Trauma Diseases 0.000 description 1
- 102400000057 Neuregulin-2 Human genes 0.000 description 1
- 101800000675 Neuregulin-2 Proteins 0.000 description 1
- 102100023206 Neuromodulin Human genes 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000906034 Orthops Species 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 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
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 1
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010040021 Sensory abnormalities Diseases 0.000 description 1
- 206010040030 Sensory loss Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 208000002847 Surgical Wound Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 206010073696 Wallerian degeneration Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 210000003489 abdominal muscle Anatomy 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 238000012084 abdominal surgery Methods 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 210000003766 afferent neuron Anatomy 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000002567 autonomic effect Effects 0.000 description 1
- 210000003192 autonomic ganglia Anatomy 0.000 description 1
- 210000001099 axilla Anatomy 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 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 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229940087373 calcium oxide Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000007348 cell dedifferentiation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007958 cherry flavor Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940070400 clinidine Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000010878 colorectal surgery Methods 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 208000006111 contracture Diseases 0.000 description 1
- 230000009519 contusion Effects 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000001856 erectile effect Effects 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 229960004887 ferric hydroxide Drugs 0.000 description 1
- 230000000893 fibroproliferative effect Effects 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 238000002683 hand surgery Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000009442 healing mechanism Effects 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 210000000194 hypogastric plexus Anatomy 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 208000036260 idiopathic disease Diseases 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 239000007926 intracavernous injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 230000003447 ipsilateral effect Effects 0.000 description 1
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 210000002540 macrophage Anatomy 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
- 238000012423 maintenance Methods 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 102000035118 modified proteins Human genes 0.000 description 1
- 108091005573 modified proteins Proteins 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000003007 myelin sheath Anatomy 0.000 description 1
- 230000023105 myelination Effects 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 208000028412 nervous system injury Diseases 0.000 description 1
- 230000007372 neural signaling Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000001272 neurogenic effect Effects 0.000 description 1
- 230000004007 neuromodulation Effects 0.000 description 1
- 230000007991 neuronal integrity Effects 0.000 description 1
- 230000006576 neuronal survival Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 230000003018 neuroregenerative effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- HKIQZBZCKQBMJT-UHFFFAOYSA-J nickel(2+) disulfate Chemical compound [Ni++].[Ni++].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O HKIQZBZCKQBMJT-UHFFFAOYSA-J 0.000 description 1
- 230000003040 nociceptive effect Effects 0.000 description 1
- 230000002474 noradrenergic effect Effects 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000037324 pain perception Effects 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000001734 parasympathetic effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229960001621 povidone-iodine Drugs 0.000 description 1
- 238000011045 prefiltration Methods 0.000 description 1
- 238000003825 pressing Methods 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
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 230000008458 response to injury Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000001991 scapula Anatomy 0.000 description 1
- 210000001044 sensory neuron Anatomy 0.000 description 1
- 230000021317 sensory perception Effects 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003356 suture material Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000009960 sympathetic pathway Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 238000007483 tonsillectomy Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000008734 wallerian degeneration Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
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
- A61K38/18—Growth factors; Growth regulators
-
- 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
- A61K38/18—Growth factors; Growth regulators
- A61K38/1883—Neuregulins, e.g.. p185erbB2 ligands, glial growth factor, heregulin, ARIA, neu differentiation factor
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
- A61K49/16—Antibodies; Immunoglobulins; Fragments thereof
-
- 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
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/475—Assays involving growth factors
- G01N2333/4756—Neuregulins, i.e. p185erbB2 ligands, glial growth factor, heregulin, ARIA, neu differentiation factor
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/34—Genitourinary disorders
- G01N2800/344—Disorders of the penis and the scrotum and erectile dysfuncrion
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Urology & Nephrology (AREA)
- Reproductive Health (AREA)
- Genetics & Genomics (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Biophysics (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Gynecology & Obstetrics (AREA)
- Pathology (AREA)
- Cell Biology (AREA)
- Food Science & Technology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
Abstract
【解決手段】末梢神経損傷を受けるリスクのある対象、または末梢神経損傷を既に有する対象に、ニューレグリンの有効量を投与する段階を含む、末梢神経損傷を防止または処置する方法。ニューレグリンを手術手技の前に投与する方法。
【選択図】なし
Description
本発明は、神経の外傷または損傷に関する。より詳しくは、末梢神経損傷を防止、処置、または改善するために、ニューレグリンまたはその機能的セグメントを用いることに関する。
末梢神経は一般的に、自動車事故、オートバイ事故、手術、刃物および弾丸による創傷、ならびに母子双方に対する出生時の損傷を含む外傷によって損傷を受ける。神経損傷の一般的な外科的原因には、前立腺切除および乳房切除が挙げられる。術中の他の一般的な損傷は、長時間の肢位または不可避もしくは偶発的な神経圧迫の結果である。神経が損傷を受けると、傷害を受けた神経によって支配される体の領域において感覚および/または機能の喪失が起こる。たとえば、前立腺切除による神経の損傷後では、一般的に勃起機能障害が起こる。乳房切除後では、上肢および/または肩甲骨の固有の機能がしばしば失われる。さらに、出生時の損傷または上腕神経叢に対する傷害を伴う他の外傷後では、同側の肢の機能障害が起こる。
末梢神経損傷を受けるリスクのある対象、または末梢神経損傷を既に有する対象にニューレグリンの有効量を投与する段階を含む、末梢神経損傷を防止または処置する方法。
[本発明1002]
ニューレグリンが手術手技の前に投与される、本発明1001の方法。
[本発明1003]
手術手技が前立腺癌手術である、本発明1001の方法。
[本発明1004]
前立腺癌手術が前立腺切除術である、本発明1003の方法。
[本発明1005]
ニューレグリンが乳児出産の前に妊娠中の母親に投与される、本発明1001の方法。
[本発明1006]
ニューレグリンが、乳癌処置の前に患者に投与される、本発明1001の方法。
[本発明1007]
乳癌処置が完全または部分的乳房切除術である、本発明1004の方法。
[本発明1008]
勃起機能障害を起こす末梢神経損傷を有する対象、またはそのような末梢神経損傷を受けるリスクのある対象にそれぞれ、ニューレグリンの有効量を投与する段階を含む、末梢神経損傷に起因する勃起機能障害を処置または予防する方法。
[本発明1009]
以下の段階を含む、患者における勃起機能障害の病因を診断する方法:
勃起障害を有する患者にニューレグリンの有効量を投与する段階;およびその後、
勃起機能障害が軽減するか否かを同定する段階であって、
それにより、投与する段階の後に勃起機能障害が軽減した場合、患者は末梢神経傷害の結果としての勃起機能障害を有すると診断される、前記段階。
本発明の他の目的、特色、および長所は、以下の詳細な説明から明らかとなるであろう。しかしながら、本発明の精神および範囲内の様々な変化および改変がこの詳細な説明から当業者に明らかであろうことから、詳細な説明および具体例は本発明の特定の態様を示しながら例証のために与えられているに過ぎないことを理解すべきである。
末梢神経に対する損傷は、たとえば外傷、事故、または手術によって引き起こされる様々な事象、圧迫、挫傷、相互作用、挫滅、または伸長の共通の結果である。神経損傷に至る外部要因は多様であるが、神経レベルでの症状発現は共通の特色である(論評に関しては、Lee and Wolfe, J Am Acad Orthop Surg, 8(4), p. 243, 2008を参照されたい)。任意の原因の外傷による損傷はしばしば、有髄化、神経上膜、神経周膜、神経内膜、および軸索に対して傷害を引き起こす。最も軽症の症例では、損傷は主にミエリンおよび神経上膜に起こり、その後数日または数週間以内に完全な回復が自然に起こる。
性的不能または勃起機能障害(ED)とも呼ばれる障害は、米国だけでも2000万人の男性が罹患している一般的な問題である。陰茎の勃起は、神経の完全性および機能的血管の双方に依存する神経血管現象である。性的刺激が与えられると、神経伝達物質(特に酸化窒素)が海綿体神経終末および内皮細胞から放出される。その結果起こる動脈および細動脈平滑筋の弛緩が動脈流を増加させる。海綿体内部に貯留された血液は、陰茎を勃起状態にする。
「ニューレグリン」、「ニューレグリン-1」、「NRG-1」、「ヘレグリン」とは、ErbB1、ErbB3、またはErbB4受容体に結合して、ErbB2受容体と対を形成する(二量体化する)ポリペプチドを意味する。たとえば、ニューレグリンは、その各々の全内容が参照により本明細書に組み入れられる、米国特許第5,530,109号;第5,716,930号;および第7,037,888号に記述されるp185erbB2リガンド遺伝子によってコードされうる;ニューレグリンはまた、NRG-2、3、および4遺伝子によってコードされうる。ニューレグリンは、GGF2またはその任意の活性断片でありうる;これはまた、GGF2の保存的変種またはGGF2を含む分子でありうる。当技術分野におけるいくつかの用途において、「ニューレグリン」という用語は、完全なニューレグリン分子のEGF-様ドメインのみを指すことが意図される;これはまた、「ニューレグリン様」タンパク質、ペプチド、またはポリペプチドとしても知られる。
(GenBankアクセッション番号AAB59622、参照により本明細書に組み入れられる)である。本発明のある局面において、ニューレグリンポリペプチドまたはそのセグメントは、GGF2のアミノ酸配列と75、80、85、90、91、92、93、94、95、96、97、98、99、または100%同一または相同である。本発明のある局面において、ニューレグリン様ポリペプチドは、GGF2のEGF-様ドメインのアミノ酸配列と75、80、85、86、97、88、89、90、91、92、93、94、95、96、97、98、99、または100%同一もしくは相同である。
本発明の薬学的製剤は、薬学的に許容される担体に溶解または分散されたペプチドの有効量を含む。「薬学的または薬理学的に許容される」という句は、対象、たとえば適切であればヒトに投与した場合に、有害な、アレルギーまたは他の望ましくない反応を通常生じない組成物を指す。そのような薬学的組成物の調製は、参照により本明細書に組み入れられる、Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990によって例示されるように、本開示に照らして当業者に公知である。その上、ヒトでの投与目的に関して、調製物は、たとえばUSFDA Office of Biological Standardsによって必要とされる無菌性、発熱性、一般安全性、および純度標準を満たすべきであることが理解されるであろう。
海綿体神経損傷のラットモデルは典型的に、以下の方法論を用いる。ラットをイソフルランによって麻酔する。体温を37℃に維持するために動物を温熱パッドの上に置く。腹部の毛を刈って、無菌的なクリニジン溶液(ポビドンヨード)によって拭く。腹腔の正中下腹部開口部を作製して、両方の海綿体神経および骨盤神経節(MPG)を露出する。海綿体神経の損傷は、血管鉗子によって海綿体神経を片側あたり2分間挫滅することによって引き起こされる。ニューレグリンに関連する試験において、2つのニューレグリン群を損傷の48時間前に処置した。
このプロトコールを行うために、4%フルオロゴールドの海綿体内注射を行い、1週目に骨盤神経節(MPG)組織を採取し4%パラホルムアルデヒド、0.1 Mリン酸緩衝液中で終夜固定した後、20%スクロース中に入れた。厚さ20μmの凍結切片を作製した。Infinityカメラおよびイメージングシステムを用いて画像を得た後、フルオロゴールド増強細胞数に関して盲検的に分析した。次に、MPG標本スライドガラスを無作為に選択して(10個/動物)、無傷のニューロン数を確認するために細胞計数を行った(たとえば、Dail, W. G., Trujillo, D., de la Rosa, D. and Walton, G.: Autonomic innervation of reproductive organs: analysis of the neurons whose axons project in the main penile nerve in the pelvic plexus of the rat. Anat Rec, 224: 94, 1989; Laurikainen A, Hiltunen JO, Vanhatalo S, Klinge E, Saarma M: Glial cell line-derived neurotrophic factor is expressed in penis of adult rat and retrogradely transported in penile parasympathetic and sensory nerves. (Cell Tissue Res 2000, 302:321-9を参照されたい)。
海綿体の近位部分の長軸方向の凍結切片をnNos、VaChTに関して染色した。洗浄は全て、1% triton-Xを含有するTris緩衝液によって行った。組織を5%正常ヤギ血清によって1時間ブロックした後、
a)nNOs(Sigma;1/1000)、または
b)VaChT(Abcam;1/150)、または
c)TH(Millipore;1/5000)
と共にそれぞれ、4℃で終夜インキュベートした。
海綿体内の海綿体神経の軸索終板から放出された酸化窒素(NO)は、内皮NOと共に、平滑筋の弛緩を引き起こし、陰茎勃起の血行力学的変化を開始すると共に、腫脹の維持に関与する。現在、海綿体神経の損傷後の性交能の回復は、残っている神経組織の軸索再生および終末器官(神経NO活性化を可能にする)の機能的な神経再支配の成否に、少なくとも部分的に依存すると理解されている。海綿体神経が損なわれた後の陰茎の動物モデル試験において、十分に定義された病理生物学的変化が観察されている。これらの病理生物学的変化は、ニューラプラクシーから致死性の軸索傷害にまで及ぶ可能性があり、これには平滑筋のアポトーシス、内皮のアポトーシス、酸化窒素シンターゼ(NOS)神経密度の低減、トランスフォーミング増殖因子β(TGF-β)などの線維増殖性サイトカインのアップレギュレーション、平滑筋の線維症もしくは喪失、または変化したソニック・ヘッジホッグタンパク質などの病理生物学的シグナル伝達応答を挙げることができる。
陰茎を神経支配する骨盤神経節ニューロンは、nNOSおよびコリン作動神経マーカーを発現するが、陰茎の交感神経ノルアドレナリン神経支配は主に交感神経鎖を介して生じ、陰茎神経または骨盤神経節を通らない。このプロトコールの結果は、ニューレグリン処置が、小胞アセチルコリントランスポーター(VaChT)に関する海綿体内染色に基づいて、海綿体神経の再生およびその標的(陰茎海綿体)への再投射、および/または神経保護を助けたことを示している。術後EDの主な病因は神経原性であるが、齧歯類での試験から、陰茎神経損傷後に、形態学的および機能的変化も同様に海綿体組織内で起こることが判明した(たとえば、Keast JR. Plasticity of pelvic autonomic ganglia and urogenital innervation. Int Rev Cytol 2006;248: 141-208; Andersson KE, Hedlund P, Alm P. Sympathetic pathways and adrenergic innervation of the penis. Int J Impot Res 2000;12:S5-12; Mulhall JM, Bella AJ, Briganti A, McCullough A, Brock G. Erectile Function Rehabilitation in the Radical Prostatectomy Patient. J Sex Med 7(4), 1687-1698, 2010を参照されたい)。
THはアドレナリン作動神経線維のマーカーであり、体部における神経保存を裏付けるために用いられる。体部の近位部分の凍結切片を長軸方向に作製し、カテコラミン合成マーカーであるチロシンヒドロキシラーゼに対する一次抗体によって染色した(Impaired Cavernous Reinnervation after Penile Nerve Injury in Rats with Features of the Metabolic Syndrome Matthew R. Nangle, BSc, PhD, Joseph Proietto, MBBS, PhD,†and Janet R. Keast, BSc, PhD J Sex Med 2009;6:3032-3044)。
末梢神経損傷はほとんどいかなる外科的状況においても起こりうる。神経損傷の可能性は、任意の手術における組織切開の位置および程度に相関する。たとえば乳房切除術は、腋窩および腕のしびれ(たとえば、肋間上腕神経損傷に対する損傷)、翼状肩甲骨(長胸神経損傷に対する損傷)、広背筋の麻痺(胸背神経損傷に対する損傷)が挙げられる、末梢神経損傷に起因する合併症を有することが多い(Watt-Boolsen et al., 1988; Aitken and Minton, 1983)。
Claims (9)
- 末梢神経損傷を受けるリスクのある対象、または末梢神経損傷を既に有する対象にニューレグリンの有効量を投与する段階を含む、末梢神経損傷を防止または処置する方法。
- ニューレグリンが手術手技の前に投与される、請求項1記載の方法。
- 手術手技が前立腺癌手術である、請求項1記載の方法。
- 前立腺癌手術が前立腺切除術である、請求項3記載の方法。
- ニューレグリンが乳児出産の前に妊娠中の母親に投与される、請求項1記載の方法。
- ニューレグリンが、乳癌処置の前に患者に投与される、請求項1記載の方法。
- 乳癌処置が完全または部分的乳房切除術である、請求項4記載の方法。
- 勃起機能障害を起こす末梢神経損傷を有する対象、またはそのような末梢神経損傷を受けるリスクのある対象にそれぞれ、ニューレグリンの有効量を投与する段階を含む、末梢神経損傷に起因する勃起機能障害を処置または予防する方法。
- 以下の段階を含む、患者における勃起機能障害の病因を診断する方法:
勃起障害を有する患者にニューレグリンの有効量を投与する段階;およびその後、
勃起機能障害が軽減するか否かを同定する段階であって、
それにより、投与する段階の後に勃起機能障害が軽減した場合、患者は末梢神経傷害の結果としての勃起機能障害を有すると診断される、前記段階。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US25158309P | 2009-10-14 | 2009-10-14 | |
US61/251,583 | 2009-10-14 | ||
US25216109P | 2009-10-16 | 2009-10-16 | |
US61/252,161 | 2009-10-16 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2012534366A Division JP5832437B2 (ja) | 2009-10-14 | 2010-10-14 | 末梢神経損傷を処置するためのニューレグリンの使用 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017043750A Division JP2017114906A (ja) | 2009-10-14 | 2017-03-08 | 末梢神経損傷を処置するためのニューレグリンの使用 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2016065064A true JP2016065064A (ja) | 2016-04-28 |
JP6109906B2 JP6109906B2 (ja) | 2017-04-05 |
Family
ID=43480932
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2012534366A Expired - Fee Related JP5832437B2 (ja) | 2009-10-14 | 2010-10-14 | 末梢神経損傷を処置するためのニューレグリンの使用 |
JP2015210351A Expired - Fee Related JP6109906B2 (ja) | 2009-10-14 | 2015-10-27 | 末梢神経損傷を処置するためのニューレグリンの使用 |
JP2017043750A Pending JP2017114906A (ja) | 2009-10-14 | 2017-03-08 | 末梢神経損傷を処置するためのニューレグリンの使用 |
JP2019175592A Ceased JP2020015751A (ja) | 2009-10-14 | 2019-09-26 | 末梢神経損傷を処置するためのニューレグリンの使用 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2012534366A Expired - Fee Related JP5832437B2 (ja) | 2009-10-14 | 2010-10-14 | 末梢神経損傷を処置するためのニューレグリンの使用 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017043750A Pending JP2017114906A (ja) | 2009-10-14 | 2017-03-08 | 末梢神経損傷を処置するためのニューレグリンの使用 |
JP2019175592A Ceased JP2020015751A (ja) | 2009-10-14 | 2019-09-26 | 末梢神経損傷を処置するためのニューレグリンの使用 |
Country Status (17)
Country | Link |
---|---|
US (3) | US9078861B2 (ja) |
EP (4) | EP2488194B1 (ja) |
JP (4) | JP5832437B2 (ja) |
KR (3) | KR101933543B1 (ja) |
CN (2) | CN102596225B (ja) |
AU (1) | AU2010306777C1 (ja) |
BR (1) | BR112012008821A2 (ja) |
CA (1) | CA2777243A1 (ja) |
ES (3) | ES2635313T3 (ja) |
HK (3) | HK1245142A1 (ja) |
IL (3) | IL219100A0 (ja) |
MX (2) | MX2012004386A (ja) |
NZ (3) | NZ599499A (ja) |
PL (3) | PL3235504T3 (ja) |
RU (3) | RU2657770C1 (ja) |
WO (1) | WO2011047183A2 (ja) |
ZA (1) | ZA201202638B (ja) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2763184T3 (es) | 2008-07-17 | 2020-05-27 | Acorda Therapeutics Inc | Dosificación terapéutica de una neurregulina en el tratamiento o profilaxis de la insuficiencia cardíaca |
CA2777243A1 (en) * | 2009-10-14 | 2011-04-21 | Acorda Therapeutics, Inc. | Use of a neuregulin to treat peripheral nerve injury |
WO2013149163A1 (en) * | 2012-03-30 | 2013-10-03 | Acorda Therapeutics, Inc. | Use of neuregulin to treat peripheral nerve injury |
WO2016122169A1 (ko) * | 2015-01-26 | 2016-08-04 | 주식회사 바이오코즈글로벌코리아 | 뉴레귤린을 포함하는 상처 또는 안구건조증의 치료용 약학 조성물 |
IL283079B2 (en) * | 2018-11-15 | 2024-01-01 | Axogen Corp | Materials and methods for nerve repair with nerve grafts of animal origin |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5716930A (en) | 1991-04-10 | 1998-02-10 | Ludwig Institute For Cancer Research | Glial growth factors |
US5530109A (en) | 1991-04-10 | 1996-06-25 | Ludwig Institute For Cancer Research | DNA encoding glial mitogenic factors |
US7037888B1 (en) | 1992-04-03 | 2006-05-02 | Acorda Therapeutics, Inc. | Methods for treating muscle diseases and disorders |
US6087323A (en) | 1992-04-03 | 2000-07-11 | Cambridge Neuroscience, Inc. | Use of neuregulins as modulators of cellular communication |
IL127892A0 (en) * | 1996-07-12 | 1999-10-28 | Genentech Inc | Gamma-heregulin |
US6994856B1 (en) * | 1997-07-24 | 2006-02-07 | Genentech, Inc. | ErbB4 receptor-specific neuregulin related ligands and uses therefor |
US6098873A (en) * | 1999-02-19 | 2000-08-08 | Pack `N` Stack, Inc. | One piece folded and glued container with tabbed columns |
WO2001026607A2 (en) * | 1999-10-08 | 2001-04-19 | Uab Research Foundation | Smdf and ggf neuregulin splice variant isoforms and uses thereof |
ES2252216T3 (es) * | 2000-02-11 | 2006-05-16 | Proteosys Ag | Utilizacion de neorregulina-beta como indicador y/o diana. |
BR0111125A (pt) * | 2000-05-23 | 2004-12-28 | Cenes Pharmaceuticals Inc | Moléculas de ácido nucléico de nrg-2, polipeptìdeos, e métodos diagnóstico e terapêuticos |
AU2002219830A1 (en) * | 2000-11-10 | 2002-05-21 | The Board Of Trustees Of The Leland Stanford Junior University | Methods for treating disorders of neuronal deficiency with bone marrow-derived cells |
US20040115175A1 (en) * | 2000-11-10 | 2004-06-17 | The Board Of Trustees Of The Leland | Methods for treating disorders of neuronal deficiency with bone marrow-derived cells |
RU2349340C2 (ru) * | 2002-10-10 | 2009-03-20 | Мерк Патент Гмбх | Биспецифические антитела к erb-b и их применение для лечения опухолей |
JP2006290881A (ja) * | 2005-03-15 | 2006-10-26 | Ono Pharmaceut Co Ltd | (2r)−2−プロピルオクタン酸を含有してなる運動機能障害の治療剤 |
US7776817B2 (en) * | 2005-09-02 | 2010-08-17 | Morehouse School Of Medicine | Neuregulins for prevention and treatment of damage from acute assault on vascular and neuronal tissue and as regulators of neuronal stem cell migration |
JP5697455B2 (ja) | 2008-02-29 | 2015-04-08 | アコーダ セラピューティクス インコーポレイテッド | グリア成長因子2の所望の血漿レベルを達成するための方法 |
ES2763184T3 (es) | 2008-07-17 | 2020-05-27 | Acorda Therapeutics Inc | Dosificación terapéutica de una neurregulina en el tratamiento o profilaxis de la insuficiencia cardíaca |
CA2777243A1 (en) * | 2009-10-14 | 2011-04-21 | Acorda Therapeutics, Inc. | Use of a neuregulin to treat peripheral nerve injury |
JP2013535507A (ja) | 2010-08-13 | 2013-09-12 | ジョージタウン ユニバーシティ | Ggf2および使用方法 |
WO2013149163A1 (en) | 2012-03-30 | 2013-10-03 | Acorda Therapeutics, Inc. | Use of neuregulin to treat peripheral nerve injury |
-
2010
- 2010-10-14 CA CA2777243A patent/CA2777243A1/en not_active Abandoned
- 2010-10-14 NZ NZ59949910A patent/NZ599499A/en not_active IP Right Cessation
- 2010-10-14 PL PL17168874T patent/PL3235504T3/pl unknown
- 2010-10-14 RU RU2015156584A patent/RU2657770C1/ru active
- 2010-10-14 KR KR1020127012296A patent/KR101933543B1/ko active IP Right Grant
- 2010-10-14 AU AU2010306777A patent/AU2010306777C1/en not_active Ceased
- 2010-10-14 MX MX2012004386A patent/MX2012004386A/es unknown
- 2010-10-14 WO PCT/US2010/052715 patent/WO2011047183A2/en active Application Filing
- 2010-10-14 JP JP2012534366A patent/JP5832437B2/ja not_active Expired - Fee Related
- 2010-10-14 CN CN201080046238.8A patent/CN102596225B/zh not_active Expired - Fee Related
- 2010-10-14 CN CN201510239035.5A patent/CN104984322B/zh active Active
- 2010-10-14 NZ NZ625673A patent/NZ625673A/en not_active IP Right Cessation
- 2010-10-14 EP EP10768844.2A patent/EP2488194B1/en not_active Not-in-force
- 2010-10-14 KR KR1020187037049A patent/KR102225480B1/ko active IP Right Grant
- 2010-10-14 US US12/904,891 patent/US9078861B2/en active Active - Reinstated
- 2010-10-14 ES ES14184157.7T patent/ES2635313T3/es active Active
- 2010-10-14 EP EP19197578.8A patent/EP3639844A1/en not_active Withdrawn
- 2010-10-14 MX MX2015016200A patent/MX350374B/es unknown
- 2010-10-14 NZ NZ713972A patent/NZ713972A/en not_active IP Right Cessation
- 2010-10-14 PL PL10768844.2T patent/PL2488194T3/pl unknown
- 2010-10-14 ES ES17168874T patent/ES2763086T3/es active Active
- 2010-10-14 PL PL14184157T patent/PL2813238T3/pl unknown
- 2010-10-14 EP EP17168874.0A patent/EP3235504B1/en active Active
- 2010-10-14 EP EP14184157.7A patent/EP2813238B1/en not_active Not-in-force
- 2010-10-14 KR KR1020217005890A patent/KR102379876B1/ko active IP Right Grant
- 2010-10-14 ES ES10768844.2T patent/ES2569121T3/es active Active
- 2010-10-14 BR BR112012008821-1A patent/BR112012008821A2/pt not_active IP Right Cessation
-
2012
- 2012-04-05 IL IL219100A patent/IL219100A0/en active IP Right Grant
- 2012-04-12 ZA ZA2012/02638A patent/ZA201202638B/en unknown
-
2013
- 2013-02-05 HK HK18104851.0A patent/HK1245142A1/zh unknown
- 2013-02-05 HK HK13101610.3A patent/HK1174548A1/zh not_active IP Right Cessation
- 2013-02-05 HK HK15105648.8A patent/HK1204951A1/xx not_active IP Right Cessation
-
2015
- 2015-04-17 US US14/689,923 patent/US20150216936A1/en not_active Abandoned
- 2015-10-27 JP JP2015210351A patent/JP6109906B2/ja not_active Expired - Fee Related
-
2017
- 2017-03-08 JP JP2017043750A patent/JP2017114906A/ja active Pending
-
2018
- 2018-05-21 RU RU2018118552A patent/RU2715908C2/ru active
- 2018-07-11 US US16/032,696 patent/US20180311312A1/en not_active Abandoned
- 2018-09-03 IL IL261561A patent/IL261561B/en active IP Right Grant
-
2019
- 2019-09-26 JP JP2019175592A patent/JP2020015751A/ja not_active Ceased
-
2020
- 2020-02-14 RU RU2020106891A patent/RU2020106891A/ru unknown
- 2020-09-08 IL IL277220A patent/IL277220A/en unknown
Non-Patent Citations (1)
Title |
---|
CHEN, L.E. ET AL.: ""Recombinant human glial growth factor 2 (rhGGF2) improves functional recovery of crushed peripheral", NEUROCHEM. INT., vol. 33, no. 4, JPN5012017934, 1 October 1998 (1998-10-01), GB, pages 341 - 351, XP002312528, ISSN: 0003367202, DOI: 10.1016/S0197-0186(98)00037-0 * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7108724B2 (ja) | 末梢神経損傷を処置するためのニューレグリンの使用 | |
JP6109906B2 (ja) | 末梢神経損傷を処置するためのニューレグリンの使用 | |
RU2575570C2 (ru) | Применение нейрегулина для лечения повреждения периферических нервов | |
NZ768817A (en) | Use of a neuregulin to treat peripheral nerve injury |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20160728 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20161026 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170130 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20170209 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20170308 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6109906 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |