JP7381471B2 - 脱髄疾患の治療 - Google Patents
脱髄疾患の治療 Download PDFInfo
- Publication number
- JP7381471B2 JP7381471B2 JP2020537770A JP2020537770A JP7381471B2 JP 7381471 B2 JP7381471 B2 JP 7381471B2 JP 2020537770 A JP2020537770 A JP 2020537770A JP 2020537770 A JP2020537770 A JP 2020537770A JP 7381471 B2 JP7381471 B2 JP 7381471B2
- Authority
- JP
- Japan
- Prior art keywords
- signaling pathway
- hedgehog signaling
- sag
- testosterone
- steroid hormone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 208000016192 Demyelinating disease Diseases 0.000 title claims description 35
- 238000011282 treatment Methods 0.000 title description 21
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims description 158
- 239000003270 steroid hormone Substances 0.000 claims description 81
- 229960003604 testosterone Drugs 0.000 claims description 79
- 230000008410 smoothened signaling pathway Effects 0.000 claims description 65
- 239000000203 mixture Substances 0.000 claims description 49
- 239000000556 agonist Substances 0.000 claims description 33
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- 230000000694 effects Effects 0.000 claims description 22
- 108010080146 androgen receptors Proteins 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 19
- 239000004034 viscosity adjusting agent Substances 0.000 claims description 17
- 201000006417 multiple sclerosis Diseases 0.000 claims description 16
- 210000003169 central nervous system Anatomy 0.000 claims description 14
- 239000011148 porous material Substances 0.000 claims description 14
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 12
- 206010028570 Myelopathy Diseases 0.000 claims description 11
- 239000003446 ligand Substances 0.000 claims description 11
- 238000009472 formulation Methods 0.000 claims description 10
- 201000001119 neuropathy Diseases 0.000 claims description 9
- 230000007823 neuropathy Effects 0.000 claims description 9
- 230000001737 promoting effect Effects 0.000 claims description 9
- 241000283973 Oryctolagus cuniculus Species 0.000 claims description 8
- 206010033799 Paralysis Diseases 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- 238000009499 grossing Methods 0.000 claims description 7
- VFSUUTYAEQOIMW-YHBQERECSA-N 3-chloro-N-[trans-4-(methylamino)cyclohexyl]-N-[3-(pyridin-4-yl)benzyl]-1-benzothiophene-2-carboxamide Chemical compound C1C[C@@H](NC)CC[C@@H]1N(C(=O)C1=C(C2=CC=CC=C2S1)Cl)CC1=CC=CC(C=2C=CN=CC=2)=C1 VFSUUTYAEQOIMW-YHBQERECSA-N 0.000 claims description 6
- 230000002757 inflammatory effect Effects 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 230000000750 progressive effect Effects 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 208000010693 Charcot-Marie-Tooth Disease Diseases 0.000 claims description 3
- 208000030939 Chronic inflammatory demyelinating polyneuropathy Diseases 0.000 claims description 3
- 241000283073 Equus caballus Species 0.000 claims description 3
- 241000282326 Felis catus Species 0.000 claims description 3
- 208000035895 Guillain-Barré syndrome Diseases 0.000 claims description 3
- 208000034800 Leukoencephalopathies Diseases 0.000 claims description 3
- 206010049567 Miller Fisher syndrome Diseases 0.000 claims description 3
- 206010069350 Osmotic demyelination syndrome Diseases 0.000 claims description 3
- 241001494479 Pecora Species 0.000 claims description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 3
- 208000009885 central pontine myelinolysis Diseases 0.000 claims description 3
- 201000005795 chronic inflammatory demyelinating polyneuritis Diseases 0.000 claims description 3
- 208000036546 leukodystrophy Diseases 0.000 claims description 3
- 208000008795 neuromyelitis optica Diseases 0.000 claims description 3
- 208000020911 optic nerve disease Diseases 0.000 claims description 3
- 206010036807 progressive multifocal leukoencephalopathy Diseases 0.000 claims description 3
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 claims description 2
- 102000001307 androgen receptors Human genes 0.000 claims description 2
- 229960003473 androstanolone Drugs 0.000 claims description 2
- 208000021090 palsy Diseases 0.000 claims description 2
- 208000027232 peripheral nervous system disease Diseases 0.000 claims 2
- 230000002638 denervation Effects 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 43
- 238000000034 method Methods 0.000 description 43
- 210000004248 oligodendroglia Anatomy 0.000 description 40
- 241001465754 Metazoa Species 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
- 239000005557 antagonist Substances 0.000 description 30
- 239000003981 vehicle Substances 0.000 description 29
- 241000699670 Mus sp. Species 0.000 description 28
- 102000006386 Myelin Proteins Human genes 0.000 description 25
- 108010083674 Myelin Proteins Proteins 0.000 description 25
- 108010016200 Zinc Finger Protein GLI1 Proteins 0.000 description 25
- 210000005012 myelin Anatomy 0.000 description 25
- 239000013543 active substance Substances 0.000 description 23
- 210000003050 axon Anatomy 0.000 description 23
- -1 fatty acid esters Chemical class 0.000 description 23
- 239000003795 chemical substances by application Substances 0.000 description 20
- 201000002491 encephalomyelitis Diseases 0.000 description 19
- 230000014509 gene expression Effects 0.000 description 18
- 238000012744 immunostaining Methods 0.000 description 18
- 102100032187 Androgen receptor Human genes 0.000 description 17
- 238000011002 quantification Methods 0.000 description 17
- KISWVXRQTGLFGD-UHFFFAOYSA-N 2-[[2-[[6-amino-2-[[2-[[2-[[5-amino-2-[[2-[[1-[2-[[6-amino-2-[(2,5-diamino-5-oxopentanoyl)amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)p Chemical compound C1CCN(C(=O)C(CCCN=C(N)N)NC(=O)C(CCCCN)NC(=O)C(N)CCC(N)=O)C1C(=O)NC(CO)C(=O)NC(CCC(N)=O)C(=O)NC(CCCN=C(N)N)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 KISWVXRQTGLFGD-UHFFFAOYSA-N 0.000 description 16
- 210000004556 brain Anatomy 0.000 description 16
- 235000014113 dietary fatty acids Nutrition 0.000 description 16
- 239000000194 fatty acid Substances 0.000 description 16
- 229930195729 fatty acid Natural products 0.000 description 16
- 102000053171 Glial Fibrillary Acidic Human genes 0.000 description 14
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 14
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 14
- 239000000377 silicon dioxide Substances 0.000 description 14
- 210000000278 spinal cord Anatomy 0.000 description 14
- 241000699666 Mus <mouse, genus> Species 0.000 description 13
- 102000001393 Platelet-Derived Growth Factor alpha Receptor Human genes 0.000 description 13
- 108010068588 Platelet-Derived Growth Factor alpha Receptor Proteins 0.000 description 13
- FOORCIAZMIWALX-JJIBRWJFSA-N (e)-n-(4-benzylpiperazin-1-yl)-1-(3,5-dimethyl-1-phenylpyrazol-4-yl)methanimine Chemical compound CC1=NN(C=2C=CC=CC=2)C(C)=C1\C=N\N(CC1)CCN1CC1=CC=CC=C1 FOORCIAZMIWALX-JJIBRWJFSA-N 0.000 description 12
- 102000047918 Myelin Basic Human genes 0.000 description 12
- 239000003098 androgen Substances 0.000 description 12
- 239000004094 surface-active agent Substances 0.000 description 12
- 101710107068 Myelin basic protein Proteins 0.000 description 11
- 230000004069 differentiation Effects 0.000 description 11
- 230000011664 signaling Effects 0.000 description 11
- KVQOGDQTWWCZFX-UHFFFAOYSA-N 2-[[3-[[2-(dimethylamino)phenyl]methyl]-2-pyridin-4-yl-1,3-diazinan-1-yl]methyl]-N,N-dimethylaniline Chemical group CN(C)C1=CC=CC=C1CN1C(C=2C=CN=CC=2)N(CC=2C(=CC=CC=2)N(C)C)CCC1 KVQOGDQTWWCZFX-UHFFFAOYSA-N 0.000 description 10
- 101100260702 Mus musculus Tinagl1 gene Proteins 0.000 description 10
- 101150088826 arg1 gene Proteins 0.000 description 10
- 230000003902 lesion Effects 0.000 description 10
- 210000004498 neuroglial cell Anatomy 0.000 description 10
- ASWBNKHCZGQVJV-UHFFFAOYSA-N (3-hexadecanoyloxy-2-hydroxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C ASWBNKHCZGQVJV-UHFFFAOYSA-N 0.000 description 9
- 101150053137 AIF1 gene Proteins 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 230000001172 regenerating effect Effects 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 244000060234 Gmelina philippensis Species 0.000 description 8
- 229930040373 Paraformaldehyde Natural products 0.000 description 8
- 238000013459 approach Methods 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 230000023105 myelination Effects 0.000 description 8
- 229920002866 paraformaldehyde Polymers 0.000 description 8
- 235000012239 silicon dioxide Nutrition 0.000 description 8
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 7
- 206010012305 Demyelination Diseases 0.000 description 7
- 230000009459 hedgehog signaling Effects 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 210000000274 microglia Anatomy 0.000 description 7
- 210000003007 myelin sheath Anatomy 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 6
- 230000002159 abnormal effect Effects 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 210000001130 astrocyte Anatomy 0.000 description 6
- 210000000877 corpus callosum Anatomy 0.000 description 6
- 238000010820 immunofluorescence microscopy Methods 0.000 description 6
- 210000003141 lower extremity Anatomy 0.000 description 6
- 229960003511 macrogol Drugs 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 210000000130 stem cell Anatomy 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000000835 fiber Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 108010091047 neurofilament protein H Proteins 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 239000000583 progesterone congener Substances 0.000 description 5
- 230000002062 proliferating effect Effects 0.000 description 5
- 230000035755 proliferation Effects 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 150000003431 steroids Chemical class 0.000 description 5
- 210000001587 telencephalon Anatomy 0.000 description 5
- 229930006000 Sucrose Natural products 0.000 description 4
- 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 4
- 210000001642 activated microglia Anatomy 0.000 description 4
- 230000008499 blood brain barrier function Effects 0.000 description 4
- 210000001218 blood-brain barrier Anatomy 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000004359 castor oil Substances 0.000 description 4
- 235000019438 castor oil Nutrition 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 4
- 230000003210 demyelinating effect Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 229940011871 estrogen Drugs 0.000 description 4
- 239000000262 estrogen Substances 0.000 description 4
- 102000015694 estrogen receptors Human genes 0.000 description 4
- 108010038795 estrogen receptors Proteins 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 210000005230 lumbar spinal cord Anatomy 0.000 description 4
- 230000035800 maturation Effects 0.000 description 4
- 230000002025 microglial effect Effects 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 229920000620 organic polymer Polymers 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 230000001568 sexual effect Effects 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 238000013518 transcription Methods 0.000 description 4
- 230000035897 transcription Effects 0.000 description 4
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 3
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 229940127517 Hormone Receptor Modulators Drugs 0.000 description 3
- 229940030486 androgens Drugs 0.000 description 3
- 230000003376 axonal effect Effects 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 3
- 239000000890 drug combination Substances 0.000 description 3
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 230000006724 microglial activation Effects 0.000 description 3
- 210000000653 nervous system Anatomy 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229950005751 ocrelizumab Drugs 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000186 progesterone Substances 0.000 description 3
- 229960003387 progesterone Drugs 0.000 description 3
- 210000004129 prosencephalon Anatomy 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 239000008159 sesame oil Substances 0.000 description 3
- 235000011803 sesame oil Nutrition 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 210000004885 white matter Anatomy 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- UUDAMDVQRQNNHZ-UHFFFAOYSA-N (S)-AMPA Chemical compound CC=1ONC(=O)C=1CC(N)C(O)=O UUDAMDVQRQNNHZ-UHFFFAOYSA-N 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- 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 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 description 2
- AURFZBICLPNKBZ-FZCSVUEKSA-N 3beta-hydroxy-5alpha-pregnan-20-one Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 AURFZBICLPNKBZ-FZCSVUEKSA-N 0.000 description 2
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 2
- 102100021723 Arginase-1 Human genes 0.000 description 2
- 101710129000 Arginase-1 Proteins 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 102000004057 Claudin-5 Human genes 0.000 description 2
- 108090000582 Claudin-5 Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
- 108090000031 Hedgehog Proteins Proteins 0.000 description 2
- 102000003693 Hedgehog Proteins Human genes 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 206010061323 Optic neuropathy Diseases 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- 241000009328 Perro Species 0.000 description 2
- 239000004264 Petrolatum Substances 0.000 description 2
- 102100030485 Platelet-derived growth factor receptor alpha Human genes 0.000 description 2
- 101710148465 Platelet-derived growth factor receptor alpha Proteins 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- AURFZBICLPNKBZ-UHFFFAOYSA-N Pregnanolone Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 AURFZBICLPNKBZ-UHFFFAOYSA-N 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- COQLPRJCUIATTQ-UHFFFAOYSA-N Uranyl acetate Chemical compound O.O.O=[U]=O.CC(O)=O.CC(O)=O COQLPRJCUIATTQ-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000003463 adsorbent Substances 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 235000013871 bee wax Nutrition 0.000 description 2
- 239000012166 beeswax Substances 0.000 description 2
- 229940092738 beeswax Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 208000029664 classic familial adenomatous polyposis Diseases 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000002597 diffusion-weighted imaging Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000000635 electron micrograph Methods 0.000 description 2
- 238000001493 electron microscopy Methods 0.000 description 2
- 229960005309 estradiol Drugs 0.000 description 2
- 229930182833 estradiol Natural products 0.000 description 2
- 210000003194 forelimb Anatomy 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 208000010726 hind limb paralysis Diseases 0.000 description 2
- 108091008039 hormone receptors Proteins 0.000 description 2
- 229910002011 hydrophilic fumed silica Inorganic materials 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 238000010166 immunofluorescence Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 229940039717 lanolin Drugs 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000012621 metal-organic framework Substances 0.000 description 2
- VQOJFGFKIVFMDH-UHFFFAOYSA-N n-[3-(1h-benzimidazol-2-yl)-4-chlorophenyl]-3,4,5-triethoxybenzamide Chemical compound CCOC1=C(OCC)C(OCC)=CC(C(=O)NC=2C=C(C(Cl)=CC=2)C=2NC3=CC=CC=C3N=2)=C1 VQOJFGFKIVFMDH-UHFFFAOYSA-N 0.000 description 2
- 230000009707 neogenesis Effects 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 230000004112 neuroprotection Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- 230000002188 osteogenic effect Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 210000001428 peripheral nervous system Anatomy 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 229940066842 petrolatum Drugs 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- 230000006611 pharmacological activation Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229920000223 polyglycerol Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229940068984 polyvinyl alcohol Drugs 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229910021426 porous silicon Inorganic materials 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 230000002028 premature Effects 0.000 description 2
- 239000002379 progesterone receptor modulator Substances 0.000 description 2
- MDLUYYGRCGDKGL-UHFFFAOYSA-N propyl 4-[(1-hexyl-4-hydroxy-2-oxoquinoline-3-carbonyl)amino]benzoate Chemical compound O=C1N(CCCCCC)C2=CC=CC=C2C(O)=C1C(=O)NC1=CC=C(C(=O)OCCC)C=C1 MDLUYYGRCGDKGL-UHFFFAOYSA-N 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 229940075993 receptor modulator Drugs 0.000 description 2
- 239000000849 selective androgen receptor modulator Substances 0.000 description 2
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000003549 soybean oil Substances 0.000 description 2
- 235000012424 soybean oil Nutrition 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 229960004274 stearic acid Drugs 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical group C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- RXZDWPYJFCAZCW-UHFFFAOYSA-N 3-chloro-4,7-difluoro-n-[4-(methylamino)cyclohexyl]-n-[(3-pyridin-4-ylphenyl)methyl]-1-benzothiophene-2-carboxamide Chemical compound C1CC(NC)CCC1N(C(=O)C1=C(C2=C(F)C=CC(F)=C2S1)Cl)CC1=CC=CC(C=2C=CN=CC=2)=C1 RXZDWPYJFCAZCW-UHFFFAOYSA-N 0.000 description 1
- VFSUUTYAEQOIMW-UHFFFAOYSA-N 3-chloro-n-[4-(methylamino)cyclohexyl]-n-[(3-pyridin-4-ylphenyl)methyl]-1-benzothiophene-2-carboxamide Chemical compound C1CC(NC)CCC1N(C(=O)C1=C(C2=CC=CC=C2S1)Cl)CC1=CC=CC(C=2C=CN=CC=2)=C1 VFSUUTYAEQOIMW-UHFFFAOYSA-N 0.000 description 1
- USWLOKMMUTWFMD-UHFFFAOYSA-N 4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine Chemical compound C1=NC=CC(C2=C(C(=C(S2)C=2C=CN=CC=2)C=2C=CN=CC=2)C=2C=CN=CC=2)=C1 USWLOKMMUTWFMD-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 108091010877 Allograft inflammatory factor 1 Proteins 0.000 description 1
- 102100040121 Allograft inflammatory factor 1 Human genes 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 206010002961 Aplasia Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 102000002029 Claudin Human genes 0.000 description 1
- 108050009302 Claudin Proteins 0.000 description 1
- PRGILOMAMBLWNG-HNNXBMFYSA-N Colchiceine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(O)=CC=C1C1=C2C=C(OC)C(OC)=C1OC PRGILOMAMBLWNG-HNNXBMFYSA-N 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- FMGSKLZLMKYGDP-UHFFFAOYSA-N Dehydroepiandrosterone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CC=C21 FMGSKLZLMKYGDP-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 241000289659 Erinaceidae Species 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- JJGBXTYGTKWGAT-YUMQZZPRSA-N Gly-Pro-Glu Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O JJGBXTYGTKWGAT-YUMQZZPRSA-N 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 108010061414 Hepatocyte Nuclear Factor 1-beta Proteins 0.000 description 1
- 102100022123 Hepatocyte nuclear factor 1-beta Human genes 0.000 description 1
- 101001134216 Homo sapiens Macrophage scavenger receptor types I and II Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- VLSMHEGGTFMBBZ-OOZYFLPDSA-M Kainate Chemical compound CC(=C)[C@H]1C[NH2+][C@H](C([O-])=O)[C@H]1CC([O-])=O VLSMHEGGTFMBBZ-OOZYFLPDSA-M 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- 102100034184 Macrophage scavenger receptor types I and II Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 101100379142 Mus musculus Anxa1 gene Proteins 0.000 description 1
- 108700028031 Myelin Basic Proteins 0.000 description 1
- 102000055324 Myelin Proteolipid Human genes 0.000 description 1
- 108700021862 Myelin Proteolipid Proteins 0.000 description 1
- 102000002233 Myelin-Oligodendrocyte Glycoprotein Human genes 0.000 description 1
- 108010000123 Myelin-Oligodendrocyte Glycoprotein Proteins 0.000 description 1
- 102100023302 Myelin-oligodendrocyte glycoprotein Human genes 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108010081690 Pertussis Toxin Proteins 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 238000011530 RNeasy Mini Kit Methods 0.000 description 1
- 229910002054 SYLOID® 244 FP SILICA Inorganic materials 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 229940083324 Selective androgen receptor modulator Drugs 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 102000000591 Tight Junction Proteins Human genes 0.000 description 1
- 108010002321 Tight Junction Proteins Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- 102100035535 Zinc finger protein GLI1 Human genes 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 230000001548 androgenic effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002502 anti-myelin effect Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007978 cacodylate buffer Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- 150000001783 ceramides Chemical class 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000003486 chemical etching Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000007118 chronic progressive multiple sclerosis Diseases 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- PRGILOMAMBLWNG-UHFFFAOYSA-N colchicceine Natural products C1CC(NC(C)=O)C2=CC(=O)C(O)=CC=C2C2=C1C=C(OC)C(OC)=C2OC PRGILOMAMBLWNG-UHFFFAOYSA-N 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 230000002281 colonystimulating effect Effects 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 208000010934 demyelinating disease of central nervous system Diseases 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002598 diffusion tensor imaging Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- LDCRTTXIJACKKU-ONEGZZNKSA-N dimethyl fumarate Chemical compound COC(=O)\C=C\C(=O)OC LDCRTTXIJACKKU-ONEGZZNKSA-N 0.000 description 1
- 229960004419 dimethyl fumarate Drugs 0.000 description 1
- LIKFHECYJZWXFJ-UHFFFAOYSA-N dimethyldichlorosilane Chemical compound C[Si](C)(Cl)Cl LIKFHECYJZWXFJ-UHFFFAOYSA-N 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000007720 emulsion polymerization reaction Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000003822 epoxy resin Substances 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- NKHAVTQWNUWKEO-UHFFFAOYSA-N fumaric acid monomethyl ester Natural products COC(=O)C=CC(O)=O NKHAVTQWNUWKEO-UHFFFAOYSA-N 0.000 description 1
- 229910021485 fumed silica Inorganic materials 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 108010079413 glycyl-prolyl-glutamic acid Proteins 0.000 description 1
- 238000010842 high-capacity cDNA reverse transcription kit Methods 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 208000027905 limb weakness Diseases 0.000 description 1
- 231100000861 limb weakness Toxicity 0.000 description 1
- 238000009593 lumbar puncture Methods 0.000 description 1
- 108091005485 macrophage scavenger receptors Proteins 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 230000005415 magnetization Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000002418 meninge Anatomy 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- NKHAVTQWNUWKEO-NSCUHMNNSA-N monomethyl fumarate Chemical compound COC(=O)\C=C\C(O)=O NKHAVTQWNUWKEO-NSCUHMNNSA-N 0.000 description 1
- 229940005650 monomethyl fumarate Drugs 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 239000012120 mounting media Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 238000009608 myelography Methods 0.000 description 1
- 239000002071 nanotube Substances 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 210000001178 neural stem cell Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- BARWIPMJPCRCTP-UHFFFAOYSA-N oleic acid oleyl ester Natural products CCCCCCCCC=CCCCCCCCCOC(=O)CCCCCCCC=CCCCCCCCC BARWIPMJPCRCTP-UHFFFAOYSA-N 0.000 description 1
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- BARWIPMJPCRCTP-CLFAGFIQSA-N oleyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC BARWIPMJPCRCTP-CLFAGFIQSA-N 0.000 description 1
- 210000000535 oligodendrocyte precursor cell Anatomy 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920000647 polyepoxide Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 229960002847 prasterone Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 206010063401 primary progressive multiple sclerosis Diseases 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 102000003998 progesterone receptors Human genes 0.000 description 1
- 108090000468 progesterone receptors Proteins 0.000 description 1
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000001944 prunus armeniaca kernel oil Substances 0.000 description 1
- FYBHCRQFSFYWPY-UHFFFAOYSA-N purmorphamine Chemical compound C1CCCCC1N1C2=NC(OC=3C4=CC=CC=C4C=CC=3)=NC(NC=3C=CC(=CC=3)N3CCOCC3)=C2N=C1 FYBHCRQFSFYWPY-UHFFFAOYSA-N 0.000 description 1
- 238000003762 quantitative reverse transcription PCR Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 108010038379 sargramostim Proteins 0.000 description 1
- 229960002530 sargramostim Drugs 0.000 description 1
- 102000014452 scavenger receptors Human genes 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 239000011863 silicon-based powder Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 1
- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical compound NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 description 1
- 230000009974 thixotropic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Otolaryngology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Description
本出願は、米国特許法第119条に基づき、2018年1月11日に出願された米国仮出願第62/616,173号の優先権を主張し、その全内容は参照により本明細書に組み込まれる。
本明細書に記載の方法は、ステロイドホルモンおよびヘッジホッグシグナル伝達経路モジュレータでの治療が、オリゴデンドロサイトおよびミエリン産生細胞の数を劇的に増加させるという驚くべき発見に基づいている。ステロイドホルモンのみまたはヘッジホッグシグナル伝達経路モジュレータのみを使用する療法が開示されているが(例えば、El-Etr et al.,“Hormonal influences in multiple sclerosis:new therapeutic benefits for steroids,”Maturitas 68:47-51(2011)、Bielecki et al.,“Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin,”Proc.Natl.Acad.Sci.113:14829-14834(2016)、Samanta et al.,“Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination,”Nature 15:448-52(2015);US 2015/0011610、Ferent et al.,“Sonic Hedgehog signaling is a positive oligodendrocyte regulator during demyelination,”J.Neuroscience 33:1759-72(2013)を参照されたい)、本発明者らは、ヘッジホッグシグナル伝達経路モジュレータと一緒にステロイドホルモンを使用すると、オリゴデンドロサイトおよびミエリン産生細胞の産生を相乗的に増強し、髄鞘再形成の促進を改善し、脱髄疾患により効果的な治療を提供することにつながることを見出した。
ステロイドホルモン
本明細書に記載の組成物および方法に有用なヘッジホッグシグナル伝達経路モジュレータには、Shhシグナル伝達を増加させるSmoアゴニストおよびShhシグナル伝達を減少させるSmoアンタゴニスト、ならびにGliアンタゴニストが含まれる。
ステロイドホルモンおよびヘッジホッグシグナル伝達経路モジュレータは、別々の組成物で(実質的に同時にまたは順次)投与され得るか、またはそれらは同じ組成物で投与され得る。
上記のように、本明細書に記載の方法および使用によれば、ステロイドホルモンおよびヘッジホッグシグナル伝達経路モジュレータは、髄鞘再形成の促進を必要とする対象および/または脱髄疾患または状態の治療を必要とする対象などの、それを必要とする対象に投与される。対象は、ヒト、非ヒト霊長類、イヌ、ネコ、ウシ、ヒツジ、ウマ、ウサギ、マウス、またはラットなどの任意の哺乳動物であってよい。
動物の取り扱い。野生型の性腺的に無傷または去勢されたオスのC57Bl/6のマウスを、Janvier Labs Breeding Center(フランス)から8~12週齢で購入した。インビトロ実験では、同腹仔を、Janvier Labs Breeding Centerから購入した、適時交配されたC57Bl/6のメスから得たか、社内で飼育し、Wendy Macklin博士(コロラド大学、アメリカ)から得たPlp-EGFPマウスと交配させた。Mallon et al.,J.Neuroscience 22:876-885(2002)を参照されたい。すべての動物を、食物および水を自由に与えて12時間の明暗サイクルを含む標準的な条件下で収容した。すべての手順は、実験動物の管理と使用に関する欧州共同体理事会指令(European Communities Council Directive)(86/806/EEC)に従って行われ、Regional Ethics Committee CEEA26、Ministere de l’Education Nationale、de l’Enseignement et de la Rechercheによって承認された。
ヘッジホッグとアンドロゲンシグナル伝達との間の機能的相互作用
生後初期の髄鞘形成中
本発明者らは、生後の終脳の髄鞘形成の初期の間におけるヘッジホッグ(Hh)とアンドロゲンシグナル伝達との間の機能的相互作用を同定した。これに関して、ミエリン塩基性タンパク質(Mbp)、Hhシグナル伝達構成成分(Shh、Gli1)、およびアンドロゲン受容体(AR)をコードする転写物の発現プロファイルは、出生から生後15日目(P15)までのオスおよびメスのマウスの背側前脳を使用して研究した。この期間には、オリゴデンドロサイト新生の新生児波、生成されたオリゴデンドロサイト前駆細胞(OLP)の成熟、および背側前脳における髄鞘形成の生理学的プロセスが含まれる。Kessaris et al.,Nature Neuroscience 9:173-179(2006)。図1Aに示すように、Mbp転写は、P3で非常に低いレベルで検出され、その後、P8およびP15でそれぞれ約10倍および60倍の増加を示した。図1Bに示すように、Shh mRNAは、わずかであるが、プラトーに達する前のP8まで有意に増加した。予想外に、図1Cに示すように、Gli1は、P0~P15で徐々に減少した。対照的に、図1Dに示すように、アンドロゲン受容体(AR)転写は、出生時に低レベルで検出されたが、P15まで急激に増加し、オスおよびメスでそれぞれ10~24倍高いレベルに達した。Shh、Gli1、およびMbpの転写は、研究した時点で、動物の性別による有意差はなかった。対照的に、図1Dに示すように、ARの発現は、出生時のメスと比較してオスで有意に高かったが、ARは、P3およびP8で動物の性別に関係なく同等の様式で転写され、AR発現は、P15でオスと比較して、メスで予想外にわずかであるが有意に高いレベルを示した。これらの結果は、アンドロゲンおよびヘッジホッグシグナル伝達経路が髄鞘形成プロセスを制御するために通信する可能性があることを示す。
初代グリア細胞培養物は、Feutz et al,J.Neurocytol,“Isolation and characterization of defective jimpy oligodendrocytes in culture”,24:865-877(2001)に以前に記載されるように、新生(P1)のオスの仔マウスの背側終脳から調製した。簡潔に、髄膜を取り除き、背側終脳を顕微解剖し、10%の仔ウシ血清、ペニシリン(50 U/ml)、およびストレプトマイシン(50μg/ml)(Thermo Fisher Scientific,France)を補充したDMEMにおいて機械的に分離した。細胞懸濁液を、30μg/mlのポリ-l-リジン(Sigma-Aldrich)でコーティングされた0.5mlの培養培地を含む24ウェルプレートに蒔く。次に、アストロサイト、オリゴデンドロサイト(OL)、およびミクログリア細胞を含む培養物を、37℃の加湿雰囲気(90%)内で、5%のCO2および95%の空気中でインキュベートする。
SAGによるSmoの活性化は、脱髄のLPCモデルにおける新たな成熟オリゴデンドロサイトの産生および再生促進ミクログリアの早熟な増加を促進する。
脱髄に対するSmoアゴニストSAGによるSmo活性化の効果を以下のように調査した。LPC誘導脱髄は、若いオスの成体マウスにおいて、SAGの不在下または存在下で、Ferent et al.,J.Neuroscience 33:1759-1772(2013)に以前に記載されるように行われた。簡潔に、特に神経外科専用のハミルトンシリンジ(NH BIO,France)を使用して、LPC1%(Sigma-Aldrich)を含む溶液2μlを、SAG(0.2μM)または対応するビヒクルと共に右脳梁に定位注射して、片側に脱髄病変を誘導した。注射は次の座標で(ブレグマに対して)行われた:前後(AP)+1mm、外側+1mm、背腹(DV)-2.2mm。深く麻酔したマウスから脳を取り出し、4%のPFAを経心的に灌流した。組織を新たな4%のPFA溶液で4時間後固定した後、30%のスクロースに凍結保存し、液体窒素で凍結し、クリオスタットで薄切にした(14μm)。各治療条件の各時点で4~5匹のマウスを使用した。病変後2日目および10日目(dpl)にマウスを屠殺し、PDGFRα、Olig2/APC、Ki67/PDGFRα、GFAP、およびIba1/Arg1の免疫染色のために調製した。免疫染色の画像は、免疫蛍光顕微鏡を使用して取得し(データ示さず)、結果は、PDGFRα(図4A)、Olig2/APC(図4B)、Ki67/PDGFRα(図4C)、GFAP(図4D)、Iba1/Arg1(図4E)について細胞の数/表面単位を評価することによって定量化された。
SAG+Tは実験的自己免疫性脳脊髄炎を緩和する。
実験的自己免疫性脳脊髄炎(EAE)の前に、9~10週齢の去勢したオスのマウスを馴化のために1週間維持した(n=10匹の動物/条件)。病状は、提供者(Hooke Laboratories,MA,USA)の指示に従って誘導された。簡潔に、マウスを、完全フロイントアジュバント中のMOG35-55ペプチド(ミエリンオリゴデンドロサイト糖タンパク質/MBP断片35-55)のエマルジョンを皮下注射し(各部位に前条件付け混合物0.1mlを使用して2つの部位に)、続いて、同じ日(0日目)に、1回目のPBS中の百日咳毒素、および1日目に2回目(250ng/用量)を腹腔内注射することによって免疫化した。マウスを、免疫後7日目から30日目まで、1日1回盲目的に次の尺度に従ってスコアリングした:0.0=運動機能の明らかな変化なし;0.5=尾の先端が下垂;1.0=尾の下垂;1.5=尾の下垂および後肢抑制;2.0=尾の下垂および後肢の衰弱または頭部後屈の兆候;2.5=尾の下垂および後肢の引きずり、または頭部後屈の兆候;3.0=尾の下垂および後肢の完全麻痺または前肢片側と後肢片側の麻痺を伴う尾の下垂;3.5=尾の下垂および後肢の完全麻痺、また動物は横にされた場合、自身で直立することができない;4.0=尾の下垂、最小限の移動および摂食を伴う完全な後肢および部分的な前肢の麻痺;4.5=完全な後肢および部分的な前肢の麻痺、ケージの周りの移動はなく、動物は警戒心がないように思われる;5.0=動物の安楽死を必要とする極度の麻痺。
Claims (10)
- それを必要とする対象における髄鞘再形成を促進するための、ステロイドホルモンおよびヘッジホッグシグナル伝達経路モジュレータを含む医薬品であって、
前記ステロイドホルモンが、テストステロン及びジヒドロテストステロンから選択されるアンドロゲン受容体リガンドであり、前記ヘッジホッグシグナル伝達経路モジュレータが、平滑化アゴニスト(Smoアゴニスト) 3-クロロ-N-[トランス-4-(メチルアミノ)シクロヘキシル]-N-[[3-(4-ピリジニル)フェニル]メチル]ベンゾ[b]チオフェン-2-カルボキサミド(SAG)である、医薬品。 - 前記ステロイドホルモンが、テストステロンである、請求項1に記載の医薬品。
- 前記ステロイドホルモンおよび前記ヘッジホッグシグナル伝達経路モジュレータが、実質的に同時にまたは順次、別々の組成物で投与されるか、または同じ組成物で投与される、請求項1又は2に記載の医薬品。
- 前記ステロイドホルモンおよび前記ヘッジホッグシグナル伝達経路モジュレータの一方または両方が、(a)前記製剤の約60重量%~約98重量%の量で存在する少なくとも1つの親油性もしくは部分的に親油性の担体と、(b)前記製剤の約1重量%~約20重量%の量で存在する表面張力低下活性を有する少なくとも1つの化合物と、(c)前記製剤の約0.5重量%~約10重量%の量で存在する少なくとも1つの粘度調整剤と、をさらに含む鼻腔内医薬組成物で、鼻腔内投与される、請求項1~3のいずれか一項に記載の医薬品。
- 鼻腔内医薬組成物が、前記ステロイドホルモンおよび前記ヘッジホッグシグナル伝達経路モジュレータを含む、請求項4に記載の医薬品。
- 鼻腔内医薬組成物が、ステロイドホルモンを含み、前記ヘッジホッグシグナル伝達経路モジュレータが、平滑化アゴニスト 3-クロロ-N-[トランス-4-(メチルアミノ)シクロヘキシル]-N-[[3-(4-ピリジニル)フェニル]メチル]ベンゾ[b]チオフェン-2-カルボキサミド(SAG)である、請求項4に記載の医薬品。
- 前記ステロイドホルモンおよび前記ヘッジホッグシグナル伝達経路モジュレータの一方または両方が、多孔性賦形剤を含む鼻腔内医薬組成物として鼻腔内投与され、前記ステロイドホルモンおよび前記ヘッジホッグシグナル伝達経路モジュレータの一方または両方が、前記多孔性賦形剤の細孔内に位置する前記多孔性賦形剤の表面に積載される、請求項1~6のいずれか一項に記載の医薬品。
- 前記ステロイドホルモンおよび前記ヘッジホッグシグナル伝達経路モジュレータの両方が、前記多孔性賦形剤の細孔内に位置する前記多孔性賦形剤の表面に積載される、請求項7に記載の医薬品。
- 前記対象が、ヒト、非ヒト霊長類、イヌ、ネコ、ウシ、ヒツジ、ウマ、ウサギ、マウス、またはラットである、請求項1~8のいずれか一項に記載の医薬品。
- 前記対象が、多発性硬化症、筋萎縮性側索硬化症、デビック病、炎症性脱髄疾患、中枢神経系神経障害、橋中心髄鞘崩壊症、脊髄症、脊髄癆、梅毒性脊髄症、進行性多巣性白質脳症のような白質脳症、白質萎縮症、およびアルツハイマー病から選択される中枢神経系の脱髄疾患、または、ギラン・バレー症候群、慢性炎症性脱髄性多発神経障害、抗MAG末梢神経障害、シャルコー・マリー・トゥース病、圧迫性麻痺に易罹病性の遺伝性神経障害、末梢神経障害、脊髄症、視神経症、および進行性炎症性神経障害から選択される末消神経系の脱髄疾患から選択される脱髄疾患に罹患している、請求項1~9のいずれか一項に記載の医薬品。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862616173P | 2018-01-11 | 2018-01-11 | |
US62/616,173 | 2018-01-11 | ||
PCT/IB2019/050198 WO2019138356A1 (en) | 2018-01-11 | 2019-01-10 | Treatment of demyelinating diseases |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2021510372A JP2021510372A (ja) | 2021-04-22 |
JPWO2019138356A5 JPWO2019138356A5 (ja) | 2022-01-17 |
JP7381471B2 true JP7381471B2 (ja) | 2023-11-15 |
Family
ID=65409134
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020537770A Active JP7381471B2 (ja) | 2018-01-11 | 2019-01-10 | 脱髄疾患の治療 |
Country Status (9)
Country | Link |
---|---|
US (3) | US10596181B2 (ja) |
EP (1) | EP3737471A1 (ja) |
JP (1) | JP7381471B2 (ja) |
KR (1) | KR20200116103A (ja) |
CN (1) | CN111902188A (ja) |
CA (1) | CA3087840A1 (ja) |
RU (1) | RU2020126425A (ja) |
SG (1) | SG11202006374VA (ja) |
WO (1) | WO2019138356A1 (ja) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SG11202006374VA (en) | 2018-01-11 | 2020-07-29 | M et P Pharma AG | Treatment of demyelinating diseases |
WO2022174378A1 (zh) * | 2021-02-19 | 2022-08-25 | 骏运投资有限公司 | 痘苗病毒致炎兔皮提取物治疗神经系统脱髓鞘疾病的用途 |
CN112798771B (zh) * | 2021-03-31 | 2021-07-30 | 宝枫生物科技(北京)有限公司 | 用于诊断脑白质病变的生物标志物及其应用 |
CN115177726B (zh) * | 2021-04-01 | 2023-11-28 | 中国科学技术大学 | Gpr34及其抑制剂在制备脱髓鞘相关疾病治疗药物中的用途 |
WO2023086113A1 (en) * | 2021-11-11 | 2023-05-19 | Muhammed Majeed | Compositions for the management of demyelinating disorders |
CN114621924B (zh) * | 2022-04-03 | 2024-05-17 | 中国科学院长春应用化学研究所 | 一种多孔碳球纳米酶掺杂的氢键有机框架壳层及其制备方法 |
KR20230159034A (ko) | 2022-05-13 | 2023-11-21 | 동아대학교 산학협력단 | 탈수초성 말초신경병증의 예방 또는 치료용 약학 조성물 |
WO2024173529A1 (en) * | 2023-02-15 | 2024-08-22 | The Board Of Trustees Of The Leland Stanford Junior University | Enhancing nerve regeneration and repair with a smoothened agonist applied to sites of nerve repair or surgery |
CN117607432B (zh) * | 2024-01-17 | 2024-04-09 | 首都医科大学附属北京地坛医院 | Msr1蛋白及其特异性抗体在制备神经梅毒或神经损伤诊断产品中的应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120082623A1 (en) | 2009-03-30 | 2012-04-05 | Kottmann Andreas H | SHH Regulation and Methods Thereof |
US20150011610A1 (en) | 2012-01-27 | 2015-01-08 | New York University | Method for enhancing remyelination using gli1 inhibitors |
WO2017208209A1 (en) | 2016-06-03 | 2017-12-07 | M et P Pharma AG | Nasal pharmaceutical compositions with a porous excipient |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4760092A (en) | 1985-10-29 | 1988-07-26 | The Rockefeller University | Treatment of demyelinating diseases |
GB8921326D0 (en) | 1989-09-21 | 1989-11-08 | Beecham Group Plc | Novel treatment |
US7192931B2 (en) | 2000-10-12 | 2007-03-20 | Neuren Pharmaceuticals Ltd. | Treatment of demyelinating diseases |
WO2004035086A2 (en) | 2002-10-16 | 2004-04-29 | Hunter Samuel F | Method for treatment of demyelinating central nervous system disease using gm-csf |
PT1530965E (pt) | 2003-11-11 | 2006-05-31 | Udo Mattern | Sistema de administracao de libertacao controlada de hormonas sexuais para aplicacao nasal |
US8784869B2 (en) | 2003-11-11 | 2014-07-22 | Mattern Pharma Ag | Controlled release delivery system for nasal applications and methods of treatment |
US20060140820A1 (en) | 2004-12-28 | 2006-06-29 | Udo Mattern | Use of a container of an inorganic additive containing plastic material |
CN101600417B (zh) | 2006-10-04 | 2012-05-30 | M&P专利股份公司 | 用于神经递质的经鼻施用的控制释放递送系统 |
WO2008096271A2 (en) | 2007-02-08 | 2008-08-14 | Ralf Gold | Neuroprotection in demyelinating diseases |
RU2355413C1 (ru) | 2007-12-06 | 2009-05-20 | Закрытое Акционерное Общество "Биоген Технолоджиз" | Фармацевтическое средство для лечения демиелинизирующих заболеваний нервной системы, средство, способствующее восстановлению миелиновой оболочки нервного волокна, и способ лечения демиелинизирующих заболеваний нервной системы |
FR2924942B1 (fr) | 2007-12-14 | 2012-06-15 | Pf Medicament | Compositions pharmaceutiques transcutanees contenant une hormone steroidienne |
WO2011103389A1 (en) | 2010-02-19 | 2011-08-25 | Cornell University | Method to treat autoimmune demyelinating diseases and other autoimmune or inflammatory diseases |
JP2014508809A (ja) | 2011-03-22 | 2014-04-10 | ザ・ポピュレイション・カウンシル,インコーポレイテッド | アンドロゲンを用いたミエリン再生 |
CN110461340A (zh) | 2017-01-20 | 2019-11-15 | 马特恩制药股份公司 | 用于降低暴露于空气污染物的风险的鼻用药物组合物 |
SG11202006374VA (en) | 2018-01-11 | 2020-07-29 | M et P Pharma AG | Treatment of demyelinating diseases |
-
2019
- 2019-01-10 SG SG11202006374VA patent/SG11202006374VA/en unknown
- 2019-01-10 EP EP19704874.7A patent/EP3737471A1/en active Pending
- 2019-01-10 CA CA3087840A patent/CA3087840A1/en active Pending
- 2019-01-10 KR KR1020207023016A patent/KR20200116103A/ko not_active Application Discontinuation
- 2019-01-10 CN CN201980018285.2A patent/CN111902188A/zh active Pending
- 2019-01-10 RU RU2020126425A patent/RU2020126425A/ru unknown
- 2019-01-10 WO PCT/IB2019/050198 patent/WO2019138356A1/en unknown
- 2019-01-10 JP JP2020537770A patent/JP7381471B2/ja active Active
- 2019-07-09 US US16/506,830 patent/US10596181B2/en active Active
-
2020
- 2020-03-11 US US16/815,969 patent/US10898495B2/en active Active
-
2021
- 2021-01-25 US US17/157,337 patent/US11723911B2/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120082623A1 (en) | 2009-03-30 | 2012-04-05 | Kottmann Andreas H | SHH Regulation and Methods Thereof |
US20150011610A1 (en) | 2012-01-27 | 2015-01-08 | New York University | Method for enhancing remyelination using gli1 inhibitors |
WO2017208209A1 (en) | 2016-06-03 | 2017-12-07 | M et P Pharma AG | Nasal pharmaceutical compositions with a porous excipient |
Non-Patent Citations (2)
Title |
---|
Brain,2013年,Vol.136,pp.132-146 |
PLOS ONE,2015年,Vol.10, e0144550 |
Also Published As
Publication number | Publication date |
---|---|
CN111902188A (zh) | 2020-11-06 |
KR20200116103A (ko) | 2020-10-08 |
US10898495B2 (en) | 2021-01-26 |
WO2019138356A1 (en) | 2019-07-18 |
EP3737471A1 (en) | 2020-11-18 |
US20190328750A1 (en) | 2019-10-31 |
US10596181B2 (en) | 2020-03-24 |
RU2020126425A (ru) | 2022-02-11 |
CA3087840A1 (en) | 2019-07-18 |
US20200206244A1 (en) | 2020-07-02 |
US20210283143A1 (en) | 2021-09-16 |
SG11202006374VA (en) | 2020-07-29 |
JP2021510372A (ja) | 2021-04-22 |
US11723911B2 (en) | 2023-08-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7381471B2 (ja) | 脱髄疾患の治療 | |
Bhat et al. | Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders | |
JP6608309B2 (ja) | Cmt及び関連疾患の処置のための新規な治療的アプローチ | |
JP2020063264A (ja) | 持続性抑制を増加させ、二次性不眠症を治療する方法 | |
CN109310769B (zh) | 用rxr激动剂与甲状腺激素的组合的自身免疫疾病的治疗 | |
KR20200062385A (ko) | Rxr 아고니스트와 갑상선 호르몬의 조합을 사용한 신경계 질환의 치료 | |
JP2018076332A (ja) | (3aR)−1,3a,8−トリメチル−1,2,3,3a,8,8a−ヘキサヒドロピロロ[2,3−b]インドール−5−イルフェニルカルバメートの有効量およびその使用方法 | |
US20100004244A1 (en) | Use of cb2 receptor agonists for promoting neurogenesis | |
JP2023169413A (ja) | 精神病性障害を治療するための方法および組成物 | |
Blázquez et al. | Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination | |
JP6650650B2 (ja) | 神経系疾患治療剤 | |
Wu et al. | IL-10 protects against OPC ferroptosis by regulating lipid reactive oxygen species levels post stroke | |
JP7051693B2 (ja) | PIK3CA関連過成長症候群(PROS CLOVaS症候群)の処置に使用するためのBYL719(アルペリシブ) | |
US20150290176A1 (en) | Use of mtor inhibitors to treat vascular cognitive impairment | |
Al Abadey | Investigating the effects of Kappa opioid receptor agonists on remyelination in a preclinical model of multiple sclerosis | |
Sloan et al. | Diazepam-treated female rats: flumazenil-and PK 11195-induced withdrawal in the hippocampus CA1 | |
WO2023039226A2 (en) | Treatments and methods for treating alzheimer's disease | |
EP4117787A1 (en) | Agents and compositions for the treatment of glioblastoma | |
Lupone et al. | 42nd Annual Meeting of the Society for Neuroscience, New Orleans, Louisiana, USA-October 13-17, 2012 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220106 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220106 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230213 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230329 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230810 |
|
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: 20231005 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20231102 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7381471 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |