JPWO2010027028A1 - 脳機能低下の改善剤 - Google Patents
脳機能低下の改善剤 Download PDFInfo
- Publication number
- JPWO2010027028A1 JPWO2010027028A1 JP2010527818A JP2010527818A JPWO2010027028A1 JP WO2010027028 A1 JPWO2010027028 A1 JP WO2010027028A1 JP 2010527818 A JP2010527818 A JP 2010527818A JP 2010527818 A JP2010527818 A JP 2010527818A JP WO2010027028 A1 JPWO2010027028 A1 JP WO2010027028A1
- Authority
- JP
- Japan
- Prior art keywords
- disorder
- brain function
- acetyl
- mannosamine
- decrease
- 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
- 230000003925 brain function Effects 0.000 title claims abstract description 57
- 230000007423 decrease Effects 0.000 title claims abstract description 40
- 230000006872 improvement Effects 0.000 title claims description 14
- OVRNDRQMDRJTHS-ZTVVOAFPSA-N N-acetyl-D-mannosamine Chemical compound CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-ZTVVOAFPSA-N 0.000 claims abstract description 57
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 33
- 235000013305 food Nutrition 0.000 claims abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 15
- 230000003449 preventive effect Effects 0.000 claims abstract description 14
- 239000003937 drug carrier Substances 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 38
- 208000035475 disorder Diseases 0.000 claims description 35
- 208000026139 Memory disease Diseases 0.000 claims description 22
- 230000006866 deterioration Effects 0.000 claims description 20
- 230000032683 aging Effects 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 19
- 230000002265 prevention Effects 0.000 claims description 18
- 230000007659 motor function Effects 0.000 claims description 10
- 208000027534 Emotional disease Diseases 0.000 claims description 9
- 230000036541 health Effects 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 235000013376 functional food Nutrition 0.000 claims description 5
- 230000003247 decreasing effect Effects 0.000 claims description 4
- 235000013373 food additive Nutrition 0.000 claims description 3
- 239000002778 food additive Substances 0.000 claims description 3
- 230000000069 prophylactic effect Effects 0.000 claims description 2
- 208000017194 Affective disease Diseases 0.000 claims 2
- 208000019022 Mood disease Diseases 0.000 claims 2
- 230000006735 deficit Effects 0.000 claims 1
- 241000699670 Mus sp. Species 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 13
- 206010027175 memory impairment Diseases 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- -1 etc.) Substances 0.000 description 7
- 208000024827 Alzheimer disease Diseases 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 238000007427 paired t-test Methods 0.000 description 6
- 206010012289 Dementia Diseases 0.000 description 5
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 5
- 230000001149 cognitive effect Effects 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 5
- 208000019901 Anxiety disease Diseases 0.000 description 4
- 201000011240 Frontotemporal dementia Diseases 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 230000036506 anxiety Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000012346 open field test Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 3
- 208000009829 Lewy Body Disease Diseases 0.000 description 3
- 201000002832 Lewy body dementia Diseases 0.000 description 3
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 3
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 230000035622 drinking Effects 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 235000013402 health food Nutrition 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 229950006780 n-acetylglucosamine Drugs 0.000 description 3
- 235000016709 nutrition Nutrition 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 239000008399 tap water Substances 0.000 description 3
- 235000020679 tap water Nutrition 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 208000028698 Cognitive impairment Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 2
- 102000048245 N-acetylneuraminate lyases Human genes 0.000 description 2
- 108700023220 N-acetylneuraminate lyases Proteins 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000037023 motor activity Effects 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-CBPJZXOFSA-N 2-amino-2-deoxy-D-mannopyranose Chemical compound N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-CBPJZXOFSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 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
- 206010013710 Drug interaction Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 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
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- OVRNDRQMDRJTHS-OZRXBMAMSA-N N-acetyl-beta-D-mannosamine Chemical compound CC(=O)N[C@@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-OZRXBMAMSA-N 0.000 description 1
- SQVRNKJHWKZAKO-PFQGKNLYSA-N N-acetyl-beta-neuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-PFQGKNLYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010074268 Reproductive toxicity Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- 238000010162 Tukey test Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007665 chronic toxicity Effects 0.000 description 1
- 231100000160 chronic toxicity Toxicity 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- 230000021824 exploration behavior Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007087 memory ability Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 231100000372 reproductive toxicity Toxicity 0.000 description 1
- 230000007696 reproductive toxicity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
- C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
- C07H5/06—Aminosugars
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Pain & Pain Management (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Hospice & Palliative Care (AREA)
- Epidemiology (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Fodder In General (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
〔1〕 N−アセチル−D−マンノサミンを含有してなる、脳機能低下の予防または改善剤。
〔2〕 脳機能低下が老化に伴う脳機能低下である前記〔1〕記載の予防または改善剤。
〔3〕 場所の記憶障害、物体の記憶障害、情動障害および運動機能低下からなる群より選ばれる障害の予防または改善を目的とするものである前記〔1〕または〔2〕に記載の予防または改善剤。
〔4〕 医薬である、前記〔1〕〜〔3〕いずれかに記載の予防または改善剤。
〔5〕 保健機能食品または食品添加物である、前記〔1〕〜〔3〕いずれかに記載の予防または改善剤。
〔6〕 N−アセチル−D−マンノサミンの有効量および医薬として許容されうる担体を含有してなる、脳機能低下に起因する障害を予防、改善または治療するための医薬組成物。
〔7〕 障害が老化に伴う脳機能低下に起因するものである前記〔6〕記載の医薬組成物。
〔8〕 障害が場所の記憶障害、物体の記憶障害、情動障害および運動機能低下からなる群より選ばれる前記〔6〕記載の医薬組成物。
〔9〕 N−アセチル−D−マンノサミンを添加してなる食品。
〔10〕 脳機能低下に起因する障害の予防、改善または治療用医薬を製造するためのN−アセチル−D−マンノサミンの使用。
〔11〕 障害が老化に伴う脳機能低下に起因するものである前記〔10〕記載の使用。
〔12〕 障害が場所の記憶障害、物体の記憶障害、情動障害および運動機能低下からなる群より選ばれる前記〔10〕記載の使用。
〔13〕 N−アセチル−D−マンノサミンの有効量をそれを必要とする対象に投与する工程を含む、脳機能低下に起因する障害の予防、改善または治療方法。
〔14〕 障害が老化に伴う脳機能低下に起因するものである前記〔13〕記載の方法。
〔15〕 障害が場所の記憶障害、物体の記憶障害、情動障害および運動機能低下からなる群より選ばれる前記〔13〕記載の方法。
〔16〕 N−アセチル−D−マンノサミンの有効量をそれを必要とする対象に摂取させる工程を含む、脳機能低下の予防または改善方法。
〔17〕 脳機能低下が老化に伴う脳機能低下である前記〔16〕記載の方法。
〔18〕 場所の記憶障害、物体の記憶障害、情動障害および運動機能低下からなる群より選ばれる障害の予防または改善を目的とするものである前記〔16〕または〔17〕に記載の方法。
〔19〕 前記〔1〕〜〔3〕、〔5〕いずれかに記載の予防または改善剤、および当該予防または改善剤が脳機能低下の予防または改善に使用することができることまたは使用すべきであることを記載した当該予防または改善剤に関する説明を記載した記載物を含む商業用パッケージ。
〔20〕 前記〔6〕〜〔8〕いずれかに記載の医薬組成物、および当該医薬組成物が脳機能低下に起因する障害の予防、改善または治療に使用することができることまたは使用すべきであることを記載した当該医薬組成物に関する説明を記載した記載物を含む商業用パッケージ。
置換基としてはF、Cl、Brを用いることができる。
1)以下の3群の動物(マウス:C57BL6/Njcl、オス)における物体ならびに場所の認知記憶実験を行った。実験の概略を図1に示す。
・老齢対照群:老齢マウス(47週から66週齢まで飼育、n=10)水道水を自由飲水
・老齢ManNAc投与群:老齢マウス(47週から66週齢まで飼育、n=10)水道水にManNAc(5mg/ml)を溶解し自由飲水
・若齢対照群:若齢マウス(8週から18週齢まで飼育、n=10)水道水を自由飲水
2)実験手法:不安傾向、運動活性を調べるOpen field試験を行い、引き続き場所認知記憶試験および物体認知記憶試験を定法に従い行った(図2参照)。
Open field試験(図3):見知らぬ平面空間における移動距離を、老齢マウスと若齢マウスを比較した。老齢マウスで運動活性が低い傾向にあったが、統計的有意差は検出されなかった(One Way ANOVA, p=0.32)。不安傾向の指標となる中央部分に出る時間は、若齢マウスに比較して老齢マウスでは有意に低下し(One way ANOVA with Tukey's post hoc test, p<0.001)、不安傾向の上昇が認められた。老齢マウスにManNAcを投与した場合、この不安傾向の上昇は若干減少する傾向にあるが、統計的有意差は認められなかった。
Claims (20)
- N−アセチル−D−マンノサミンを含有してなる、脳機能低下の予防または改善剤。
- 脳機能低下が老化に伴う脳機能低下である請求項1記載の予防または改善剤。
- 場所の記憶障害、物体の記憶障害、情動障害および運動機能低下からなる群より選ばれる障害の予防または改善を目的とするものである請求項1または2に記載の予防または改善剤。
- 医薬である、請求項1〜3いずれか1項に記載の予防または改善剤。
- 保健機能食品または食品添加物である、請求項1〜3いずれか1項に記載の予防または改善剤。
- N−アセチル−D−マンノサミンの有効量および医薬として許容されうる担体を含有してなる、脳機能低下に起因する障害を予防、改善または治療するための医薬組成物。
- 障害が老化に伴う脳機能低下に起因するものである請求項6記載の医薬組成物。
- 障害が場所の記憶障害、物体の記憶障害、情動障害および運動機能低下からなる群より選ばれる請求項6記載の医薬組成物。
- N−アセチル−D−マンノサミンを添加してなる食品。
- 脳機能低下に起因する障害の予防、改善または治療用医薬を製造するためのN−アセチル−D−マンノサミンの使用。
- 障害が老化に伴う脳機能低下に起因するものである請求項10記載の使用。
- 障害が場所の記憶障害、物体の記憶障害、情動障害および運動機能低下からなる群より選ばれる請求項11記載の方法。
- N−アセチル−D−マンノサミンの有効量をそれを必要とする対象に投与する工程を含む、脳機能低下に起因する障害の予防、改善または治療方法。
- 障害が老化に伴う脳機能低下に起因するものである請求項13記載の方法。
- 障害が場所の記憶障害、物体の記憶障害、情動障害および運動機能低下からなる群より選ばれる請求項13記載の方法。
- N−アセチル−D−マンノサミンの有効量をそれを必要とする対象に摂取させる工程を含む、脳機能低下の予防または改善方法。
- 脳機能低下が老化に伴う脳機能低下である請求項16記載の方法。
- 場所の記憶障害、物体の記憶障害、情動障害および運動機能低下からなる群より選ばれる障害の予防または改善を目的とするものである請求項16または17に記載の方法。
- 請求項1〜3、5いずれか1項に記載の予防または改善剤、および当該予防または改善剤が脳機能低下の予防または改善に使用することができることまたは使用すべきであることを記載した当該予防または改善剤に関する説明を記載した記載物を含む商業用パッケージ。
- 請求項6〜8いずれか1項に記載の医薬組成物、および当該医薬組成物が脳機能低下に起因する障害の予防、改善または治療に使用することができることまたは使用すべきであることを記載した当該医薬組成物に関する説明を記載した記載物を含む商業用パッケージ。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010527818A JP5553168B2 (ja) | 2008-09-04 | 2009-09-03 | 脳機能低下の改善剤 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008226858 | 2008-09-04 | ||
JP2008226858 | 2008-09-04 | ||
PCT/JP2009/065438 WO2010027028A1 (ja) | 2008-09-04 | 2009-09-03 | 脳機能低下の改善剤 |
JP2010527818A JP5553168B2 (ja) | 2008-09-04 | 2009-09-03 | 脳機能低下の改善剤 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPWO2010027028A1 true JPWO2010027028A1 (ja) | 2012-02-02 |
JP5553168B2 JP5553168B2 (ja) | 2014-07-16 |
Family
ID=41797194
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010527818A Active JP5553168B2 (ja) | 2008-09-04 | 2009-09-03 | 脳機能低下の改善剤 |
Country Status (2)
Country | Link |
---|---|
JP (1) | JP5553168B2 (ja) |
WO (1) | WO2010027028A1 (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110301103A1 (en) * | 2010-06-05 | 2011-12-08 | Chugh Sumant S | Methods of Treatment |
WO2013047773A1 (ja) | 2011-09-29 | 2013-04-04 | 国立大学法人 東京大学 | オレキシンニューロンの誘導法 |
US9480695B2 (en) | 2011-09-29 | 2016-11-01 | The University Of Tokyo | Methods for inducing orexin neurons and agent for treating narcolepsy or eating disorder |
EP3143999A4 (en) * | 2014-05-16 | 2017-12-20 | The University of Tokyo | Depression treatment agent |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3935906A1 (de) * | 1989-10-27 | 1991-05-02 | Reutter Werner | Verwendung von galaktose zur (par)enteralen ernaehrung und versorgung in der intensivmedizin sowie hierzu geeignete praeparationen |
JP4044630B2 (ja) * | 1996-05-16 | 2008-02-06 | 雪印乳業株式会社 | 脳機能改善剤 |
WO2000007602A1 (en) * | 1998-08-06 | 2000-02-17 | The Johns Hopkins University School Of Medicine | Compounds for altering cell surface sialic acids and methods of use therefor |
MXPA05008216A (es) * | 2003-01-31 | 2005-10-05 | Procter & Gamble | Medios para mejorar la apariencia del tejido queratinoso mamifero. |
-
2009
- 2009-09-03 JP JP2010527818A patent/JP5553168B2/ja active Active
- 2009-09-03 WO PCT/JP2009/065438 patent/WO2010027028A1/ja active Application Filing
Also Published As
Publication number | Publication date |
---|---|
JP5553168B2 (ja) | 2014-07-16 |
WO2010027028A1 (ja) | 2010-03-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI584805B (zh) | Prevention and treatment of influenza virus infectious diseases | |
WO2007119578A1 (ja) | 神経系細胞機能改善剤 | |
JP5553168B2 (ja) | 脳機能低下の改善剤 | |
WO2014080973A1 (ja) | 抗認知症および学習記憶改善剤 | |
US20200384001A1 (en) | Composition for prevention or treatment of neuroinflammatory disease, containing protein tyrosine phosphatase | |
US9271995B2 (en) | Agent for ameliorating brain hypofunction | |
CN106031725B (zh) | 荷叶碱和其类似物的药物应用 | |
JP2012025712A (ja) | 抗不安組成物 | |
KR20160088886A (ko) | 자폐증 스펙트럼 장애의 치료에 사용되는 도파민 d3 수용체 길항제로서의 크로모네 유도체 | |
KR101754451B1 (ko) | Pcaf 저해제를 유효성분으로 함유하는 퇴행성 뇌질환의 예방 및 치료용 조성물 | |
JP5557243B2 (ja) | 睡眠の改善剤 | |
JP7490064B2 (ja) | リスリード化合物を有効成分として含む脆弱x症候群または関連発達障害治療用組成物 | |
KR20230010217A (ko) | Nr 및/또는 nmn과 세사민류를 함유하는 조성물 | |
JP6323886B2 (ja) | うつ治療剤 | |
WO2014148136A1 (ja) | 抗アレルギー活性化合物及びその用途 | |
JP2021078397A (ja) | 脂質減少促進剤 | |
CA2933018C (en) | Therapeutic or prophylactic agent for multiple sclerosis | |
JP2015137243A (ja) | 脳内アミノ酸量の調整剤 | |
US20240156776A1 (en) | Compositions and methods for the treatment of plasmodium falciparum malaria | |
WO2019146652A1 (ja) | 抗i型アレルギー剤、及び肥満細胞又は好塩基球の脱顆粒抑制剤、並びに抗認知症剤、及び短期記憶障害改善/抑制剤 | |
US10787426B2 (en) | Method of treating autism spectrum disorders using piperazine-1-carboxamidine or pharmaceutically acceptable salt thereof | |
JP6342349B2 (ja) | 血中尿酸低減剤および医薬品 | |
KR20200031582A (ko) | 아그마틴 및 이의 약학적으로 허용 가능한 염을 포함하는 취약 x 증후군 예방 또는 치료용 약학조성물 | |
CN115998767A (zh) | 金属锰在制备治疗、预防或者改善抑郁症药物中的应用 | |
KR20210029739A (ko) | 피렌페론 화합물을 유효성분으로 포함하는 취약 x 증후군 및 관련 발달 장애치료용 조성물 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20120827 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20120827 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20131224 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140221 |
|
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: 20140415 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20140514 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5553168 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 |
|
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 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |