WO2013122188A1 - 血管内皮機能低下の予防または改善剤 - Google Patents
血管内皮機能低下の予防または改善剤 Download PDFInfo
- Publication number
- WO2013122188A1 WO2013122188A1 PCT/JP2013/053661 JP2013053661W WO2013122188A1 WO 2013122188 A1 WO2013122188 A1 WO 2013122188A1 JP 2013053661 W JP2013053661 W JP 2013053661W WO 2013122188 A1 WO2013122188 A1 WO 2013122188A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- salt
- citrulline
- glutathione
- vascular endothelial
- agent
- Prior art date
Links
- 230000003511 endothelial effect Effects 0.000 title abstract 5
- 230000007257 malfunction Effects 0.000 title abstract 5
- 230000002792 vascular Effects 0.000 title abstract 5
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims abstract description 117
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 claims abstract description 81
- 229960002173 citrulline Drugs 0.000 claims abstract description 65
- 108010024636 Glutathione Proteins 0.000 claims abstract description 64
- 150000003839 salts Chemical class 0.000 claims abstract description 57
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 claims abstract description 53
- 235000013477 citrulline Nutrition 0.000 claims abstract description 53
- 229960003180 glutathione Drugs 0.000 claims abstract description 43
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 33
- 208000024891 symptom Diseases 0.000 claims abstract description 32
- 238000004519 manufacturing process Methods 0.000 claims abstract description 27
- 239000004480 active ingredient Substances 0.000 claims abstract description 14
- 230000017531 blood circulation Effects 0.000 claims abstract description 12
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 11
- 208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 11
- 208000023589 ischemic disease Diseases 0.000 claims abstract description 7
- 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 5
- 208000010228 Erectile Dysfunction Diseases 0.000 claims abstract description 5
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims abstract description 5
- 201000001881 impotence Diseases 0.000 claims abstract description 5
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 5
- 210000002027 skeletal muscle Anatomy 0.000 claims abstract description 5
- 230000008961 swelling Effects 0.000 claims abstract description 5
- 239000003623 enhancer Substances 0.000 claims abstract description 3
- 230000003845 vascular endothelial function Effects 0.000 claims description 26
- 230000003449 preventive effect Effects 0.000 claims description 22
- 230000003247 decreasing effect Effects 0.000 claims description 15
- 230000007423 decrease Effects 0.000 claims description 14
- 230000000694 effects Effects 0.000 claims description 13
- 230000002708 enhancing effect Effects 0.000 abstract description 6
- 230000001976 improved effect Effects 0.000 abstract description 2
- 206010011953 Decreased activity Diseases 0.000 abstract 1
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 48
- 238000002360 preparation method Methods 0.000 description 21
- 238000000034 method Methods 0.000 description 14
- 108010053070 Glutathione Disulfide Proteins 0.000 description 13
- YPZRWBKMTBYPTK-BJDJZHNGSA-N glutathione disulfide Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@H](C(=O)NCC(O)=O)CSSC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O YPZRWBKMTBYPTK-BJDJZHNGSA-N 0.000 description 13
- YPZRWBKMTBYPTK-UHFFFAOYSA-N oxidized gamma-L-glutamyl-L-cysteinylglycine Natural products OC(=O)C(N)CCC(=O)NC(C(=O)NCC(O)=O)CSSCC(C(=O)NCC(O)=O)NC(=O)CCC(N)C(O)=O YPZRWBKMTBYPTK-UHFFFAOYSA-N 0.000 description 13
- -1 inorganic acid salts Chemical class 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 235000013361 beverage Nutrition 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 229940058015 1,3-butylene glycol Drugs 0.000 description 4
- 239000004475 Arginine Substances 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 4
- 235000019437 butane-1,3-diol Nutrition 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 210000003556 vascular endothelial cell Anatomy 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229930006000 Sucrose Natural products 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
- 239000006071 cream Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 239000003205 fragrance Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen 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
- RHGKLRLOHDJJDR-SCSAIBSYSA-N D-citrulline Chemical compound OC(=O)[C@H](N)CCCNC(N)=O RHGKLRLOHDJJDR-SCSAIBSYSA-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
- 108010010803 Gelatin Proteins 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical class OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 239000004373 Pullulan Substances 0.000 description 2
- 229920001218 Pullulan Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000006229 amino acid addition Effects 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 229960005261 aspartic acid Drugs 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 229950008138 carmellose Drugs 0.000 description 2
- 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 2
- 229920001436 collagen Polymers 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000314 lubricant Substances 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
- 229940049920 malate Drugs 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Chemical class 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 229920001542 oligosaccharide Polymers 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 2
- 235000019423 pullulan Nutrition 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet 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
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- PJVXUVWGSCCGHT-ZPYZYFCMSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;(3s,4r,5r)-1,3,4,5,6-pentahydroxyhexan-2-one Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO PJVXUVWGSCCGHT-ZPYZYFCMSA-N 0.000 description 1
- DROVUXYZTXCEBX-WCCKRBBISA-N (2s)-2-amino-5-(carbamoylamino)pentanoic acid;2-hydroxybutanedioic acid Chemical compound OC(=O)C(O)CC(O)=O.OC(=O)[C@@H](N)CCCNC(N)=O DROVUXYZTXCEBX-WCCKRBBISA-N 0.000 description 1
- BWSWZBCSFZAYOB-CABCVRRESA-N (2s,4r)-1-dodecanoyl-4-hydroxypyrrolidine-2-carboxylic acid Chemical compound CCCCCCCCCCCC(=O)N1C[C@H](O)C[C@H]1C(O)=O BWSWZBCSFZAYOB-CABCVRRESA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical compound CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 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 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241001071795 Gentiana Species 0.000 description 1
- 240000004670 Glycyrrhiza echinata Species 0.000 description 1
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical class OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 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 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Chemical class NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Chemical class 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 238000001467 acupuncture Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000002929 anti-fatigue Effects 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Chemical class OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 239000004227 calcium gluconate Substances 0.000 description 1
- 229960004494 calcium gluconate Drugs 0.000 description 1
- 235000013927 calcium gluconate Nutrition 0.000 description 1
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
- 239000001527 calcium lactate Substances 0.000 description 1
- 229960002401 calcium lactate Drugs 0.000 description 1
- 235000011086 calcium lactate Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 1
- SHZIWNPUGXLXDT-UHFFFAOYSA-N caproic acid ethyl ester Natural products CCCCCC(=O)OCC SHZIWNPUGXLXDT-UHFFFAOYSA-N 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000012262 fermentative production Methods 0.000 description 1
- CADNYOZXMIKYPR-UHFFFAOYSA-B ferric pyrophosphate Chemical compound [Fe+3].[Fe+3].[Fe+3].[Fe+3].[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O CADNYOZXMIKYPR-UHFFFAOYSA-B 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000002443 hepatoprotective effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 150000005165 hydroxybenzoic acids Chemical class 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940010454 licorice Drugs 0.000 description 1
- 229940069445 licorice extract Drugs 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
- 229940005654 nitrite ion Drugs 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 108010071584 oxidized low density lipoprotein Proteins 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Chemical class OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 235000008729 phenylalanine Nutrition 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 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
- 235000013599 spices Nutrition 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000004218 vascular function Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 230000002883 vasorelaxation effect Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
- A61K38/063—Glutathione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to a preventive or ameliorating agent for reducing vascular endothelial function, which contains citrulline or a salt thereof and glutathione or a salt thereof as an active ingredient and has a higher nitric oxide (NO) production enhancing action.
- a preventive or ameliorating agent for reducing vascular endothelial function which contains citrulline or a salt thereof and glutathione or a salt thereof as an active ingredient and has a higher nitric oxide (NO) production enhancing action.
- NO nitric oxide
- Citrulline is a kind of amino acid that is not used as a raw material for protein synthesis in vivo but exists in a free state. In the body, it plays an important role as a component of the NO cycle related to arginine biosynthesis and supply of NO as an arginine precursor.
- NO produced from vascular endothelial cells has various physiological activities to maintain normal vascular functions such as vasorelaxant action, oxidized LDL inhibitory action, platelet aggregation inhibitory action, anti-smooth muscle cell proliferation action, and antioxidant action.
- Arteriosclerosis is a state in which the elasticity of the blood vessel wall has decreased due to an increased inflammatory reaction in the intima of the blood vessel and accumulation of cholesterol. This makes it difficult to maintain a smooth blood flow and facilitates the formation of thrombus.
- many studies have pointed out a decrease in NO produced from vascular endothelial cells. That is, by enhancing NO production from vascular endothelial cells, it can be expected to prevent or ameliorate ischemic vascular disease caused by a decrease in vascular endothelial function such as arteriosclerosis and promote blood flow.
- Citrulline has been reported to have an anti-arteriosclerosis effect and a blood flow improvement effect through the production of NO, which is a vasodilator, by ingestion of citrulline (Non-Patent Document 1). It is used mainly in the United States. Citrulline is also used in Europe in the form of citrulline-malate as an anti-fatigue drug.
- Glutathione is a tripeptide composed of glutamic acid, cysteine, and glycine, and plays a central role in the removal mechanism of reactive oxygen species in vivo. It is also involved in a detoxification mechanism that removes foreign substances from the body.
- Non-patent document 2 hepatoprotective action
- Non-patent document 3 whitening effect
- glutathione is used as an antidote for poisoning, a drug for improving liver function, or a food material for antioxidant use.
- the NO production promoting action by glutathione is not known, and it is not known that a synergistic NO production enhancing effect can be obtained by combining glutathione and its salt with citrulline or its salt.
- the object of the present invention is to reduce the vascular endothelial function having a higher NO production enhancing action and symptoms related to arteriosclerosis that develops from the decrease in the vascular endothelial function (such as myocardial infarction, angina pectoris, peripheral artery occlusion, etc.). It is to provide a preventive or ameliorating agent for symptoms related to decreased blood flow (such as ischemic diseases) or symptoms related to decreased blood flow (such as stiff shoulders, coldness, swelling, erectile dysfunction, rough skin, decreased skeletal muscle activity, etc.).
- the present invention relates to the following (1) to (7): (1) a citrulline or a salt thereof, and a NO production enhancer containing glutathione or a salt thereof as active ingredients. (2) A preventive or ameliorating agent for reducing vascular endothelial function, comprising citrulline or a salt thereof and glutathione or a salt thereof as an active ingredient. (3) A preventive or ameliorating agent for symptoms resulting from a decrease in vascular endothelial function, containing citrulline or a salt thereof and glutathione or a salt thereof as an active ingredient.
- the prevention according to (4), wherein the symptom associated with decreased blood flow is at least one symptom selected from stiff shoulders, coldness, swelling, erectile dysfunction, rough skin, and decreased exercise performance due to decreased skeletal muscle activity or Improver.
- a safe and effective preventive or ameliorating agent for reducing vascular endothelial function having a higher NO production enhancing action containing citrulline or a salt thereof and glutathione or a salt thereof as an active ingredient can be provided. .
- FIG. 1 shows the concentration of nitrite ion Nitrite (NO 2 ), which is a stable NO metabolite in the medium after adding each concentration of sample to HUVEC.
- Mean + -SEM, N 4, * indicates a significant difference of P ⁇ 0.05.
- Citrulline used in the present invention includes L-citrulline and D-citrulline, with L-citrulline being preferred.
- Citrulline can be obtained by a chemical synthesis method, a fermentation production method, or the like.
- Citrulline can also be obtained by purchasing a commercial product. Examples of methods for chemically synthesizing citrulline include the methods described in J. Biol. Chem., 122, 477 (1938), J. Org. Chem., 6, 410 (1941). Examples of the method for fermentative production of L-citrulline include the methods described in JP-A-53-075387 and JP-A-63-068091. L-citrulline and D-citrulline can also be purchased from Sigma-Aldrich.
- citrulline salts include acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
- Acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, malate, lactate, ⁇ -ketoglutarate And organic acid salts such as gluconate and caprylate.
- metal salt examples include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt.
- alkali metal salts such as sodium salt and potassium salt
- alkaline earth metal salts such as magnesium salt and calcium salt
- aluminum salt and zinc salt examples include zinc salt.
- ammonium salts include salts such as ammonium and tetramethylammonium.
- organic amine addition salts examples include morpholine and piperidine salts.
- amino acid addition salts include salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid and the like.
- citrulline salts malate is preferably used, but other salts or two or more salts may be used in appropriate combination.
- glutathione used in the present invention examples include reduced glutathione or oxidized glutathione.
- Reduced glutathione represents a tripeptide having a structure of ⁇ -L-Glu-L-Cys-Gly, and oxidized glutathione represents a molecule in which two molecules of reduced glutathione are bound by an SS bond.
- the reduced glutathione and oxidized glutathione used in the present invention may be obtained by any production method.
- Methods for producing reduced glutathione include extraction methods from microorganisms such as yeast [Methods in Enzymology, 3, 603 (1957)], chemical synthesis methods [Bull.Chem. Soc. Jpn., 53, 2529 (1980)]
- methods for producing oxidized glutathione such as the enzymatic method (Japanese Patent Laid-Open No. Sho 61-74595), include the methods described in Acta Biochim. Pol., 17, 175 (1970).
- Reduced glutathione and oxidized glutathione can also be purchased from Sigma-Aldrich.
- the agent for preventing or improving the decrease in vascular endothelial function of the present invention may contain either reduced glutathione or oxidized glutathione alone, or may contain reduced glutathione and oxidized glutathione simultaneously.
- the reduced glutathione and oxidized glutathione contained in the preventive or ameliorating agent for vascular endothelial function lowering of the present invention may be present in the agent as salts thereof.
- the salt of reduced glutathione and oxidized glutathione include the same salts as the above citrulline salts.
- a substance that is metabolized to reduced glutathione in vivo such as N-acetylcysteine, can be used in place of glutathione.
- composition ratio of citrulline or a salt thereof and glutathione or a salt thereof in the preventive or ameliorating agent for vascular endothelial function of the present invention is 1: 100 to 100: 1, preferably 1:50 to 50: 1 by weight. Particularly preferred is 10: 1 to 1:10.
- Citrulline or a salt thereof and glutathione or a salt thereof can be administered as they are as the preventive or ameliorating agent for reducing vascular endothelial function of the present invention, but it is usually desirable to provide them as various preparations.
- the preparation contains citrulline or a salt thereof and glutathione or a salt thereof as active ingredients, but may further contain any active ingredient.
- These preparations are produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmacologically acceptable carriers.
- the dosage form of the preparation is desirably the most effective in preventing or improving the decrease in vascular endothelial function, and can include oral administration or parenteral administration such as intravenous, intraperitoneal or subcutaneous administration. However, oral administration is preferred.
- dosage forms to be administered include tablets, powders, granules, pills, suspensions, emulsions, soaking and decoction, capsules, syrups, solutions, elixirs, extracts, tinctures, fluid extracts, etc.
- parenteral preparations such as oral preparations, injection preparations, instillation preparations, cream preparations, and suppositories may be used, but they are preferably used as oral preparations.
- Liquid preparations such as syrups suitable for oral administration include saccharides such as water, sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil and soybean oil, p -Preservatives such as hydroxybenzoic acid esters, paraoxybenzoic acid derivatives such as methyl paraoxybenzoate, preservatives such as sodium benzoate, and flavors such as strawberry flavor and peppermint can be added to prepare a preparation.
- saccharides such as water, sucrose, sorbitol and fructose
- glycols such as polyethylene glycol and propylene glycol
- oils such as sesame oil, olive oil and soybean oil
- p -Preservatives such as hydroxybenzoic acid esters, paraoxybenzoic acid derivatives such as methyl paraoxybenzoate, preservatives such as sodium benzoate, and flavors such as strawberry flavor and peppermint can be added to prepare a preparation
- Also suitable for oral administration are lactose, sucrose, glucose, sucrose, saccharides such as mannitol, sorbitol, starches such as potato, wheat, corn, calcium carbonate, calcium sulfate, hydrogen carbonate Inorganic substances such as sodium and sodium chloride, excipients such as crystalline cellulose, licorice powder, gentian powder, etc., starch, agar, gelatin powder, crystalline cellulose, carmellose sodium, carmellose calcium, calcium carbonate, sodium bicarbonate , Disintegrants such as sodium alginate, magnesium stearate, talc, hydrogenated vegetable oil, macrogol, silicone oil and other lubricants, polyvinyl alcohol, hydroxypropylcellulose, methylcellulose, ethylcellulose, carmellose, gelatin, starch Binders glue solution and the like, surfactants such as fatty acid esters can be formulated by adding a plasticizer such as glycerin.
- a plasticizer such as glycerin.
- preparations suitable for oral administration include additives generally used in foods and drinks such as sweeteners, coloring agents, preservatives, thickening stabilizers, antioxidants, color formers, bleaches, fungicides, gum bases.
- Sweeteners such as sweeteners, coloring agents, preservatives, thickening stabilizers, antioxidants, color formers, bleaches, fungicides, gum bases.
- Bitterings enzymes, brighteners, acidulants, seasonings, emulsifiers, fortifiers, manufacturing agents, fragrances, spice extracts and the like may be added.
- injections preferably consist of a sterile aqueous preparation containing citrulline or a salt thereof that is isotonic with the blood of the recipient, and glutathione or a salt thereof.
- a solution for injection is prepared using a carrier such as a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution.
- Auxiliary ingredients can be added.
- citrulline or a salt thereof and glutathione or a salt thereof in the preventive or ameliorating agent for vascular endothelial function of the present invention is appropriately selected according to the type of preparation, the effect expected by administration of the preparation, etc.
- Citrulline or a salt thereof is usually 0.1 to 100% by weight, preferably 0.5 to 80% by weight, particularly preferably 1 to 70% by weight.
- the dose and frequency of administration in the preventive or ameliorating agent for vascular endothelial function of the present invention vary depending on the administration form, patient age, body weight, nature or severity of symptoms to be treated, Citrulline or a salt thereof, and glutathione or a salt thereof are usually administered once to several times a day so as to be 50 mg to 30 g, preferably 100 mg to 10 g, particularly preferably 200 mg to 3 g.
- the administration period is not particularly limited, but is usually 1 day to 1 year, preferably 1 week to 3 months.
- the agent for preventing or improving the decrease in vascular endothelial function of the present invention can be used for preventing or improving the decrease in vascular endothelial function through NO production.
- the preventive or ameliorating agent for reducing vascular endothelial function of the present invention is used for preventing or ameliorating a symptom related to arteriosclerosis resulting from a decrease in vascular endothelial function or preventing or ameliorating a symptom related to decreased blood flow. be able to.
- Examples of effects expected from the prevention or improvement of symptoms related to arteriosclerosis that develop from a decrease in vascular endothelial function include prevention or improvement of ischemic diseases such as myocardial infarction, angina pectoris, and peripheral artery occlusion, or Examples of effects expected from the prevention or improvement of symptoms related to decreased blood flow include prevention or improvement of exercise performance deterioration due to stiff shoulders, coldness, swelling, erectile dysfunction, rough skin, and decreased skeletal muscle activity.
- the symptom can be improved by administering the agent for preventing or improving the decrease in vascular endothelial function of the present invention to a person who exhibits those symptoms.
- citrulline or a salt thereof, and glutathione or a salt thereof can be used to produce a preventive or ameliorating agent for reducing vascular endothelial function.
- the present invention includes a method for increasing NO.
- the methods of the present invention comprise administering to a subject in need of increasing NO an amount of citrulline or a salt thereof, and glutathione or a salt thereof sufficient to increase the subject's NO.
- Test Example As a normal human umbilical vein endothelial cell (HUVEC), a strain derived from Clonetics (San Diego, CA, USA) was used, and an EGM-2 Bullet Kit (Takara Bio Inc.) containing 2% FBS was used as a medium. The cells were cultured in a 37 ° C., 5% CO 2 incubator, and the cells were used for experiments after 4 to 6 generations. Citrulline and reduced glutathione were manufactured by Kyowa Hakko Bio.
- a cell suspension containing an initial cell concentration adjusted to 5 ⁇ 10 5 cells / mL was seeded in a 24-well plate (IWAKI) in an amount of 0.45 mL.
- citrulline final concentration 0.3 mM: citrulline group
- reduced glutathione final concentration 1 mM: high-dose glutathione group
- a mixture of citrulline and reduced glutathione citrulline final concentration 0.3 mM, and glutathione final
- the medium was replaced with a concentration of 0.3 mM: citrulline + low dose glutathione group).
- the culture medium which added only the solvent (PBS) was used for the control group.
- citrulline's NO production action is known, as shown in FIG. 1, the citrulline group and the high-dose glutathione group were in a range that did not affect the NO production alone, as shown in FIG. .
- the NO level was about 31% higher than the control group, which significantly promoted NO production activity. The effect was recognized. From this, it is clear that the combined use of citrulline and glutathione synergistically promotes NO production activity without affecting the survival rate and proliferation ability of vascular endothelial cells. It has been shown to be a preventive or ameliorating agent for reducing vascular endothelial function.
- enteric tablet containing citrulline and glutathione An enteric tablet is produced by coating the surface of the tablet produced in Example 1 with shellac solution.
- a cream containing citrulline and glutathione Polyethylene glycol (PGE55), 2.00% by weight of monostearate, 5.00% by weight of glyceryl monostearate, 4.00% by weight of cetyl alcohol, 6.00% by weight of squalane, triethyl 2-ethylhexanoate
- a cream is prepared by blending 6.00% by weight of glyceryl, 7.00% by weight of 1,3-butylene glycol, 3.00% by weight of L-histidine, 1.00% by weight of L-citrulline, 1.00% by weight of reduced glutathione, and 66.00% by weight of purified water.
- a lotion is prepared by adding 0.05% by weight of acid, 0.20% by weight of licorice extract, 3.00% by weight of 1,3-butylene glycol and 91.65% by weight of purified water.
- a beauty solution is prepared by blending 6.0% by weight of glycol, 4.0% by weight of concentrated glycerin, 5.0% by weight of sodium hyaluronate (1% aqueous solution) and 69.0% by weight of purified water.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Neurology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Diabetes (AREA)
- Gynecology & Obstetrics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Dermatology (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
(1)シトルリンまたはその塩、およびグルタチオンまたはその塩を有効成分として含有するNO産生増強剤。
(2)シトルリンまたはその塩、およびグルタチオンまたはその塩を有効成分として含有する血管内皮機能低下の予防または改善剤。
(3)シトルリンまたはその塩、およびグルタチオンまたはその塩を有効成分として含有する血管内皮機能低下から生じる症状の予防または改善剤。
(4)血管内皮機能低下から生じる症状が、動脈硬化に関連する症状、血流低下に関連する症状より選ばれる少なくとも一つの症状である、(3)に記載の予防または改善剤。
(5)動脈硬化に関連する症状が虚血性疾患である、(4)に記載の予防または改善剤。
(6)虚血性疾患が、心筋梗塞、狭心症、末梢動脈閉塞より選ばれる少なくとも一つの症状である、(5)に記載の予防または改善剤。
(7)血流低下に関連する症状が、肩凝り、冷え症、むくみ、***不全、肌荒れ、骨格筋活動低下による運動パフォーマンス低下より選ばれる少なくとも一つの症状である、(4)に記載の予防または改善剤。
アンモニウム塩としては、アンモニウム、テトラメチルアンモニウム等の塩があげられる。
L-シトルリン120kg、還元型グルタチオン120kg、環状オリゴ糖19kg、セルロース57kgおよびプルラン1kgを流動層造粒乾燥機で造粒した。得られた造粒物とステアリン酸カルシウム3kgとをコニカルブレンダーで混合した後、ロータリー圧縮成形機で圧縮成形して錠剤を製造する。
実施例1で製造する錠剤の表面をシェラック溶液でコーティングして腸溶錠剤を製造する。
L-シトルリン120kg、還元型グルタチオン120kg、環状オリゴ糖19kg、セルロース57kg、ステアリン酸カルシウム3kgおよびプルラン1kgを、コニカルブレンダーで混合する。得られる混合物20kgと0.2kgの二酸化ケイ素とを混合攪拌して得られた混合物をカプセル充填機に投入、ハードカプセルに充填してハードカプセルを得る。得られるハードカプセルの表面をツェイン溶液でコーティングして腸溶カプセルを製造する。
L-シトルリン1.28kg、酸化型グルタチオン1.28kg、エリスリトール3kg、クエン酸0.05kg、人工甘味料3g、香料0.06kgを液温70℃で水50Lに攪拌溶解し、クエン酸でpHを3.3に調整後、プレート殺菌を用いて滅菌して瓶に充填後、パストライザー殺菌し、飲料を製造する。
シトルリン20mg、酸化型グルタチオン20mg、アルギニン20mgと適当量の果糖ぶどう糖液糖、食塩、クエン酸、香料、クエン酸Na、乳酸Ca、ピロリン酸鉄、グルコン酸Ca、塩化K、塩化Mg、甘味料とを配合し555mlの飲料を製造する。
シトルリン100mg、酸化型グルタチオン100mg、アルギニン100mg、アラニン2.5mg、グリシン2.5mg、ロイシン 2.5mg、イソロイシン 1.3mg、バリン 1.3mgと適当量の香料、甘味料を配合し300mlの飲料を製造する。
エタノール10.0重量%、L-シトルリン2.0重量%、還元型グルタチオン2.0重量%、1,3-ブチレングリコール5.0重量%、精製水83.0重量%を配合し化粧水を製造する。
ポリエチレングリコール(PGE55)、モノステアレート2.00重量%、自己乳化型モノステアリン酸グリセリン5.00重量%、セチルアルコール4.00重量%、スクワラン 6.00重量%、2-エチルヘキサン酸トリグリセリル6.00重量%、1,3-ブチレングリコール7.00重量%、L-ヒスチジン3.00重量%、L-シトルリン1.00重量%、還元型グルタチオン1.00重量%、精製水66.00重量%を配合しクリームを製造する。
L-シトルリン3.00重量%、酸化型グルタチオン3.00重量%、L-セリン1.00重量%、水溶性コラーゲン(1%水溶液)1.00重量%、クエン酸ナトリウム0.10重量%、クエン酸0.05重量%、甘草エキス0.20重量%、1,3-ブチレングリコール3.00重量%、精製水91.65重量%を配合しローションを製造する。
ポリビニールアルコール13.00重量%、L-アスパラギン酸1.00重量%、L-シトルリン5.00重量%、還元型グルタチオン5.00重量%、ラウロイルヒドロキシプロリン1.00重量%、水溶性コラーゲン (1%水溶液)2.00重量%、1,3-ブチレングリコール3.00重量%、エタノール5.00重量%、精製水70.00重量%を配合しパックを製造する。
ヒドロキシエチルセルロース(2%水溶液)12.0重量%、キサンタンガム(2%水溶液) 2.0重量%、L-シトルリン2.0重量%、還元型グルタチオン2.0重量%、1,3-ブチレングリコール6.0重量%、濃グリセリン4.0重量%、ヒアルロン酸ナトリウム(1%水溶液)5.0重量%、精製水69.0重量%を配合し美溶液を製造する。
Claims (7)
- シトルリンまたはその塩、およびグルタチオンまたはその塩を有効成分として含有するNO産生増強剤。
- シトルリンまたはその塩、およびグルタチオンまたはその塩を有効成分として含有する血管内皮機能低下の予防または改善剤。
- シトルリンまたはその塩、およびグルタチオンまたはその塩を有効成分として含有する血管内皮機能低下から生じる症状の予防または改善剤。
- 血管内皮機能低下から生じる症状が、動脈硬化に関連する症状、血流低下に関連する症状より選ばれる少なくとも一つの症状である、請求項3に記載の予防または改善剤。
- 動脈硬化に関連する症状が虚血性疾患である、請求項4に記載の予防または改善剤。
- 虚血性疾患が、心筋梗塞、狭心症、末梢動脈閉塞より選ばれる少なくとも一つの症状である、請求項5に記載の予防または改善剤。
- 血流低下に関連する症状が、肩凝り、冷え症、むくみ、***不全、肌荒れ、骨格筋活動低下による運動パフォーマンス低下より選ばれる少なくとも一つの症状である、請求項4に記載の予防または改善剤。
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES13748698T ES2761224T3 (es) | 2012-02-15 | 2013-02-15 | Agente para prevenir o mejorar la disfunción vascular endotelial |
AU2013219258A AU2013219258B2 (en) | 2012-02-15 | 2013-02-15 | Agent for preventing or ameliorating vascular endothelial malfunction |
EP13748698.1A EP2815760B1 (en) | 2012-02-15 | 2013-02-15 | Agent for preventing or ameliorating vascular endothelial malfunction |
US14/379,147 US20150011463A1 (en) | 2012-02-15 | 2013-02-15 | Agent for preventing or ameliorating vascular endothelial malfunction |
JP2013558748A JP6151646B2 (ja) | 2012-02-15 | 2013-02-15 | 血管内皮機能低下の予防または改善剤 |
US14/686,209 US20150216925A1 (en) | 2012-02-15 | 2015-04-14 | Agent for preventing or ameliorating vascular endothelial malfunction |
US15/188,359 US20160296586A1 (en) | 2012-02-15 | 2016-06-21 | Agent for preventing or ameliorating vascular endothelial malfunction |
US15/334,600 US20170042962A1 (en) | 2012-02-15 | 2016-10-26 | Agent for preventing or ameliorating vascular endothelial malfunction |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2012030849 | 2012-02-15 | ||
JP2012-030849 | 2012-02-15 |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/379,147 A-371-Of-International US20150011463A1 (en) | 2012-02-15 | 2013-02-15 | Agent for preventing or ameliorating vascular endothelial malfunction |
US14/686,209 Continuation-In-Part US20150216925A1 (en) | 2012-02-15 | 2015-04-14 | Agent for preventing or ameliorating vascular endothelial malfunction |
US15/188,359 Division US20160296586A1 (en) | 2012-02-15 | 2016-06-21 | Agent for preventing or ameliorating vascular endothelial malfunction |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2013122188A1 true WO2013122188A1 (ja) | 2013-08-22 |
Family
ID=48984297
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2013/053661 WO2013122188A1 (ja) | 2012-02-15 | 2013-02-15 | 血管内皮機能低下の予防または改善剤 |
Country Status (6)
Country | Link |
---|---|
US (2) | US20150011463A1 (ja) |
EP (1) | EP2815760B1 (ja) |
JP (1) | JP6151646B2 (ja) |
AU (1) | AU2013219258B2 (ja) |
ES (1) | ES2761224T3 (ja) |
WO (1) | WO2013122188A1 (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014112641A1 (ja) * | 2013-01-21 | 2014-07-24 | 協和発酵バイオ株式会社 | 一酸化窒素濃度上昇剤 |
JP5888574B1 (ja) * | 2015-07-02 | 2016-03-22 | 株式会社東洋新薬 | 血流改善剤 |
WO2019117702A1 (en) * | 2017-12-16 | 2019-06-20 | Kam Faii Yuen | A medicament to control and reduce hypertension |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016141331A1 (en) * | 2015-03-04 | 2016-09-09 | K.L.R.M., Llc | Methods and compositions for extending the efficacy of phosphodiesterase inhibitors for treating erectile dysfunction |
EP3629772A4 (en) * | 2017-05-31 | 2020-12-23 | Kyowa Hakko Bio Co., Ltd. | USING CITRULLINE AND GLUTATHIONE TO INCREASE MUSCLE MASS |
IT202100021728A1 (it) * | 2021-08-11 | 2023-02-11 | Andrea Salmaso | Composizione amminoacidica come agente vasodilatatore |
Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5375387A (en) | 1976-12-13 | 1978-07-04 | Kyowa Hakko Kogyo Co Ltd | Preparation of l-citrulline |
JPS6174595A (ja) | 1984-09-21 | 1986-04-16 | Kyowa Hakko Kogyo Co Ltd | 物質の製造方法 |
JPS6368091A (ja) | 1986-09-10 | 1988-03-26 | Kyowa Hakko Kogyo Co Ltd | アミノ酸の製造法 |
JP2001507696A (ja) * | 1996-12-31 | 2001-06-12 | アンチオキシダント ファーマシューティカルズ コーポレーション | グルタチオンの医薬製剤およびその投与方法 |
US20010056068A1 (en) * | 1998-03-04 | 2001-12-27 | Kristof Chwalisz | Method of treatment and prevention of nitric oxide deficiency-related disorders with citrulline and citrulline derivatives |
JP2004521083A (ja) * | 2000-10-27 | 2004-07-15 | ニトロメッド,インク. | 酸化窒素不足によって特徴づけられる血管疾患の治療方法 |
JP2006117645A (ja) * | 2004-09-21 | 2006-05-11 | Sankyo Co Ltd | HMG−CoAリダクターゼ阻害剤とグルタチオンを含有する医薬組成物 |
JP2006273789A (ja) * | 2005-03-30 | 2006-10-12 | Pias Arise Kk | セラミダーゼ阻害剤、及びその阻害剤を含む皮膚外用剤、化粧料、医薬部外品 |
US20090047340A1 (en) * | 2006-03-29 | 2009-02-19 | Guilford F Timothy | Liposomal reduced glutathione and 1-arginine, including with other ingredient(s), capable of multipath administration for reversal and prevention of obesity and for mitochondrial biogenesis |
WO2009099132A1 (ja) * | 2008-02-05 | 2009-08-13 | Kyowa Hakko Bio Co., Ltd. | グルタチオンの保存安定性向上方法 |
US20110044965A1 (en) * | 2008-04-02 | 2011-02-24 | Androsystems S.R.L. | L-citrulline for treating endothelial dysfunction and erectile dysfunction |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1110392A (en) * | 1964-09-28 | 1968-04-18 | Yamanouchi Pharma Co Ltd | Composition containing glutathione and an amino acid or amino acids, and salts thereof |
WO2007115131A2 (en) * | 2006-03-29 | 2007-10-11 | Guilford F Timothy | Liposomal reduced glutathione and 1-arginine, including other ingredient(s) |
JPWO2008105384A1 (ja) * | 2007-02-26 | 2010-06-03 | 協和発酵バイオ株式会社 | シトルリン含有錠剤 |
CN102356879B (zh) * | 2011-10-21 | 2014-08-06 | 深圳市俪斯生物科技有限公司 | 一种功能肽强化的保健食品 |
-
2013
- 2013-02-15 JP JP2013558748A patent/JP6151646B2/ja active Active
- 2013-02-15 US US14/379,147 patent/US20150011463A1/en not_active Abandoned
- 2013-02-15 AU AU2013219258A patent/AU2013219258B2/en active Active
- 2013-02-15 EP EP13748698.1A patent/EP2815760B1/en active Active
- 2013-02-15 WO PCT/JP2013/053661 patent/WO2013122188A1/ja active Application Filing
- 2013-02-15 ES ES13748698T patent/ES2761224T3/es active Active
-
2016
- 2016-06-21 US US15/188,359 patent/US20160296586A1/en not_active Abandoned
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5375387A (en) | 1976-12-13 | 1978-07-04 | Kyowa Hakko Kogyo Co Ltd | Preparation of l-citrulline |
JPS6174595A (ja) | 1984-09-21 | 1986-04-16 | Kyowa Hakko Kogyo Co Ltd | 物質の製造方法 |
JPS6368091A (ja) | 1986-09-10 | 1988-03-26 | Kyowa Hakko Kogyo Co Ltd | アミノ酸の製造法 |
JP2001507696A (ja) * | 1996-12-31 | 2001-06-12 | アンチオキシダント ファーマシューティカルズ コーポレーション | グルタチオンの医薬製剤およびその投与方法 |
US20010056068A1 (en) * | 1998-03-04 | 2001-12-27 | Kristof Chwalisz | Method of treatment and prevention of nitric oxide deficiency-related disorders with citrulline and citrulline derivatives |
JP2004521083A (ja) * | 2000-10-27 | 2004-07-15 | ニトロメッド,インク. | 酸化窒素不足によって特徴づけられる血管疾患の治療方法 |
JP2006117645A (ja) * | 2004-09-21 | 2006-05-11 | Sankyo Co Ltd | HMG−CoAリダクターゼ阻害剤とグルタチオンを含有する医薬組成物 |
JP2006273789A (ja) * | 2005-03-30 | 2006-10-12 | Pias Arise Kk | セラミダーゼ阻害剤、及びその阻害剤を含む皮膚外用剤、化粧料、医薬部外品 |
US20090047340A1 (en) * | 2006-03-29 | 2009-02-19 | Guilford F Timothy | Liposomal reduced glutathione and 1-arginine, including with other ingredient(s), capable of multipath administration for reversal and prevention of obesity and for mitochondrial biogenesis |
WO2009099132A1 (ja) * | 2008-02-05 | 2009-08-13 | Kyowa Hakko Bio Co., Ltd. | グルタチオンの保存安定性向上方法 |
US20110044965A1 (en) * | 2008-04-02 | 2011-02-24 | Androsystems S.R.L. | L-citrulline for treating endothelial dysfunction and erectile dysfunction |
Non-Patent Citations (12)
Title |
---|
ACTA BIOCHIM. POL., vol. 17, 1970, pages 175 |
AKIO MATSUMOTO ET AL.: "Igaku ni Okeru NO no Yakuwari", SHINDAN TO CHIRYO, vol. 89, no. 1, 2001, pages 135 - 140, XP008174398 * |
BULL.CHEM. SOC. JPN., vol. 53, 1980, pages 2529 |
HAYASHI,T. ET AL.: "1-Citrulline and 1-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 102, no. 38, 2005, pages 13681 - 6, XP008133300 * |
J. BIOL. CHEM., vol. 122, 1938, pages 477 |
J. ORG. CHEM., vol. 6, 1941, pages 410 |
JOURNAL OF DERMATOLOGICAL TREATMENT, 2010 |
JOURNAL OF NUTRITIONAL SCIENCE & VITAMINOLOGY, vol. 44, 1998, pages 613 - 624 |
METHODS IN ENZYMOLOGY, vol. 3, 1957, pages 603 |
PNAS, vol. 102, 2005, pages 13681 - 13686 |
PRASAD,A. ET AL.: "Glutathione reverses endothelial dysfunction and improves nitric oxide bioavailability", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, vol. 34, no. 2, 1999, pages 507 - 14, XP055159746 * |
See also references of EP2815760A4 |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014112641A1 (ja) * | 2013-01-21 | 2014-07-24 | 協和発酵バイオ株式会社 | 一酸化窒素濃度上昇剤 |
AU2014208077B2 (en) * | 2013-01-21 | 2018-05-24 | Kyowa Hakko Bio Co., Ltd. | Nitric oxide concentration elevating agent |
US11654125B2 (en) | 2013-01-21 | 2023-05-23 | Kyowa Hakko Bio Co., Ltd. | Agent for elevating nitric oxide concentration |
JP5888574B1 (ja) * | 2015-07-02 | 2016-03-22 | 株式会社東洋新薬 | 血流改善剤 |
JP2017014165A (ja) * | 2015-07-02 | 2017-01-19 | 株式会社東洋新薬 | 血流改善剤 |
WO2019117702A1 (en) * | 2017-12-16 | 2019-06-20 | Kam Faii Yuen | A medicament to control and reduce hypertension |
Also Published As
Publication number | Publication date |
---|---|
AU2013219258A1 (en) | 2014-09-04 |
JPWO2013122188A1 (ja) | 2015-05-18 |
EP2815760A4 (en) | 2015-12-09 |
EP2815760A1 (en) | 2014-12-24 |
ES2761224T3 (es) | 2020-05-19 |
US20160296586A1 (en) | 2016-10-13 |
AU2013219258B2 (en) | 2017-05-25 |
EP2815760B1 (en) | 2019-10-09 |
US20150011463A1 (en) | 2015-01-08 |
JP6151646B2 (ja) | 2017-06-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6193229B2 (ja) | 血管内皮機能低下の予防または改善剤 | |
US20230263761A1 (en) | Agent for elevating nitric oxide concentration | |
US20160296586A1 (en) | Agent for preventing or ameliorating vascular endothelial malfunction | |
WO2007142286A1 (ja) | 疲労軽減剤 | |
JP5931325B2 (ja) | 注意集中力向上剤 | |
JP6166786B2 (ja) | 脳機能低下の予防または改善剤 | |
JP5414995B2 (ja) | フコイダンを有効成分とする酸性尿改善飲食物および経口投与用医薬組成物 | |
JP2013060406A (ja) | 脳疲労改善用経口剤 | |
US20170042962A1 (en) | Agent for preventing or ameliorating vascular endothelial malfunction | |
JP6170166B2 (ja) | 脳機能低下の予防または改善剤 | |
JPWO2007119502A1 (ja) | 便通改善剤 | |
JPWO2007049628A1 (ja) | 血液流動性改善剤 | |
JP6052566B2 (ja) | 疲労臭抑制剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 13748698 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2013558748 Country of ref document: JP Kind code of ref document: A |
|
REEP | Request for entry into the european phase |
Ref document number: 2013748698 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2013748698 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14379147 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2013219258 Country of ref document: AU Date of ref document: 20130215 Kind code of ref document: A |