KR20100017708A - Novel antiphlogistic-analgesic agent - Google Patents
Novel antiphlogistic-analgesic agent Download PDFInfo
- Publication number
- KR20100017708A KR20100017708A KR1020097025589A KR20097025589A KR20100017708A KR 20100017708 A KR20100017708 A KR 20100017708A KR 1020097025589 A KR1020097025589 A KR 1020097025589A KR 20097025589 A KR20097025589 A KR 20097025589A KR 20100017708 A KR20100017708 A KR 20100017708A
- Authority
- KR
- South Korea
- Prior art keywords
- lactoalbumin
- cox
- inflammatory
- pain
- wpi
- Prior art date
Links
- 239000000730 antalgic agent Substances 0.000 title claims abstract description 27
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 41
- 235000013305 food Nutrition 0.000 claims abstract description 23
- 208000002193 Pain Diseases 0.000 claims description 33
- 230000036407 pain Effects 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 23
- 208000005171 Dysmenorrhea Diseases 0.000 claims description 22
- 230000000202 analgesic effect Effects 0.000 claims description 21
- 206010003246 arthritis Diseases 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 11
- 229940035676 analgesics Drugs 0.000 claims description 9
- 229940111134 coxibs Drugs 0.000 claims description 7
- 208000027866 inflammatory disease Diseases 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 6
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 5
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 230000000694 effects Effects 0.000 abstract description 42
- 238000012360 testing method Methods 0.000 abstract description 42
- 108010037462 Cyclooxygenase 2 Proteins 0.000 abstract description 31
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 abstract description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 21
- 230000005764 inhibitory process Effects 0.000 abstract description 18
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 abstract description 11
- 208000009386 Experimental Arthritis Diseases 0.000 abstract description 9
- 235000010418 carrageenan Nutrition 0.000 abstract description 8
- 229920001525 carrageenan Polymers 0.000 abstract description 8
- 206010030113 Oedema Diseases 0.000 abstract description 6
- 108010058864 Phospholipases A2 Proteins 0.000 abstract description 4
- 239000005445 natural material Substances 0.000 abstract description 2
- 102000004407 Lactalbumin Human genes 0.000 abstract 5
- 108090000942 Lactalbumin Proteins 0.000 abstract 5
- 235000021241 α-lactalbumin Nutrition 0.000 abstract 5
- 102100037611 Lysophospholipase Human genes 0.000 abstract 1
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 abstract 1
- 230000002411 adverse Effects 0.000 abstract 1
- 102000010445 Lactoferrin Human genes 0.000 description 27
- 108010063045 Lactoferrin Proteins 0.000 description 27
- CSSYQJWUGATIHM-IKGCZBKSSA-N l-phenylalanyl-l-lysyl-l-cysteinyl-l-arginyl-l-arginyl-l-tryptophyl-l-glutaminyl-l-tryptophyl-l-arginyl-l-methionyl-l-lysyl-l-lysyl-l-leucylglycyl-l-alanyl-l-prolyl-l-seryl-l-isoleucyl-l-threonyl-l-cysteinyl-l-valyl-l-arginyl-l-arginyl-l-alanyl-l-phenylal Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSSYQJWUGATIHM-IKGCZBKSSA-N 0.000 description 27
- 235000021242 lactoferrin Nutrition 0.000 description 27
- 229940078795 lactoferrin Drugs 0.000 description 27
- 239000000126 substance Substances 0.000 description 23
- 230000002401 inhibitory effect Effects 0.000 description 22
- 102000004190 Enzymes Human genes 0.000 description 21
- 108090000790 Enzymes Proteins 0.000 description 21
- 229940088598 enzyme Drugs 0.000 description 21
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 19
- 108090000765 processed proteins & peptides Proteins 0.000 description 19
- 235000013336 milk Nutrition 0.000 description 18
- 239000008267 milk Substances 0.000 description 18
- 210000004080 milk Anatomy 0.000 description 18
- 210000002683 foot Anatomy 0.000 description 17
- 102000004196 processed proteins & peptides Human genes 0.000 description 17
- 239000003814 drug Substances 0.000 description 16
- 102000007544 Whey Proteins Human genes 0.000 description 15
- 108010046377 Whey Proteins Proteins 0.000 description 15
- 150000001413 amino acids Chemical class 0.000 description 15
- 229920001184 polypeptide Polymers 0.000 description 15
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 14
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 206010013935 Dysmenorrhoea Diseases 0.000 description 13
- 235000018102 proteins Nutrition 0.000 description 13
- 102000004169 proteins and genes Human genes 0.000 description 13
- 108090000623 proteins and genes Proteins 0.000 description 13
- 230000009471 action Effects 0.000 description 12
- 241000283690 Bos taurus Species 0.000 description 11
- 206010061218 Inflammation Diseases 0.000 description 11
- 230000004054 inflammatory process Effects 0.000 description 11
- 108010037464 Cyclooxygenase 1 Proteins 0.000 description 10
- 102000008192 Lactoglobulins Human genes 0.000 description 10
- 108010060630 Lactoglobulins Proteins 0.000 description 10
- 239000002671 adjuvant Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 230000005906 menstruation Effects 0.000 description 9
- 235000021119 whey protein Nutrition 0.000 description 9
- 229960001259 diclofenac Drugs 0.000 description 8
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 108091033319 polynucleotide Proteins 0.000 description 8
- 239000002157 polynucleotide Substances 0.000 description 8
- 102000040430 polynucleotide Human genes 0.000 description 8
- 150000003180 prostaglandins Chemical class 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 238000009396 hybridization Methods 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 6
- 208000012659 Joint disease Diseases 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 239000005862 Whey Substances 0.000 description 6
- 229960001138 acetylsalicylic acid Drugs 0.000 description 6
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 6
- 239000000679 carrageenan Substances 0.000 description 6
- 229940113118 carrageenan Drugs 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 239000002773 nucleotide Chemical group 0.000 description 6
- 125000003729 nucleotide group Chemical group 0.000 description 6
- 239000002504 physiological saline solution Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 6
- 102000011632 Caseins Human genes 0.000 description 5
- 108010076119 Caseins Proteins 0.000 description 5
- 208000000094 Chronic Pain Diseases 0.000 description 5
- 206010065390 Inflammatory pain Diseases 0.000 description 5
- 102100026918 Phospholipase A2 Human genes 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 208000006673 asthma Diseases 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 102000016943 Muramidase Human genes 0.000 description 4
- 108010014251 Muramidase Proteins 0.000 description 4
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 208000008469 Peptic Ulcer Diseases 0.000 description 4
- 210000000988 bone and bone Anatomy 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 150000002617 leukotrienes Chemical class 0.000 description 4
- 235000010335 lysozyme Nutrition 0.000 description 4
- 239000004325 lysozyme Substances 0.000 description 4
- 229960000274 lysozyme Drugs 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 235000016709 nutrition Nutrition 0.000 description 4
- 230000027758 ovulation cycle Effects 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 230000001755 vocal effect Effects 0.000 description 4
- 239000004475 Arginine Substances 0.000 description 3
- 208000020084 Bone disease Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 241000282326 Felis catus Species 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 3
- 102000011779 Nitric Oxide Synthase Type II Human genes 0.000 description 3
- 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 description 3
- 206010030124 Oedema peripheral Diseases 0.000 description 3
- 206010037660 Pyrexia Diseases 0.000 description 3
- 229940114079 arachidonic acid Drugs 0.000 description 3
- 235000021342 arachidonic acid Nutrition 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 208000037976 chronic inflammation Diseases 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
- 230000007423 decrease Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 108010034529 leucyl-lysine Proteins 0.000 description 3
- 235000012054 meals Nutrition 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 238000001471 micro-filtration Methods 0.000 description 3
- 230000035764 nutrition Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 238000011533 pre-incubation Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 238000000108 ultra-filtration Methods 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical group OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- SHKGHIFSEAGTNL-DLOVCJGASA-N Ala-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CN=CN1 SHKGHIFSEAGTNL-DLOVCJGASA-N 0.000 description 2
- 208000033309 Analgesic asthma syndrome Diseases 0.000 description 2
- NKBQZKVMKJJDLX-SRVKXCTJSA-N Arg-Glu-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NKBQZKVMKJJDLX-SRVKXCTJSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical group OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- FVKHEKVYFTZWDX-GHCJXIJMSA-N Asn-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)N)N FVKHEKVYFTZWDX-GHCJXIJMSA-N 0.000 description 2
- SEKBHZJLARBNPB-GHCJXIJMSA-N Asn-Ile-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O SEKBHZJLARBNPB-GHCJXIJMSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000008035 Back Pain Diseases 0.000 description 2
- 229940124638 COX inhibitor Drugs 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 101000986995 Daboia russelii Acidic phospholipase A2 Drk-a1 Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- LKUWAWGNJYJODH-KBIXCLLPSA-N Gln-Ala-Ile Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LKUWAWGNJYJODH-KBIXCLLPSA-N 0.000 description 2
- FVGOGEGGQLNZGH-DZKIICNBSA-N Glu-Val-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FVGOGEGGQLNZGH-DZKIICNBSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 102000019054 Group II Phospholipases A2 Human genes 0.000 description 2
- 108010026929 Group II Phospholipases A2 Proteins 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- QYZYJFXHXYUZMZ-UGYAYLCHSA-N Ile-Asn-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N QYZYJFXHXYUZMZ-UGYAYLCHSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- KWURTLAFFDOTEQ-GUBZILKMSA-N Leu-Cys-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N KWURTLAFFDOTEQ-GUBZILKMSA-N 0.000 description 2
- KQFZKDITNUEVFJ-JYJNAYRXSA-N Leu-Phe-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC1=CC=CC=C1 KQFZKDITNUEVFJ-JYJNAYRXSA-N 0.000 description 2
- VULJUQZPSOASBZ-SRVKXCTJSA-N Leu-Pro-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O VULJUQZPSOASBZ-SRVKXCTJSA-N 0.000 description 2
- 102000003820 Lipoxygenases Human genes 0.000 description 2
- 108090000128 Lipoxygenases Proteins 0.000 description 2
- 208000008930 Low Back Pain Diseases 0.000 description 2
- GFWLIJDQILOEPP-HSCHXYMDSA-N Lys-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CCCCN)N GFWLIJDQILOEPP-HSCHXYMDSA-N 0.000 description 2
- XOFDBXYPKZUAAM-GUBZILKMSA-N Met-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N XOFDBXYPKZUAAM-GUBZILKMSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 235000019482 Palm oil Nutrition 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- IEIFEYBAYFSRBQ-IHRRRGAJSA-N Phe-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N IEIFEYBAYFSRBQ-IHRRRGAJSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 108010076504 Protein Sorting Signals Proteins 0.000 description 2
- 208000026062 Tissue disease Diseases 0.000 description 2
- CYLQUSBOSWCHTO-BPUTZDHNSA-N Trp-Val-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N CYLQUSBOSWCHTO-BPUTZDHNSA-N 0.000 description 2
- BXJQKVDPRMLGKN-PMVMPFDFSA-N Tyr-Trp-Leu Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 BXJQKVDPRMLGKN-PMVMPFDFSA-N 0.000 description 2
- OUUBKKIJQIAPRI-LAEOZQHASA-N Val-Gln-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O OUUBKKIJQIAPRI-LAEOZQHASA-N 0.000 description 2
- PMDOQZFYGWZSTK-LSJOCFKGSA-N Val-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)C(C)C PMDOQZFYGWZSTK-LSJOCFKGSA-N 0.000 description 2
- 230000006022 acute inflammation Effects 0.000 description 2
- 208000038016 acute inflammation Diseases 0.000 description 2
- 208000005298 acute pain Diseases 0.000 description 2
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 2
- 108010045514 alpha-lactorphin Proteins 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000005018 casein Substances 0.000 description 2
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 2
- 235000021240 caseins Nutrition 0.000 description 2
- 230000006020 chronic inflammation Effects 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 235000013365 dairy product Nutrition 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000007123 defense Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- -1 for example Natural products 0.000 description 2
- 235000013350 formula milk Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 235000013376 functional food Nutrition 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 108010073628 glutamyl-valyl-phenylalanine Proteins 0.000 description 2
- 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 description 2
- 108010045126 glycyl-tyrosyl-glycine Proteins 0.000 description 2
- 108010092114 histidylphenylalanine Proteins 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 229940088592 immunologic factor Drugs 0.000 description 2
- 239000000367 immunologic factor Substances 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 230000003821 menstrual periods Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 208000004296 neuralgia Diseases 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 239000002540 palm oil Substances 0.000 description 2
- 208000011906 peptic ulcer disease Diseases 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 235000020183 skimmed milk Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000008961 swelling Effects 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
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- BMUDPLZKKRQECS-UHFFFAOYSA-K 3-[18-(2-carboxyethyl)-8,13-bis(ethenyl)-3,7,12,17-tetramethylporphyrin-21,24-diid-2-yl]propanoic acid iron(3+) hydroxide Chemical compound [OH-].[Fe+3].[N-]1C2=C(C)C(CCC(O)=O)=C1C=C([N-]1)C(CCC(O)=O)=C(C)C1=CC(C(C)=C1C=C)=NC1=CC(C(C)=C1C=C)=NC1=C2 BMUDPLZKKRQECS-UHFFFAOYSA-K 0.000 description 1
- 206010000084 Abdominal pain lower Diseases 0.000 description 1
- BGNLUHXLSAQYRQ-FXQIFTODSA-N Ala-Glu-Gln Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O BGNLUHXLSAQYRQ-FXQIFTODSA-N 0.000 description 1
- NOGFDULFCFXBHB-CIUDSAMLSA-N Ala-Leu-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)O)N NOGFDULFCFXBHB-CIUDSAMLSA-N 0.000 description 1
- HCBKAOZYACJUEF-XQXXSGGOSA-N Ala-Thr-Gln Chemical compound N[C@@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCC(N)=O)C(=O)O HCBKAOZYACJUEF-XQXXSGGOSA-N 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 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
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- VYLVOMUVLMGCRF-ZLUOBGJFSA-N Asn-Asp-Ser Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O VYLVOMUVLMGCRF-ZLUOBGJFSA-N 0.000 description 1
- TVVYVAUGRHNTGT-UGYAYLCHSA-N Asp-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(O)=O TVVYVAUGRHNTGT-UGYAYLCHSA-N 0.000 description 1
- SBHUBSDEZQFJHJ-CIUDSAMLSA-N Asp-Asp-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(O)=O SBHUBSDEZQFJHJ-CIUDSAMLSA-N 0.000 description 1
- WLKVEEODTPQPLI-ACZMJKKPSA-N Asp-Gln-Asn Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O WLKVEEODTPQPLI-ACZMJKKPSA-N 0.000 description 1
- JRBVWZLHBGYZNY-QEJZJMRPSA-N Asp-Gln-Trp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O JRBVWZLHBGYZNY-QEJZJMRPSA-N 0.000 description 1
- LDLZOAJRXXBVGF-GMOBBJLQSA-N Asp-Ile-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC(=O)O)N LDLZOAJRXXBVGF-GMOBBJLQSA-N 0.000 description 1
- CJUKAWUWBZCTDQ-SRVKXCTJSA-N Asp-Leu-Lys Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O CJUKAWUWBZCTDQ-SRVKXCTJSA-N 0.000 description 1
- YQKYLDVPCOGIRB-SEKJGCFDSA-N Asp-Leu-Thr-Asp Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O YQKYLDVPCOGIRB-SEKJGCFDSA-N 0.000 description 1
- YWLDTBBUHZJQHW-KKUMJFAQSA-N Asp-Lys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N YWLDTBBUHZJQHW-KKUMJFAQSA-N 0.000 description 1
- MYLZFUMPZCPJCJ-NHCYSSNCSA-N Asp-Lys-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MYLZFUMPZCPJCJ-NHCYSSNCSA-N 0.000 description 1
- YIDFBWRHIYOYAA-LKXGYXEUSA-N Asp-Ser-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YIDFBWRHIYOYAA-LKXGYXEUSA-N 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000012904 Bartter disease Diseases 0.000 description 1
- 208000010062 Bartter syndrome Diseases 0.000 description 1
- 108050008461 Beta-lactoglobulin Proteins 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 102400000967 Bradykinin Human genes 0.000 description 1
- 101100275473 Caenorhabditis elegans ctc-3 gene Proteins 0.000 description 1
- 102000005701 Calcium-Binding Proteins Human genes 0.000 description 1
- 108010045403 Calcium-Binding Proteins Proteins 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000027932 Collagen disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000271532 Crotalus Species 0.000 description 1
- YMBAVNPKBWHDAW-CIUDSAMLSA-N Cys-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N YMBAVNPKBWHDAW-CIUDSAMLSA-N 0.000 description 1
- VXLXATVURDNDCG-CIUDSAMLSA-N Cys-Lys-Asp Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CS)N VXLXATVURDNDCG-CIUDSAMLSA-N 0.000 description 1
- YQEHNIKPAOPBNH-DCAQKATOSA-N Cys-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CS)N YQEHNIKPAOPBNH-DCAQKATOSA-N 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 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
- 108010082495 Dietary Plant Proteins Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010061459 Gastrointestinal ulcer Diseases 0.000 description 1
- CKNUKHBRCSMKMO-XHNCKOQMSA-N Gln-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)N)N)C(=O)O CKNUKHBRCSMKMO-XHNCKOQMSA-N 0.000 description 1
- PVBBEKPHARMPHX-DCAQKATOSA-N Glu-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCC(O)=O PVBBEKPHARMPHX-DCAQKATOSA-N 0.000 description 1
- ILWHFUZZCFYSKT-AVGNSLFASA-N Glu-Lys-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O ILWHFUZZCFYSKT-AVGNSLFASA-N 0.000 description 1
- HAGKYCXGTRUUFI-RYUDHWBXSA-N Glu-Tyr-Gly Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CCC(=O)O)N)O HAGKYCXGTRUUFI-RYUDHWBXSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- OLPPXYMMIARYAL-QMMMGPOBSA-N Gly-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)CN OLPPXYMMIARYAL-QMMMGPOBSA-N 0.000 description 1
- DGKBSGNCMCLDSL-BYULHYEWSA-N Gly-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)CN DGKBSGNCMCLDSL-BYULHYEWSA-N 0.000 description 1
- GNNJKUYDWFIBTK-QWRGUYRKSA-N Gly-Tyr-Asp Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O GNNJKUYDWFIBTK-QWRGUYRKSA-N 0.000 description 1
- HQSKKSLNLSTONK-JTQLQIEISA-N Gly-Tyr-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 HQSKKSLNLSTONK-JTQLQIEISA-N 0.000 description 1
- SBVMXEZQJVUARN-XPUUQOCRSA-N Gly-Val-Ser Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O SBVMXEZQJVUARN-XPUUQOCRSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- VIJMRAIWYWRXSR-CIUDSAMLSA-N His-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CN=CN1 VIJMRAIWYWRXSR-CIUDSAMLSA-N 0.000 description 1
- UWSMZKRTOZEGDD-CUJWVEQBSA-N His-Thr-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O UWSMZKRTOZEGDD-CUJWVEQBSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- IOVUXUSIGXCREV-DKIMLUQUSA-N Ile-Leu-Phe Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 IOVUXUSIGXCREV-DKIMLUQUSA-N 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
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 206010023230 Joint stiffness Diseases 0.000 description 1
- 206010023232 Joint swelling Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 208000011200 Kawasaki disease Diseases 0.000 description 1
- DLFAACQHIRSQGG-CIUDSAMLSA-N Leu-Asp-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O DLFAACQHIRSQGG-CIUDSAMLSA-N 0.000 description 1
- PJYSOYLLTJKZHC-GUBZILKMSA-N Leu-Asp-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCC(N)=O PJYSOYLLTJKZHC-GUBZILKMSA-N 0.000 description 1
- MYGQXVYRZMKRDB-SRVKXCTJSA-N Leu-Asp-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN MYGQXVYRZMKRDB-SRVKXCTJSA-N 0.000 description 1
- PNUCWVAGVNLUMW-CIUDSAMLSA-N Leu-Cys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(O)=O PNUCWVAGVNLUMW-CIUDSAMLSA-N 0.000 description 1
- KTOIECMYZZGVSI-BZSNNMDCSA-N Leu-Phe-His Chemical compound C([C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(O)=O)C1=CC=CC=C1 KTOIECMYZZGVSI-BZSNNMDCSA-N 0.000 description 1
- DAYQSYGBCUKVKT-VOAKCMCISA-N Leu-Thr-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O DAYQSYGBCUKVKT-VOAKCMCISA-N 0.000 description 1
- AAKRWBIIGKPOKQ-ONGXEEELSA-N Leu-Val-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O AAKRWBIIGKPOKQ-ONGXEEELSA-N 0.000 description 1
- 206010024453 Ligament sprain Diseases 0.000 description 1
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Chemical group CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 description 1
- QUYCUALODHJQLK-CIUDSAMLSA-N Lys-Asp-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O QUYCUALODHJQLK-CIUDSAMLSA-N 0.000 description 1
- IWWMPCPLFXFBAF-SRVKXCTJSA-N Lys-Asp-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O IWWMPCPLFXFBAF-SRVKXCTJSA-N 0.000 description 1
- NNKLKUUGESXCBS-KBPBESRZSA-N Lys-Gly-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O NNKLKUUGESXCBS-KBPBESRZSA-N 0.000 description 1
- ZXFRGTAIIZHNHG-AJNGGQMLSA-N Lys-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CCCCN)N ZXFRGTAIIZHNHG-AJNGGQMLSA-N 0.000 description 1
- GAHJXEMYXKLZRQ-AJNGGQMLSA-N Lys-Lys-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O GAHJXEMYXKLZRQ-AJNGGQMLSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000007466 Male Infertility Diseases 0.000 description 1
- YKWHHKDMBZBMLG-GUBZILKMSA-N Met-Cys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCSC)N YKWHHKDMBZBMLG-GUBZILKMSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 208000019430 Motor disease Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241001646725 Mycobacterium tuberculosis H37Rv Species 0.000 description 1
- 108700035964 Mycobacterium tuberculosis HsaD Proteins 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 101100168274 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cox-3 gene Proteins 0.000 description 1
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 1
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 1
- 208000001294 Nociceptive Pain Diseases 0.000 description 1
- YKUGPVXSDOOANW-KKUMJFAQSA-N Phe-Leu-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O YKUGPVXSDOOANW-KKUMJFAQSA-N 0.000 description 1
- 108010001441 Phosphopeptides Proteins 0.000 description 1
- 206010065016 Post-traumatic pain Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010036618 Premenstrual syndrome Diseases 0.000 description 1
- AQSMZTIEJMZQEC-DCAQKATOSA-N Pro-His-Ser Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC2=CN=CN2)C(=O)N[C@@H](CO)C(=O)O AQSMZTIEJMZQEC-DCAQKATOSA-N 0.000 description 1
- 101710093543 Probable non-specific lipid-transfer protein Proteins 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 235000019484 Rapeseed oil Nutrition 0.000 description 1
- 208000033464 Reiter syndrome Diseases 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- QKQDTEYDEIJPNK-GUBZILKMSA-N Ser-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CO QKQDTEYDEIJPNK-GUBZILKMSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000027520 Somatoform disease Diseases 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 108010073771 Soybean Proteins Proteins 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
- OYTNZCBFDXGQGE-XQXXSGGOSA-N Thr-Gln-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](C)C(=O)O)N)O OYTNZCBFDXGQGE-XQXXSGGOSA-N 0.000 description 1
- LKEKWDJCJSPXNI-IRIUXVKKSA-N Thr-Glu-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 LKEKWDJCJSPXNI-IRIUXVKKSA-N 0.000 description 1
- HPQHHRLWSAMMKG-KATARQTJSA-N Thr-Lys-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)O)N)O HPQHHRLWSAMMKG-KATARQTJSA-N 0.000 description 1
- GYUUYCIXELGTJS-MEYUZBJRSA-N Thr-Phe-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O GYUUYCIXELGTJS-MEYUZBJRSA-N 0.000 description 1
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 1
- QJIODPFLAASXJC-JHYOHUSXSA-N Thr-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O QJIODPFLAASXJC-JHYOHUSXSA-N 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- MNMYOSZWCKYEDI-JRQIVUDYSA-N Tyr-Asp-Thr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MNMYOSZWCKYEDI-JRQIVUDYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003270 Vitamin B Chemical group 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003316 Vitamin D Chemical group 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Chemical group C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 229930003448 Vitamin K Chemical group 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 108010005233 alanylglutamic acid Proteins 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical group OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 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
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 239000001166 ammonium sulphate Substances 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 108010077245 asparaginyl-proline Proteins 0.000 description 1
- 235000008452 baby food Nutrition 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 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 1
- 239000011230 binding agent Substances 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 235000015895 biscuits Nutrition 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 150000001746 carotenes Chemical group 0.000 description 1
- 235000005473 carotenes Nutrition 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 235000013351 cheese Nutrition 0.000 description 1
- 230000002113 chemopreventative effect Effects 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 210000003022 colostrum Anatomy 0.000 description 1
- 235000021277 colostrum Nutrition 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000012495 crackers Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 235000015140 cultured milk Nutrition 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 210000001513 elbow Anatomy 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960005293 etodolac Drugs 0.000 description 1
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 210000003811 finger Anatomy 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 235000013611 frozen food Nutrition 0.000 description 1
- 235000011306 frozen processed food Nutrition 0.000 description 1
- 235000015203 fruit juice Nutrition 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 102000034238 globular proteins Human genes 0.000 description 1
- 108091005896 globular proteins Proteins 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 239000007986 glycine-NaOH buffer Substances 0.000 description 1
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 1
- 108010087823 glycyltyrosine Proteins 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000005205 gut mucosa Anatomy 0.000 description 1
- 210000004247 hand Anatomy 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 229940109738 hematin Drugs 0.000 description 1
- 235000020256 human milk Nutrition 0.000 description 1
- 210000004251 human milk Anatomy 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 description 1
- 229960002373 loxoprofen Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 208000001725 mucocutaneous lymph node syndrome Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000001254 oxidized starch Substances 0.000 description 1
- 235000013808 oxidized starch Nutrition 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 208000027753 pain disease Diseases 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Chemical group CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- 235000013550 pizza Nutrition 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000020610 powder formula Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000003259 prostaglandin group Chemical group 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- IKGXIBQEEMLURG-NVPNHPEKSA-N rutin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-NVPNHPEKSA-N 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- FNKQXYHWGSIFBK-RPDRRWSUSA-N sapropterin Chemical compound N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 FNKQXYHWGSIFBK-RPDRRWSUSA-N 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 210000002832 shoulder Anatomy 0.000 description 1
- 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 1
- 231100000046 skin rash Toxicity 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000014214 soft drink Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940001941 soy protein Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000008409 synovial inflammation Effects 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000003371 toe Anatomy 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 108010080629 tryptophan-leucine Proteins 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 229960004747 ubidecarenone Drugs 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 108010073969 valyllysine Proteins 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Chemical group O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Chemical group 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Chemical group 0.000 description 1
- 150000003710 vitamin D derivatives Chemical group 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Chemical group 0.000 description 1
- 150000003721 vitamin K derivatives Chemical group 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 235000008939 whole milk Nutrition 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 235000021249 α-casein Nutrition 0.000 description 1
- 235000021247 β-casein Nutrition 0.000 description 1
- 235000021246 κ-casein Nutrition 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/19—Dairy proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Rheumatology (AREA)
- Zoology (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Reproductive Health (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Endocrinology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
본 발명은 α-락토알부민을 함유하는 소염진통작용을 갖는 음식물 및 의약 조성물에 관한 것이다.The present invention relates to a food and pharmaceutical composition having an anti-inflammatory action containing α-lactoalbumin.
최근, 소염진통을 위해 일상적으로 처방되는 약제로서, 비스테로이드계 소염진통제로 총칭되는 아스피린, 인도메타신, 이부프로펜, 디클로페낙 등, 수십 종류의 합성화합물과, 스테로이드로 속칭되는 합성 글루코코르티코이드 호르몬(glucocorticoid hormone) 등이 있다.Recently, as a medicine prescribed daily for anti-inflammatory pain, dozens of synthetic compounds such as aspirin, indomethacin, ibuprofen, diclofenac, collectively referred to as nonsteroidal anti-inflammatory drugs, and synthetic glucocorticoid hormone ).
아스피린은 프로스타글란딘(PG) 합성효소 「시클로옥시게나제(COX)」의 활성을 억제한다. COX의 활성 저하에 의해 PG가 감소하고, 동통 유발물질(브래디키닌(bradykinin))의 활성이 억제되어, 아스피린의 진통작용이 발현한다. 아스피린과 마찬가지로 COX에 작용하여 소염진통효과를 발휘하는 약은 작용 메커니즘이 상이한 스테로이드제와 구별하기 위해, 「비스테로이드계 소염진통제(non-steroidal anti-inflammatory drugs: NSAIDs)」로 불리고 있다.Aspirin inhibits the activity of prostaglandin (PG) synthase "cyclooxygenase (COX)". PG decreases due to the decrease in COX activity, the activity of pain-causing substances (bradykinin) is suppressed, and the analgesic action of aspirin is expressed. Like aspirin, drugs that exert an anti-inflammatory analgesic effect on COX are called "non-steroidal anti-inflammatory drugs (NSAIDs)" to distinguish them from steroids with different mechanisms of action.
NSAIDs에는 소화관 궤양을 일으키기 쉬운 결점이 있다. 그 주된 원인은, NSAIDs가 혈관 확장과 점막의 보호에 작용하는 PG(PGE2, PGI2)를 감소시켜 버리는 것에 있다. 또한, COX 활성의 억제에 의해, 리폭시게나제의 활성이 항진되어 류코트리엔이 증가하여, 위액의 분비가 감소한다. 동시에, 소화관 점막을 파괴하는 활성산소가 증가하여, 궤양이 일어난다.NSAIDs have defects that are susceptible to gastrointestinal ulcers. The main reason is that NSAIDs reduce PG (PGE 2 , PGI 2 ) which acts on vasodilation and mucosal protection. In addition, by suppressing COX activity, the activity of lipoxygenase is enhanced to increase leukotriene, and the secretion of gastric juice is reduced. At the same time, free radicals that destroy the gut mucosa increase, resulting in ulcers.
이와 같은 NSAIDs의 부작용을 줄일 목적으로 록소프로펜 등의 프로드러그 타입이 개발되었다. 그러나, 프로드러그 타입의 작용 메커니즘은 종래의 NSAIDs와 동일하여, 부작용 감소효과에는 한도가 있다.Prodrug types such as loxoprofen have been developed for the purpose of reducing such side effects of NSAIDs. However, the mechanism of action of the prodrug type is the same as that of conventional NSAIDs, and there is a limit to the side effect reduction effect.
NSAIDs에 의한 소화기장애의 해소는 소염진통제 개발에 있어서의 오랜 연구과제였다. 이 난제에 빛을 비춘 것이 새로운 COX의 발견이다. 1991년에 발견된 COX-2는 외상이나 염증이 일어나면 급격히 증가한다. 한편, 체내에 원래 존재하여, 위점막의 보호에 작용하는 프로스타글란딘류(PGE2, PGI2)를 생산하는 타입은 COX-1으로 분류되었다. 이에, COX-2의 활성을 선택적으로 저해하는 물질은 부작용이 적은 소염진통제가 될 수 있다.The elimination of digestive disorders by NSAIDs has long been a challenge in the development of anti-inflammatory analgesics. The light on this challenge is the discovery of a new COX. COX-2, discovered in 1991, rapidly increases when trauma or inflammation occurs. On the other hand, the types of prostaglandins (PGE 2 , PGI 2 ) that existed in the body and act on the protection of the gastric mucosa were classified as COX-1. Accordingly, the substance selectively inhibiting the activity of COX-2 may be an anti-inflammatory analgesic with less side effects.
NSAIDs의 부작용에는 위장장애 이외에, 신장애, 간장애, 피부의 발진 등 외에, 중대한 부작용으로서 천식발작의 유발이 있다. 종래부터 있는 비선택성의 NSAIDs와 같이, 주작용인 COX-2의 저해와 함께, COX-1의 작용이 억제되면, 아라키돈산의 대사가 류코트리엔 생산측으로 치우치기 때문에 리폭시게나제의 활성이 상승하고, 기관지를 수축시키는 류코트리엔이 증가하여, 천식이 유발된다. 소염진통제에 의한 천식은 「아스피린 천식」으로 불리나, 아스피린 뿐 아니라, 종래형 NSAIDs 전반에 아스피린 천식을 유발할 위험이 있다. 그런데, COX-2만을 저해하는 약제는 류코트리엔을 증가시키지 않기 때문에, 천식 유발의 위험이 적다고 일컬어지고 있다. 이 측면에서도, COX-2 선택적 저해제에 대한 기대는 높다. 1994년에 발매된 에토돌락은 COX-2로의 작용이 10배 강하고, 비교적 소화기장애가 적은 소염진통제로서 사용되고 있다. 또한, 멜록시캄이 1996년에 남아프리카, 프랑스, 영국 등에서 발매되어, 그 후 2001년에 일본에서도 시판되었다.Side effects of NSAIDs include gastrointestinal disorders, nephropathy, liver disorders, skin rashes, and the like, as well as causing asthma attacks. Like conventional non-selective NSAIDs, when the action of COX-1 is suppressed along with inhibition of COX-2, which is the main action, the activity of lipoxygenase increases because the metabolism of arachidonic acid is biased toward leukotriene production. Leukotriene, which constricts neutrophils, increases, leading to asthma. Asthma by anti-inflammatory analgesics is called "aspirin asthma," but there is a risk of causing aspirin asthma not only in aspirin, but also in conventional NSAIDs. By the way, since the drug which inhibits only COX-2 does not increase leukotriene, it is said that there is little risk of causing asthma. In this respect too, expectations for COX-2 selective inhibitors are high. Etodolac, released in 1994, is used as an anti-inflammatory
식품 중에 포함되는 단백질 중 몇몇은 소염진통작용을 갖는다. 예를 들면, 소염진통작용을 갖는 단백질로서, 락토페린이 알려져 있다. 락토페린은 1939년에 발견된 분자량 약 8만의 철 결합성 당단백질이다. 모유, 특히 초유에 많이 포함되고, 몸의 외부로부터의 세균, 바이러스 등의 공격을 방지하는 감염 방어인자로서 기능한다. 락토페린의 안전성은 높이 평가되고 있어, 우유로부터 추출한 락토페린은 육아용 조제분유 등의 유아용 음식품에까지 첨가되고 있다. 요즘은 다양한 병에 관한 락토페린의 연구가 주목을 받고 있다. 실험동물 모델에 있어서 병원 미생물 및 바이러스 감염에 대한 생체 방어능의 강화(예를 들면 비특허문헌 1), 각종 병태 모델에 있어서의 항염증작용, IgE 생산억제효과(예를 들면 비특허문헌 2), 화학 발암제에 의한 발암의 예방효과(예를 들면 비특허문헌 3), 암세포에 의한 혈관신생을 저해하는 효과(예를 들면 비특허문헌 4) 등등, 다양한 면역 관련의 생명현상을 조절하는 기능이 보고되어 있다. 락토페린이 내인성 및 외인성 오피오이드(opioid)의 진통효과를 증강시키는 것도 명확해져 있다(예를 들면 특허문헌 1).Some of the proteins in foods have anti-inflammatory action. For example, lactoferrin is known as a protein having anti-inflammatory action. Lactoferrin is an iron-bound glycoprotein of about 80,000 molecular weight, discovered in 1939. It is widely contained in breast milk, especially colostrum, and functions as an infection defense factor that prevents attacks of bacteria, viruses, and the like from the outside of the body. The safety of lactoferrin is highly appreciated, and lactoferrin extracted from milk is added to infant foods such as infant formula. Nowadays, lactoferrin's research on various diseases is drawing attention. Enhancement of biological defense against pathogenic microorganisms and viral infections in experimental animal models (e.g., Non-Patent Document 1), anti-inflammatory activity in various condition models, IgE production inhibitory effect (e.g., Non-patent Document 2) Preventive effects of carcinogenesis by chemical carcinogens (e.g., non-patent document 3), effects of inhibiting angiogenesis by cancer cells (e.g., non-patent document 4), etc. Is reported. It is also clear that lactoferrin enhances the analgesic effect of endogenous and exogenous opioids (for example, patent document 1).
또한, 염화 라이소자임은 18종 129개의 아미노산으로 되는 효소성을 갖는 염기성 단백질로, 소염작용을 갖는다. 진통작용에 대해서는 마우스에 50~300 ㎎/㎏을 피하 또는 경구 투여하여, 진통작용(열판법)을 측정한 결과, 작용은 전혀 확인되지 않았다고 보고되어 있다(비특허문헌 5).In addition, lysozyme chloride is a basic protein having enzymaticity consisting of 129 amino acids of 18 species, and has an anti-inflammatory effect. As for the analgesic action, 50 to 300 mg / kg of mice was administered subcutaneously or orally, and analgesic action (hot plate method) was measured. As a result, no action was reported (Non-Patent Document 5).
또한 최근, 유청이나 유청의 생산 분획이 COX-2 저해활성을 갖는 것이 보고되어 있다(특허문헌 7).Recently, whey and whey production fractions have been reported to have COX-2 inhibitory activity (Patent Document 7).
그런데, α-락토알부민은 유청 단백질의 약 25%를 차지하는, 분자량 14,000의 구상(球狀) 단백질이다. α-락토알부민은 라이소자임과의 사이에, 단백질 구조 유사성 및 유전자서열에 있어서의 높은 상동성이 있다(비특허문헌 6). α-락토알부민의 성질로서는 칼슘 결합성 단백질인 것, 시스틴 함량이 높은 것이 알려져 있으며, 또한, 소화관 운동 조절작용(예를 들면 특허문헌 2), 소장관장애의 예방 또는 수복 촉진작용, 항궤양작용(예를 들면 비특허문헌 7, 특허문헌 5, 특허문헌 6)이 알려져 있다.However, α-lactoalbumin is a globular protein having a molecular weight of 14,000, which accounts for about 25% of whey protein. α-lactoalbumin has high protein homology and high homology to lysozyme (Non-Patent Document 6). The properties of α-lactoalbumin are known to be calcium-binding proteins and high cystine contents. Further, the action of gastrointestinal motility (for example, Patent Literature 2), the prevention of small intestinal tract disorders or the promotion of repair, and the antiulcer effect (For example, nonpatent literature 7, patent document 5, and patent document 6) are known.
또한, α-락토알부민에는 월경전증후군의 증상을 억제하는 것이 보고되어 있다(특허문헌 8). 그러나, 그 작용 메커니즘에 대해서는 명확해져 있지 않다.In addition, it has been reported that α-lactoalbumin suppresses the symptoms of premenstrual syndrome (Patent Document 8). However, the mechanism of action is not clear.
특허문헌 1: 일본국 특허 제3806427호 공보Patent Document 1: Japanese Patent No. 3806427
특허문헌 2: 일본국 특허 제3756449호 공보Patent Document 2: Japanese Patent No. 3756449
특허문헌 3: 일본국 특허공개 평5-268879호 공보Patent Document 3: Japanese Patent Application Laid-Open No. 5-268879
특허문헌 4: 일본국 특허 제2916047호 공보Patent Document 4: Japanese Patent No. 2916047
특허문헌 5: 일본국 특허 제3756449호 공보Patent Document 5: Japanese Patent No. 3756449
특허문헌 6: 일본국 특허 제3481931호 공보Patent Document 6: Japanese Patent No. 3481931
특허문헌 7: 일본국 특허공표 제2007-505078호 공보Patent Document 7: Japanese Patent Publication No. 2007-505078
특허문헌 8: 일본국 특허공표 제2007-500755호 공보Patent Document 8: Japanese Patent Application Publication No. 2007-500755
비특허문헌 1: Lactoferrin; Structure, Function and Applications. Excerpta Medica Intern. Congress Series 1195 (2000), pp377-381Non Patent Literature 1: Lactoferrin; Structure, Function and Applications. Excerpta Medica Intern. Congress Series 1195 (2000), pp 377-381
비특허문헌 2: Arthritis Rheum. 43 (2000) 2073-2080[Non-Patent Document 2] Arthritis Rheum. 43 (2000) 2073-2080
비특허문헌 3: Drug Metab. Pharmacokin. 19 (2004) 245-263[Non-Patent Document 3] Drug Metab. Pharmacokin. 19 (2004) 245-263
비특허문헌 4: Japan Medical Society 2005년 10월호 락토페린 실용화 연구의 새로운 전개 제10회 암 화학 예방효과와 락토페린 안도 구니오Non-Patent Document 4: Japan Medical Society October 2005 New Development of Lactoferrin Commercialization Research 10th Cancer Chemopreventive Effect and Lactoferrin Andunio
비특허문헌 5: 의약품 인터뷰 폼 리플랩<염화 라이소자임 제제> 18페이지 에이자이 주식회사[Non-Patent Document 5] Drug Interview Form, Leaf Replep <Lysozyme Chloride Formulation>,
비특허문헌 6: Proc Natl Acad Sci U S A. 1992 July 1; 89(13): 5887-5891.Non-Patent Document 6: Proc Natl Acad Sci U S A. 1992 July 1; 89 (13): 5887-5891.
비특허문헌 7: Biosci. Biotechnol. Biochem., 67 (3), 577-583, 2003Non-Patent Document 7: Biosci. Biotechnol. Biochem., 67 (3), 577-583, 2003
발명의 개시Disclosure of Invention
발명이 해결하고자 하는 과제Problems to be Solved by the Invention
본 발명은 상기 사정을 감안하여 이루어진 것으로, 부작용이 적고, 안전성이 높아, 장기간에 걸쳐서 의약품이나 음식품으로서 섭취 가능한 신규 소염진통제를 제공하는 것을 목적으로 한다.This invention is made | formed in view of the said situation, and an object of this invention is to provide the new anti-inflammatory analgesic agent which has few side effects, high safety, and can be ingested as a medicine or food-drinks for a long time.
과제를 해결하기 위한 수단Means to solve the problem
본 발명자 등은 상기 과제를 해결하기 위해 예의 연구를 행하였다. 본 발명자 등은 안전성을 고려하여, 식품에 함유되는 천연물질 중에서 소염작용을 갖는 물질을 세밀히 탐색하였다. α-락토알부민에 대해서 소염진통작용을 검토한바, α-락토알부민은 인 비트로(in vitro)에 있어서 시클로옥시게나제(COX)-2 저해활성, 포스포리파제 A2 저해활성을 나타내었다. 또한 카라기닌 발 부종 모델(carrageenin foot edema model), 애쥬번트 관절염 모델, 초산 라이징법(acetic acid writhing test)에 의한 인 비보(in vivo)의 검증에 의해서 급성염증, 실험적 만성염증, 및 동통에 대한 치료효과를 갖는 것이 명확해졌다. 또한 본 발명자 등이 α-락토알부민의 효소 저해활성을 검토한바, COX-1보다도 COX-2를 선택적으로 저해하는 것이 명확해져, α-락토알부민을 소염진통제로서 이용할 수 있는 것을 발견하였다. α-락토알부민의 안전성의 높음은 COX-2 선택적 저해작용으로부터 예상될 뿐 아니라, 오랜 식경험에 의해 담보되고 있다고 할 수 있다. 종래, 식물(食物) 중의 단백질에 있어서, 락토페린의 소염진통효과가 알려져 있으나, 그 효과의 작용 메커니즘은 반드시 해명되어 있지는 않다. 또한 염화 라이소자임은 소염효과를 갖지만, 진통효과는 갖지 않는다. 한편, 본원 발명자는 소염진통효과를 갖는 식품 중의 단백질로서 α-락토알부민을 발견하였을 뿐 아니라, 그 효과가 COX-2 선택적 저해작용에 의한 것임을 명확하게 하였다. COX-2 선택적 저해제는 종래의 NSAIDs의 부작용 문제를 해결할 수 있을 것으로 생각되고 있어, 본 발명자 등에 의한 상기 지견(知見)은 α-락토알부민이 신규 소염진통제로서 매우 유용한 용도를 갖는 것을 증명한다. 즉, 본 발명은 α-락토알부민의 신규용도에 관하여, 구체적으로는 이하의 발명을 제공하는 것이다.MEANS TO SOLVE THE PROBLEM This inventor earnestly researched in order to solve the said subject. In view of safety, the present inventors have carefully searched for substances having an anti-inflammatory effect among natural substances contained in foods. The anti-inflammatory analgesic effect of α-lactoalbumin was examined, and α-lactoalbumin showed cyclooxygenase (COX) -2 inhibitory activity and phospholipase A2 inhibitory activity in vitro. In addition, the validation of carrageenin foot edema model, adjuvant arthritis model, and in vivo by acetic acid writhing test can be used for acute inflammation, experimental chronic inflammation, and pain. It has become clear that it has a therapeutic effect. In addition, the inventors of the present invention examined the enzyme inhibitory activity of α-lactoalbumin, and it was clear that COX-2 was selectively inhibited over COX-1, and it was found that α-lactoalbumin can be used as an anti-inflammatory analgesic. The high safety of α-lactoalbumin is expected not only from COX-2 selective inhibitory action but also from long-term dietary experience. Conventionally, the anti-inflammatory analgesic effect of lactoferrin is known in the protein in plants, but the mechanism of action of the effect is not necessarily elucidated. Lysozyme chloride also has an anti-inflammatory effect, but no analgesic effect. On the other hand, the inventors of the present invention not only found α-lactoalbumin as a protein in foods having an anti-inflammatory analgesic effect, but also clarified that the effect was due to COX-2 selective inhibition. It is thought that COX-2 selective inhibitors could solve the side effect problem of conventional NSAIDs, and the above findings by the present inventors demonstrate that α-lactoalbumin has a very useful use as a novel anti-inflammatory analgesic. That is, this invention provides the following invention specifically about the novel use of (alpha)-lactoalbumin.
(1) α-락토알부민을 유효성분으로 하는 COX-2 선택적 저해제,(1) a COX-2 selective inhibitor containing α-lactoalbumin as an active ingredient,
(2) α-락토알부민을 유효성분으로 하는 소염진통제,(2) anti-inflammatory analgesic containing α-lactoalbumin as an active ingredient,
(3) 소염진통제의 제조를 위한 α-락토알부민의 사용,(3) use of α-lactoalbumin for the manufacture of anti-inflammatory analgesics,
(4) 염증성 질환 치료제인, 청구항 2에 기재된 소염진통제,(4) the anti-inflammatory analgesic agent according to
(5) 염증성 질환이 관절염 또는 관절 류머티즘인, 청구항 4에 기재된 소염진통제,(5) the anti-inflammatory analgesic agent according to
(6) 동통성 질환 치료제인, 청구항 2에 기재된 소염진통제,(6) the anti-inflammatory analgesic agent according to
(7) 동통성 질환이 월경통인, 청구항 6에 기재된 소염진통제,(7) the anti-inflammatory analgesic agent according to
(8) α-락토알부민을 유효성분으로 하는 소염진통용 음식품,(8) anti-inflammatory analgesic foods containing α-lactoalbumin as an active ingredient,
(9) α-락토알부민의 치료적 유효량을 포유동물에 투여하는 염증성 질환의 치료방법,(9) a method of treating inflammatory diseases in which a therapeutically effective amount of α-lactoalbumin is administered to a mammal,
(10) α-락토알부민의 치료적 유효량을 포유동물에 투여하는 동통성 질환의 치료방법.(10) A method of treating pain disorders in which a mammal is administered a therapeutically effective amount of α-lactoalbumin.
발명의 효과Effects of the Invention
본 발명에 의해 신규 소염진통제가 제공되었다. 본 발명의 신규 소염진통제는 COX-2를 선택적으로 저해하기 때문에, 소화성 궤양이나 천식 등의 부작용의 발생은 적어, 장기간에 걸쳐서 섭취 가능할 것으로 생각된다. α-락토알부민은 상기와 같이 포유류의 유즙 중에 포함되어 있어, 오랜 식경험으로부터 안전하다는 인식이 있다. 또한 실제로 α-락토알부민의 안전성은 과학적으로 검증되어 있고, 예를 들면 특허문헌 5는 랫트를 사용한 α-락토알부민의 급성독성시험의 결과에서, 최대용량인 2,000 ㎎/㎏ 체중의 α-락토알부민 투여에 의해서도, 공시험과 마찬가지로 사망예는 확인되지 않았다고 보고하고 있다. 또한 원래 식품 중에 존재하는 물질인 것으로부터, 의약품으로서 뿐 아니라, 음식품으로서 가공·유통시키는 것도 기대할 수 있다. 또한, 우유 등의 비교적 저렴한 원료로부터 얻을 수 있기 때문에, 대량생산이 가능하다.Novel anti-inflammatory drugs have been provided by the present invention. Since the novel anti-inflammatory analgesic agent of the present invention selectively inhibits COX-2, side effects such as peptic ulcer and asthma are less likely to be ingested for a long time. α-lactoalbumin is included in milk of mammals as described above, and it is recognized that it is safe from a long food experience. In fact, the safety of α-lactoalbumin has been scientifically verified. For example, Patent Document 5 shows that the maximum dose of α-lactoalbumin, 2,000 mg / kg body weight, is the result of an acute toxicity test of α-lactoalbumin using rats. It has been reported that death was not confirmed by administration as in the blank test. Moreover, since it is a substance existing in food originally, it can be expected to process and distribute not only as a medicine but as a food-drink. In addition, since it can be obtained from relatively inexpensive raw materials such as milk, mass production is possible.
우유 중의 락토페린은 공업적으로는 우유로부터 분리 기술에 의해 취출(取出)된다. 락토페린의 함유량은 산지, 사료 등에 따라서 다소 차이는 있으나, 일본 국내산 우유의 경우는 통상 200 ㎎/㎏으로 극미량이다. 그 때문에, 미량의 락토페린을 취출하기에 충분한 젖(乳)을 일본 국내에서는 조달할 수 없어, 일본에서는 전혀 생산되고 있지 않아, 모두 수입에 의존하고 있는 상황에 있다.Lactoferrin in milk is industrially taken out by the separation technique from milk. The content of lactoferrin is somewhat different depending on the place of origin, the feed, etc., but in the case of domestic milk in Japan, it is usually a very small amount of 200 mg / kg. Therefore, milk sufficient to extract trace amounts of lactoferrin cannot be procured in Japan, and it is not produced in Japan at all, and all depend on imports.
또한, 우유 중의 α-락토알부민의 함유량은 산지, 사료 등에 따라서 다소 차이는 있으나, 일본 국내산 우유의 경우는 통상 1.2 g/㎏이다. 락토페린에 비해 풍부하게 함유되어 있고, 공업적 분리도 용이하다. 그 때문에, 안정적 확보가 가능해질 뿐 아니라, 조달 비용도 저렴해진다.The content of α-lactoalbumin in milk varies somewhat depending on the place of origin, feed, and the like, but is generally 1.2 g / kg for milk produced in Japan. It is richer than lactoferrin and is easy to industrially separate. Therefore, not only can it be secured securely, but also procurement cost becomes low.
도면의 간단한 설명Brief description of the drawings
도 1은 카라기닌 발 부종 억제시험 모델에서의 발 용적의 추이를 나타내는 도면이다. 1군 6마리의 평균값 + 표준오차로 나타내었다. control은 대조, WPI는 유청 단백질 분리물, bLG는 β-락토글로불린, aLA는 α-락토알부민, LF는 락토페린을 나타낸다. *:vs. control, p<0.05(Dunnet의 다중비교검정)BRIEF DESCRIPTION OF THE DRAWINGS It is a figure which shows the change of foot volume in a carrageenan foot edema suppression test model. The mean value of 6 animals of 1 group + standard error was shown. Control is control, WPI is whey protein isolate, bLG is β-lactoglobulin, aLA is α-lactoalbumin, and LF is lactoferrin. *: vs. control, p <0.05 (Dunnet's multiple comparison test)
도 2는 애쥬번트 관절염(치료) 모델에서의 발 용적의 추이를 나타내는 도면이다. 1군 6마리의 평균값 + 표준오차로 나타내었다. Vehicle은 대조, bLG는 β-락토글로불린, aLA는 α-락토알부민, LF는 락토페린, Dicro는 디클로페낙을 나타낸다. *, **, ***:vs. Vehicle, p<0.05, 0.01, 0.001(Dunnet의 다중비교검정)FIG. 2 is a graph showing the change of the foot volume in the adjuvant arthritis (treatment) model. The mean value of 6 animals of 1 group + standard error was shown. Vehicle is control, bLG is β-lactoglobulin, aLA is α-lactoalbumin, LF is lactoferrin, and Dicro is diclofenac. *, **, ***: vs. Vehicle, p <0.05, 0.01, 0.001 (Dunnet's multiple comparison test)
도 3은 애쥬번트 관절염(동통) 모델에서의 명제(鳴啼)반응의 횟수를 나타내는 도면이다. 1군 6마리의 평균값 + 표준오차로 나타내었다. Vehicle은 대조, bLG는 β-락토글로불린, aLA는 α-락토알부민, LF는 락토페린, Dicro는 디클로페낙을 나타낸다. *, **:vs. Vehicle, p<0.05, 0.01(Dunnet의 다중비교검정)3 is a diagram showing the number of prostatic reactions in the adjuvant arthritis (pain) model. The mean value of 6 animals of 1 group + standard error was shown. Vehicle is control, bLG is β-lactoglobulin, aLA is α-lactoalbumin, LF is lactoferrin, and Dicro is diclofenac. *, **: vs. Vehicle, p <0.05, 0.01 (Dunnet's multiple comparison test)
도 4는 초산 라이징 시험 모델에서의 고민(苦悶)동작의 횟수를 나타내는 도면이다. 1군 6마리의 평균값 + 표준오차로 나타내었다. Vehicle은 대조, WPI는 유청 단백질 분리물, bLG는 β-락토글로불린, aLA는 α-락토알부민, LF는 락토페린, Dicro는 디클로페낙을 나타낸다. *, **:vs. Vehicle, p<0.05, 0.01(Dunnet의 다중비교검정)It is a figure which shows the frequency | count of trouble operation in an acetic acid rising test model. The mean value of 6 animals of 1 group + standard error was shown. Vehicle represents control, WPI represents whey protein isolate, bLG represents β-lactoglobulin, aLA represents α-lactoalbumin, LF represents lactoferrin, and Dicro represents diclofenac. *, **: vs. Vehicle, p <0.05, 0.01 (Dunnet's multiple comparison test)
도 5는 α-락토알부민의, 월경통에 대한 개선효과를 랜덤화 더블 블라인드 크로스 오버 시험에 있어서의, 월경통의 통증 정도에 관한 결과를 나타내는 도면이다.Fig. 5 is a diagram showing the results of the degree of pain of dysmenorrhea in the randomized double-blind crossover test of α-lactoalbumin for improvement of menstrual pain.
도 6은 α-락토알부민의, 월경통에 대한 개선효과를 랜덤화 더블 블라인드 크로스 오버 시험에 있어서의, 월경통에 의한 일상생활으로의 영향 정도에 관한 결과를 나타내는 도면이다.Fig. 6 is a diagram showing the results of the degree of the effect of α-lactoalbumin on dysmenorrhea in the randomized double-blind crossover test, which affects daily life due to dysmenorrhea.
도 7은 α-락토알부민의, 월경통에 대한 개선효과를 랜덤화 더블 블라인드 크로스 오버 시험에 있어서의, 진통제의 사용 정도에 관한 결과를 나타내는 도면이다.Fig. 7 shows the results of the degree of use of analgesics in a randomized double-blind crossover test of α-lactoalbumin for improvement of menstrual pain.
발명을 실시하기Implement the invention 위한 최선의 형태 Best form for
이하, 본 발명을 상세하게 설명한다. 단, 본 발명은 이하의 바람직한 실시태양에 한정되지 않고, 본 발명의 범위 내에서 자유롭게 변경할 수 있는 것이다.EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail. However, this invention is not limited to the following preferable embodiment, It can change freely within the range of this invention.
본 발명은 α-락토알부민을 유효성분으로 하는 COX-2 선택적 저해제에 관한 것이다. 본 발명에 있어서 COX-2 선택적 저해제란, COX-1 저해효과보다도 COX-2 저해효과가 강한 물질을 의미한다. 본 발명의 α-락토알부민은 특별히 유래는 상관없지만, 바람직하게는 인간 및/또는 비인간 포유동물(소, 양, 염소, 말 등) 유래이고, 보다 바람직하게는 인간 또는 소의 α-락토알부민이다. 이들의 α-락토알부민의 아미노산 서열이나 염기서열은 이미 공지이고, EMBL, DDBJ, NCBI 등의 데이터베이스에 등록되어 있다. 예를 들면 소 α-락토알부민은 DDBJ에 ACCESSION No.J05147로서 등록되어 있다. 소 α-락토알부민의 염기서열을 서열번호: 1에, 아미노산 서열을 서열번호: 2에 나타낸다. 서열번호: 2에 기재된 아미노산 서열에 있어서, 제1번 위치부터 제19번 위치는 시그널 펩티드이다. 또한, 서열번호: 2에 기재된 아미노산 서열에 있어서, 제29번 위치의 아르기닌(R)이 글루타민(Q)으로 치환된 변이체의 존재가 알려져 있다(「밀크 종합사전」p.35, 아사쿠라쇼텐). 우유 중에 분비되는 α-락토알부민은 시그널 펩티드가 절단된 성숙 펩티드이다. 본원 실시예에서 사용한 α-락토알부민은 상기 소 성숙 펩티드이다.The present invention relates to a COX-2 selective inhibitor comprising α-lactoalbumin as an active ingredient. In the present invention, a COX-2 selective inhibitor means a substance having a stronger COX-2 inhibitory effect than a COX-1 inhibitory effect. The α-lactoalbumin of the present invention is not particularly derived, but is preferably derived from human and / or non-human mammals (cows, sheep, goats, horses, etc.), and more preferably human or bovine α-lactoalbumin. The amino acid sequence and base sequence of these (alpha)-lactoalbumin are already well-known, and are registered in the databases of EMBL, DDBJ, NCBI, etc. For example, bovine α-lactoalbumin is registered in DDBJ as ACCESSION No. J05147. The base sequence of bovine α-lactoalbumin is shown in SEQ ID NO: 1, and the amino acid sequence is shown in SEQ ID NO: 2. In the amino acid sequence set forth in SEQ ID NO: 2,
α-락토알부민은 인간, 소, 양, 염소 등의 포유류의 젖 등으로부터, 황산암모늄 침전법(「최신 개고 유업기술 편람」낙농기술보급학회, 122-125 페이지, 1975), 한외여과법(특허문헌 3), 이온 교환법(특허문헌 4) 등의 공지기술에 의해 제조할 수 있다. 우유 중의 α-락토알부민의 함유량은 산지, 사료 등에 따라서 다소의 차이는 있으나, 일본 국내산 우유의 경우는 통상 1.2 g/㎏으로, 제조원료로서 우유를 사용하면 다량의 α-락토알부민을 조제할 수 있다. 또한, 아미노산 서열 및 염기서열을 토대로, 화학적으로 합성하거나, 당업자에게 주지의 유전자공학적 수법으로 제조해도 된다. 보다 간편하게는, 시판의 α-락토알부민(예를 들면 다비스코사제 등)을 사용할 수 있다.α-lactoalbumin is derived from the milk of mammals such as humans, cows, sheep and goats by precipitation of ammonium sulphate ("The Latest High Dairy Technology Manual", Dairy Technology Promotion Society, 122-125, 1975), Ultrafiltration (Patent Literature). 3) It can manufacture by well-known techniques, such as the ion exchange method (patent document 4). Although the content of α-lactoalbumin in milk varies slightly depending on the place of origin and feed, it is usually 1.2 g / kg for domestic milk, and a large amount of α-lactoalbumin can be prepared by using milk as a raw material. have. Moreover, you may synthesize | combine chemically based on an amino acid sequence and a nucleotide sequence, or you may manufacture by genetic engineering methods well known to those skilled in the art. More conveniently, commercially available α-lactoalbumin (for example, manufactured by Dabisco Co., Ltd.) can be used.
또한 본 발명에 있어서, 사용 가능한 α-락토알부민은 전술한 인간 또는 비인간 포유동물의 천연형으로서 알려지는 공지 아미노산 서열로 되는 것에 한정되지 않고, COX-2 선택적 저해활성을 갖는 한, 상기 아미노산 서열에 변이가 존재하는 변이체의 폴리펩티드여도 된다. 이러한 폴리펩티드의 예로서는, 천연형의 변이체, 동족체(homologue), 인위적 변이체 등을 들 수 있고, 구체적으로는, 천연형의 α-락토알부민아미노산 서열에 1 또는 복수의 아미노산이 부가, 결실, 치환, 삽입된 서열을 포함하는 폴리펩티드나, 천연형의 α-락토알부민을 코드하는 폴리뉴클레오티드의 상보가닥에 스트린젠트한 조건에서 하디브리다이즈하는 폴리뉴클레오티드가 코드하는 폴리펩티드를 들 수 있으며, 보다 구체적으로는, 서열번호: 2에 기재된 아미노산 서열에 1 또는 복수의 아미노산이 부가, 결실, 치환, 삽입된 서열을 포함하는, COX-2 선택적 저해활성을 갖는 폴리펩티드를 들 수 있고, 또한 다른 예로서, 서열번호: 1에 기재된 염기서열의 코드 영역을 포함하는 폴리뉴클레오티드의 상보가닥에 스트린젠트한 조건에서 하이브리다이즈하는 폴리뉴클레오티드가 코드하는, COX-2 선택적 저해활성을 갖는 폴리펩티드를 들 수 있다.In the present invention, the α-lactoalbumin which can be used is not limited to the known amino acid sequence known as the natural form of the human or non-human mammal described above, and as long as it has COX-2 selective inhibitory activity, The polypeptide of the variant in which the mutation exists may be used. Examples of such polypeptides include naturally occurring variants, homologues, and artificial variants. Specifically, one or more amino acids are added, deleted, substituted, or inserted into the native α-lactoalbuminamino acid sequence. Polypeptides comprising a sequence comprising a sequence or a polypeptide encoded by a polynucleotide that hybridizes to a complementary strand of a polynucleotide encoding a native α-lactoalbumin under conditions that are stringent, and more specifically, And polypeptides having COX-2 selective inhibitory activity, including sequences in which one or a plurality of amino acids are added, deleted, substituted, or inserted into the amino acid sequence of SEQ ID NO: 2, and as another example, SEQ ID NO: Hybridized under conditions stringent to the complementary strand of the polynucleotide comprising the code region of the nucleotide sequence of 1; Li a nucleotide code, there may be mentioned a polypeptide having a selective COX-2 inhibitory activity.
상기 변이체 폴리펩티드는 당업자에게 주지의 기술에 의해서 제조할 수 있다. 예를 들면, 유선(乳腺) 등의 α-락토알부민을 발현하는 동물세포로부터 total mRNA를 조제하고, 천연형 α-락토알부민의 염기서열을 토대로 설계한 프라이머를 사용해서 RT-PCR을 행하여, 얻어진 DNA를 적당한 프로모터와 함께 숙주 벡터계에 도입하여 발현시킴으로써, 변이체 폴리펩티드를 얻을 수 있다. 또는 동물세포로부터 cDNA 라이브러리를 제작하고, 천연형 α-락토알부민의 염기서열을 토대로 제작한 프로브를 사용하여, 그 cDNA 라이브러리 중에서 그 프로브에 스트린젠트한 조건에서 하이브리다이즈하는 폴리뉴클레오티드를 선택하고, 그 폴리뉴클레오티드를 적당한 숙주에 도입하여 발현시켜, 변이체 폴리펩티드를 얻을 수 있다. 상기 프로모터나 숙주 벡터계는 당업자라면 공지의 프로모터나 숙주 벡터계 중에서 적절히 선택 가능하다.Such variant polypeptides can be prepared by techniques known to those skilled in the art. For example, a total mRNA was prepared from animal cells expressing α-lactoalbumin such as mammary gland, and RT-PCR was obtained using a primer designed based on the nucleotide sequence of native α-lactoalbumin. Variant polypeptides can be obtained by introducing and expressing DNA into a host vector system with a suitable promoter. Alternatively, a cDNA library was prepared from animal cells, and a polynucleotide hybridized under conditions conducive to the probe was selected from the cDNA library using a probe prepared based on the nucleotide sequence of native α-lactoalbumin. Variant polypeptide can be obtained by introducing the polynucleotide into an appropriate host and expressing it. The promoter or host vector system can be appropriately selected by those skilled in the art from a known promoter or host vector system.
상기 스트린젠트한 하이브리다이제이션 조건은 당업자라면 적절히 선택할 수 있다. 일례를 나타내면, 25% 포름아미드, 보다 엄격한 조건에서는 50% 포름아미드, 4×SSC, 50 mM Hepes pH 7.0, 10×덴하르트 용액, 20 ㎍/㎖ 변성 연어 정자 DNA를 포함하는 하이브리다이제이션 용액 중, 42℃에서 하룻밤 프리하이브리다이제이션을 행한 후, 표지한 프로브를 첨가하고, 42℃에서 하룻밤 보온함으로써 하이브리다이제이션을 행한다. 그 후의 세정에 있어서의 세정액 및 온도조건은 「1×SSC, 0.1% SDS, 37℃」정도에서, 보다 엄격한 고스트린젠트한 조건으로서는 「0.5×SSC, 0.1% SDS, 42℃」정도에서, 더욱 엄격한 고스트린젠트한 조건으로서는 「0.2×SSC, 0.1% SDS, 65℃」 정도에서 실시할 수 있다. 이와 같이 하이브리다이제이션의 세정 조건이 엄격해질수록 프로브 서열과 높은 상동성을 갖는 폴리뉴클레오티드의 단리를 기대할 수 있다. 단, 상기 SSC, SDS 및 온도 조건의 조합은 예시이며, 당업자라면, 하이브리다이제이션의 스트린젠시를 결정하는 상기 또는 다른 요소(예를 들면, 프로브 농도, 프로브 길이, 하이브리다이제이션 반응시간 등)를 적절히 조합함으로써, 상기와 동일한 스트린젠시를 실현하는 것이 가능하다.The stringent hybridization conditions can be appropriately selected by those skilled in the art. In one example, in a hybridization solution comprising 25% formamide, under more
이와 같은 하이브리다이제이션 기술을 이용하여 단리되는 폴리뉴클레오티드가 코드하는 폴리펩티드는, 통상, 상기 천연형 폴리펩티드와 아미노산 서열에 있어서 높은 상동성을 갖는다. 높은 상동성이란, 적어도 40% 이상, 바람직하게는 60% 이상, 더욱 바람직하게는 80% 이상, 더욱 바람직하게는 90% 이상, 더욱 바람직하게는 적어도 95%의 상동성을 갖는다.Polypeptides encoded by polynucleotides isolated using such hybridization techniques usually have high homology to the above-described native polypeptide and amino acid sequence. High homology means homology of at least 40%, preferably at least 60%, more preferably at least 80%, more preferably at least 90%, even more preferably at least 95%.
또는 천연형 α-락토알부민의 염기서열에, 카세트 변이법이나 PCR에 의한 변이법 등에 의해서 인위적인 변이를 부위 특이적 또는 랜덤으로 도입하고, 상기 폴리뉴클레오티드를 적당한 숙주 벡터계를 사용하여 발현시킴으로써, 변이체 폴리펩티드를 얻을 수 있다. 상기와 같이 조제한 폴리펩티드가 COX-2 선택적 저해활성을 갖는지 여부는, 공지 수법에 의해서 COX-1 및 2에 대한 그 폴리펩티드의 저해활성을 측정함으로써 확인할 수 있고, 예를 들면 후술하는 본원 실시예에 기재된 방법으로 확인할 수 있다. 이와 같은 COX-2 선택적 저해활성을 갖는 변이체 폴리펩티드의 아미노산 서열은 천연형의 아미노산 서열에 대해 높은 상동성을 가지며, 예를 들면 상동성은 80% 이상 또는 85% 이상이고, 바람직하게는 90% 이상이며, 보다 바람직하게는 95% 이상이다.Or by introducing site-specific or random site-specific mutations into the nucleotide sequence of native α-lactoalbumin by a cassette mutation method or PCR mutation method, and expressing the polynucleotide using an appropriate host vector system. Polypeptides can be obtained. Whether or not the polypeptide prepared as described above has COX-2 selective inhibitory activity can be confirmed by measuring the inhibitory activity of the polypeptide against COX-1 and 2 by a known method, for example, as described in Examples described later. This can be confirmed by the method. The amino acid sequence of the variant polypeptide having such COX-2 selective inhibitory activity has high homology to the native amino acid sequence, for example, the homology is 80% or more or 85% or more, preferably 90% or more. More preferably, it is 95% or more.
본 실시형태에 있어서, 후술하는 실시예로부터 명확한 바와 같이, 소염진통작용을 향수하기 위해서는, 제형, 증상, 체중 등에 따라서 상이하나, 그 유효성분인 α-락토알부민류는 1일에 체중 1 ㎏당 단백질 환산으로 약 0.002 ㎎~약 1,000 ㎎, 바람직하게는 약 0.01 ㎎~약 200 ㎎, 가장 바람직하게는 약 0.2 ㎎~약 40 ㎎을 투여(섭취)할 수 있다.In the present embodiment, as is clear from the examples described later, in order to perfume the anti-inflammatory analgesic effect, it differs depending on the dosage form, symptoms, weight, etc., but the α-lactoalbumins, the active ingredient, per kg of body weight per day In terms of protein, about 0.002 mg to about 1,000 mg, preferably about 0.01 mg to about 200 mg, and most preferably about 0.2 mg to about 40 mg can be administered (ingested).
본 발명의 소염진통제의 유효성분인 α-락토알부민의 투여량은, 일반적으로는 유효성분으로서 1일당 약 0.1 ㎎~약 50,000 ㎎, 바람직하게는 약 0.5 ㎎~약 10,000 ㎎, 가장 바람직하게는 약 10 ㎎~약 2,000 ㎎을, 한번에 또는 분할하여, 본 발명의 조성물에 의한 처치가 필요로 되고 있는 환자에 대해, 식전, 식사 후, 식간 및/또는 취침 전에 투여할 수 있다. 투여량은 개별적으로, 투여되는 환자의 연령, 체중, 및 투여목적에 따라서 정하는 것도 가능하다.The dosage of α-lactoalbumin, the active ingredient of the anti-inflammatory analgesic agent of the present invention, is generally about 0.1 mg to about 50,000 mg per day, preferably about 0.5 mg to about 10,000 mg, and most preferably about 10 mg to about 2,000 mg can be administered at one time or in divided portions to a patient in need of treatment with the composition of the present invention before meals, after meals, between meals and / or before bedtime. Dosages can also be determined individually, depending on the age, weight, and purpose of the patient being administered.
본 발명의 소염진통제는 의약품 또는 음식품 중 어느 형태로도 이용할 수 있따. 예를 들면, 의약품으로서 직접 투여함으로써, 또는 특정 보건용 식품 등의 특별용도 식품이나 영양기능식품으로서 직접 섭취함으로써 각종 염증·통증의 치료 및/또는 예방하는 것이 기대된다. 또한, 액상, 페이스트상, 고형, 분말 등의 형태를 불문하고, 각종 식품(우유, 청량음료, 발효유, 요구르트, 치즈, 빵, 비스킷, 크래커, 피자 크러스트, 조제분유, 유동식, 병자용 식품, 영양식품, 냉동식품, 가공식품 기타 시판 식품 등)에 첨가하여, 이를 섭취해도 된다.Anti-inflammatory drugs of the present invention can be used in any form of medicines or food and drink. For example, it is expected to treat and / or prevent various inflammations and pains by directly administering them as medicines or directly ingesting them as special purpose foods or nutritional functional foods such as specific health foods. Various types of foods (milk, soft drinks, fermented milk, yogurt, cheese, bread, biscuits, crackers, pizza crust, powdered formulas, formulas, bottled foods, nutrition), regardless of the form of liquids, pastes, solids, powders, etc. Food, frozen foods, processed foods, and other commercially available foods).
본 발명의 소염진통제를 함유하는 식품에는 물, 단백질, 당질, 지질, 비타민류, 미네랄류, 유기산, 유기염기, 과즙, 향미료류 등을 혼합하여 사용할 수 있다. 단백질로서는, 예를 들면 전지분유, 탈지분유, 부분탈지분유, 카제인, 유청분말, 유청 단백질, 유청 단백질 농축물, 유청 단백질 분리물, α-카제인, β-카제인, κ-카제인, β-락토글로불린, 락토페린, 대두 단백질, 계란 단백질, 육단백질 등의 동식물성 단백질, 이들의 분해물; 버터, 유청 미네랄, 크림, 유청, 비단백태 질소, 시알산, 인지질, 젖당 등의 각종 젖 유래 성분 등을 들 수 있다. 카제인 포스포펩티드, 아르기닌, 리신 등의 펩티드나 아미노산을 포함하고 있어도 된다. 당질로서는, 예를 들면 당류, 가공전분(덱스트린 외에, 가용성 전분, 브리티시 전분, 산화전분, 전분 에스테르, 전분 에테르 등), 식물섬유 등을 들 수 있다. 지질로서는, 예를 들면, 라드, 어유 등, 이들의 분별유, 수소 첨가유, 에스테르 교환유 등의 동물성 유지; 팜유, 홍화유, 콘유, 평지씨유, 야자유, 이들의 분별유, 수소 첨가유, 에스테르 교환유 등의 식물성 유지 등을 들 수 있다. 비타민류로서는, 예를 들면 비타민 A, 카로틴류, 비타민 B군, 비타민 C, 비타민 D군, 비타민 E, 비타민 K군, 비타민 P, 비타민 Q, 나이아신, 니코틴산, 판토텐산, 비오틴, 이노시톨, 콜린, 엽산 등을 들 수 있고, 미네랄류로서는, 예를 들면 칼슘, 칼륨, 마그네슘, 나트륨, 구리, 철, 망간, 아연, 셀렌 등을 들 수 있다. 유기산으로서는, 예를 들면 사과산, 구연산, 유산, 타르타르산 등을 들 수 있다. 본 발명의 소염진통제를 함유하는 음식품의 제조에 있어서, 이들은 합성품이어도 되고 천연물 유래품 중 어느 것이어도 되며, 및/또는 많이 포함하는 식품을 원재료로서 사용해도 된다. 이들의 성분은 2종 이상을 조합하여 사용할 수 있다. 식품의 형태로서는, 고체여도 되고 액체여도 상관없다. 또한 겔상 등이어도 된다.Foods containing an anti-inflammatory analgesic agent of the present invention can be used by mixing water, protein, sugar, lipids, vitamins, minerals, organic acids, organic bases, fruit juices, spices and the like. As the protein, for example, whole milk powder, skim milk powder, partially skim milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, α-casein, β-casein, κ-casein, β-lactoglobulin Animal and vegetable proteins such as lactoferrin, soy protein, egg protein, and hexaprotein, and their degradation products; And various milk derived components such as butter, whey mineral, cream, whey, nonprotein nitrogen, sialic acid, phospholipid, lactose and the like. You may contain peptides and amino acids, such as casein phosphopeptide, arginine, and lysine. Examples of the saccharides include sugars, processed starch (soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), plant fiber, and the like, in addition to dextrin. As a lipid, For example, animal fats and oils, such as these fractionation oil, hydrogenated oil, and transesterified oil; And vegetable oils such as palm oil, safflower oil, corn oil, rapeseed oil, palm oil, fractionated oils thereof, hydrogenated oils, and transesterified oils. As vitamins, for example, vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline, folic acid Etc. As minerals, calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium, etc. are mentioned, for example. Examples of the organic acid include malic acid, citric acid, lactic acid, tartaric acid, and the like. In the preparation of the food-drinks containing the anti-inflammatory analgesic agent of this invention, these may be synthetic | combination goods, any of natural-derived products, and / or food containing many may be used as a raw material. These components can be used in combination of 2 or more type. The form of the food may be either solid or liquid. Moreover, gel form etc. may be sufficient.
본 발명의 소염진통제를 의약품으로서 사용하는 경우에는 각종 형태로 투여할 수 있다. 그 형태로서, 예를 들면 정제, 캡슐제, 과립제, 산제, 시럽제 등에 의한 경구 투여를 들 수 있으나, 주사제나 액제 등의 제제로 가공하여 경관(經管), 정맥주사, 피내(皮內), 근육주사 등 다른 투여형태여도 된다. 이들의 각종 제제는 통상의 방법에 따라서 주제에 부형제, 결합제, 붕괴제, 활택제, 교취제, 용해보조제, 현탁제, 코팅제, 용제, 등장화제 등의 의약의 제제기술분야에 있어서 통상 사용할 수 있는 기지의 보조제를 사용하여 제제화할 수 있다. 또한, 적당량의 칼슘을 포함하고 있어도 된다. 추가적으로 적당량의 비타민, 미네랄, 유기산, 당류, 아미노산, 펩티드류 등을 첨가해도 된다.When the anti-inflammatory analgesic agent of the present invention is used as a medicine, it can be administered in various forms. As the form thereof, for example, oral administration by tablets, capsules, granules, powders, syrups, etc. may be used, but it is processed into preparations such as injections or liquids, and is used for cervical, intravenous, intradermal, muscle Other dosage forms such as injection may be used. These various formulations are known and commonly used in the field of preparation of pharmaceuticals such as excipients, binders, disintegrants, lubricants, odorants, dissolution aids, suspending agents, coating agents, solvents, isotonic agents, etc. according to conventional methods. Formulations may be formulated using an adjuvant. In addition, an appropriate amount of calcium may be included. In addition, an appropriate amount of vitamins, minerals, organic acids, sugars, amino acids, peptides and the like may be added.
본 발명의 소염진통제는 염증성 질환의 치료에 사용할 수 있다. 본 발명의 소염진통제는, 예를 들면 관절염, 관절 류머티즘(약년성(若年性), 만성), 궤양성 대장염, 클론병에 적용 가능하나, 이들에 한정되지 않고, 염증을 수반하는 질환 전반에 적용 가능하다.Anti-inflammatory drugs of the present invention can be used for the treatment of inflammatory diseases. The anti-inflammatory analgesic agent of the present invention can be applied to, for example, arthritis, rheumatoid arthritis (running, chronic), ulcerative colitis, and clonal disease, but is not limited to these, and is generally applied to diseases involving inflammation. It is possible.
관절염에는 감염성, 면역성, 결정성 등의 종류가 존재한다. 구체적으로는, 결핵, 통풍, 만성 관절 류머티즘, 변형성 관절증, 급성 류머티즘열, 건선성 관절염, 약년성 관절 류머티즘, 스틸병(Still's disease), 라이터증후군(Reiter's syndrome), 강직성척추염 등이 알려져 있다(이무라 히로오, 오가타 에츠로, 다카쿠 후미마로, 다루이 세이이치로편 「최신 내과학대계 제74권 관절질환 <골·관절질환 2>」, 나카야마쇼텐 발행, p.19, 1995년). 이들 질환의 치료에 사용되는 제(劑)의 하나로서 COX 저해제 등의 NSAIDs가 사용되고 있다.Types of arthritis include infectious, immune, and crystalline. Specifically, tuberculosis, gout, chronic arthritis rheumatoid, deformed arthrosis, acute rheumatism fever, psoriatic arthritis, acute joint rheumatism, Still's disease, Reiter's syndrome, ankylosing spondylitis are known. La Hiroo, Etsuro Ogata, Fumimaru Takaku, and Seichiro Darui, `` Latest Internal Medicine, Vol. 74 Joint Disease <Bone and
관절 류머티즘은 다발성 관절염이 일어나는 만성 염증성 질환이다. 그 정확한 원인은 불명확하나, 체질 소인, 면역학적 요인, 환경인자의 3개가 중요시되고 있다. 면역학적 요인의 경우는, 사이토카인이라는 물질을 분비하여 면역에 있어서 중요한 작용을 하고 있는 림프구가 이상한 작용을 하는 결과, 이상한 항체가 출현하여 자기 관절의 조직에 결합하여 관절염을 일으키는 것으로 알려져 있다. 초기 증상의 대부분은, 기상시에 관절이 뻣뻣해지고, 관절의 통증과 종창이 일어난다. 관절의 통증은 자발통(自發痛)(안정시), 압통(壓痛), 운동통(運動痛) 등 다양하다. 기타, 관절의 부음, 열, 발적 등의 증상을 나타낸다. 관절염은 활막(滑膜)이 염증을 일으킨 활막염으로, 수족의 관절에 대칭적으로 많이 보인다. 자주 병에 걸리는 관절은 손가락·발가락, 손, 발, 팔꿈치, 무릎, 어깨 등으로, 진행되면 변형되는 경우도 있다. 일단, 관절 류머티즘이 발증하면 완전한 치료는 곤란하여, 환자는 평생 이 병과 함께 하게 된다.Joint rheumatism is a chronic inflammatory disease in which multiple arthritis occurs. The exact cause is unclear, but three factors of constitution, immunological factors, and environmental factors are important. In the case of immunological factors, it is known that lymphocytes, which play an important role in immunity by secreting a substance called cytokine, have a strange effect. As a result, strange antibodies appear and bind to tissues of their joints to cause arthritis. Most of the initial symptoms are stiff joints during waking, pain and swelling of the joints. Joint pain is varied, such as spontaneous pain (stable), tenderness (壓痛), exercise pain (運動 痛). Other symptoms include swollen joints, fever, and redness. Arthritis is a synovial inflammation in which the synovial membrane is inflamed. It is symmetrically seen in the joints of the limbs. Frequently, the joints that get sick are deformed as they progress to the fingers, toes, hands, feet, elbows, knees, and shoulders. Once joint rheumatism develops, complete treatment is difficult and the patient will be with the disease for life.
요즘, 만성 관절 류머티즘 등의 관절의 염증성 동통 또는 뼈의 접합부위의 염증성 동통을 완화하기 위해 일상적으로 처방되는 약제는, NSAIDs로 불리는 아스피린, 인도메타신, 이부프로펜, 디클로페낙 등, 수십 종류의 합성화합물과, 스테로이드로 불리는 합성 글루코코르티코이드 등이다.Nowadays, medicines routinely prescribed to alleviate inflammatory pain in joints such as chronic joint rheumatism or inflammatory pain in bone junctions include dozens of synthetic compounds, such as aspirin, indomethacin, ibuprofen, and diclofenac, which are called NSAIDs. And synthetic glucocorticoids called steroids.
염증성 동통을 매개하는 것은 프로스타글란딘으로, NSAIDs에 의해서 COX를 저해하여 프로스타글란딘 생합성을 감소/정지시키면, 동통은 완화된다. 그러나, 이미 기술한 바와 같이 이들의 약제는 장기 투여하면 소화성 궤양을 높은 빈도로 유발한다. 따라서, 소화성 궤양을 유발시키지 않고, 고도의 안전성을 가지고 관절의 염증성 동통을 개선할 수 있는 방법이 오랫동안 탐구되어 왔다. 최근의 NSAIDs의 화제는, 염증부위에서 유도되는 COX-2를 특이적으로 저해하여, NSAIDs의 부작용이었던 소화성 궤양을 줄일 수 있는 COX-2 저해제이다(이무라 히로오, 오가타 에츠로, 다카쿠 후미마로, 다루이 세이이치로편, 「최신 내과학 대계 제74권 관절질환 <골·관절질환 2>」, 나카야마쇼텐 발행, P.19, 1995년, 및 후쿠시마 마사노리편, 「머크 매뉴얼 의학정보 가정판」, 닛케이 BP사, p.233-235, 1999년).It is prostaglandin that mediates inflammatory pain, which is alleviated by inhibiting COX by NSAIDs to reduce / stop prostaglandin biosynthesis. However, as already described, their agents cause a high frequency of peptic ulcers after prolonged administration. Thus, methods for improving inflammatory pain in joints with a high degree of safety without causing peptic ulcers have long been explored. Recently, the topic of NSAIDs is a COX-2 inhibitor that specifically inhibits COX-2 induced at the inflammatory site and reduces peptic ulcer that was a side effect of NSAIDs (Hiroo Imura, Etsuro Ogata, Takaku Fumimaro). , Seichiro Darui, `` Latest Internal Medicine, Vol. 74 Joint Diseases <Bone and
또한, 본 발명의 소염진통제는 염증을 수반하지 않는 통증의 완화에도 유효하게 사용할 수 있다. 통증에는 급성통과 만성통 2종류 있다. 급성통이란(예를 들면, 발목의 염좌와 같이) 신체에 상처나 어떠한 장애가 일어났다는 경고의 신호이다. 통증에 반응함으로써, 원인을 제거하여, 악화를 방지하고자 하는 반응이다. 그에 반해 만성통이란 경고의 신호가 역할을 하지 못하여, 어떠한 치료를 해도 통증이 사라지지 않는 경우를 말한다. 만성통에는 신경인성 동통, 침해수용성 동통, 또는 이들의 혼합형 등이 있다.In addition, the anti-inflammatory analgesic agent of the present invention can be effectively used for the relief of pain not accompanied by inflammation. There are two types of pain, acute pain and chronic pain. Acute pain (such as ankle sprains) is a warning sign of a wound or any disorder in the body. By responding to pain, it is a reaction to eliminate the cause and prevent deterioration. On the other hand, chronic pain means that the warning signal does not play a role, and pain does not go away with any treatment. Chronic pain includes neuropathic pain, nociceptive pain, or a combination thereof.
시클로옥시게나제(COX)는 프로스타글란딘(PG) 생합성의 효소로서 알려져 있다. COX에는 현재 적어도 COX-1, COX-2, COX-3의 3종류의 존재가 보고되어 있다. COX-1은 생리적으로 존재하고 있어, 위나 신장 등의 생리작용을 담당하고 있다. LPS 등의 자극이나 염증에 관계없이 그 농도는 변동하지 않는다. 한편, COX-2는 염증이나 조직장애 등에 관계한다. 정상상태에서는 발현하지 않으나, LPS, IL-1 등의 자극이나 염증 등에 의해서 주로 유주(遊走)세포로부터 새롭게 생산되어, 덱사메타손에 의해 생산억제를 받는다. 즉, COX-2를 선택적으로 저해한 경우, 위나 신장 등에 대한 부작용이 적어, 염증이나 조직장애 등을 개선하는 효과를 기대할 수 있다.Cyclooxygenase (COX) is known as an enzyme of prostaglandin (PG) biosynthesis. At least three kinds of COX-1, COX-2, and COX-3 have been reported in COX. COX-1 exists physiologically, and is responsible for physiological actions such as stomach and kidney. The concentration does not change regardless of irritation or inflammation of LPS. COX-2, on the other hand, is involved in inflammation and tissue disorders. Although it is not expressed in a normal state, it is mainly produced newly from lactose cells by stimulation or inflammation of LPS, IL-1, etc., and is suppressed by dexamethasone. In other words, when COX-2 is selectively inhibited, side effects to the stomach and the kidney are less likely, and the effect of improving inflammation or tissue disorder can be expected.
COX 억제제의 적응증으로서는, (1) 만성 관절 류머티즘, 변형성 관절증, 오십견, 경견완증후군, 요통, 건초염, 통풍 등의 류머티즘성 질환이나 운동기(運動器) 질환, (2) 수술 후·외상후 통증, 암성 동통, 치과영역의 통증, 증후성 신경통, 결석통, 월경통 등의 동통성 질환, (3) 각종 감염증, 악성 종양, 교원병 등의 발열을 수반하는 질환, (4) 뇌경색, 일과성 허혈발작, 허혈성 심질환, 가와사키병, 단백뇨, 암전이 등의 항혈전이나 항혈소판 작용을 이용하는 적응증, (5) 엔도톡신 쇼크, 동맥관개존증, 저혈압, Bartter 증후군, 남자불임증, 면역억제, 면역요법의 강화 등의 주로 PG 합성 억제작용에 의한 적응증 등이 알려져 있다(이무라 히로오, 오가타 에츠로, 다카쿠 후미마로, 다루이 세이이치로편, 「최신 내과학 대계 제74권 관절질환 <골·관절질환 2>」, 나카야마쇼텐 발행, p.77-78, 1995년). 따라서, COX-2 저해활성을 갖는 본 발명의 소염진통제는 염증을 수반하는 질환 전반에 한정되지 않고, 상기의 각종 질환에도 적용이 가능하다.Indications for COX inhibitors include: (1) chronic joint rheumatism, deformable arthrosis, fifty shoulders, dog's shoulder syndrome, low back pain, rheumatism and motor disorders such as hay fever and gout, and (2) postoperative and post-traumatic pain and cancer. Pain, dental pain, symptomatic neuralgia, stone pain, dysmenorrhea, painful disorders, (3) various infections, malignant tumors, fever, such as collagen disease, (4) cerebral infarction, transient ischemic attack, ischemic heart disease Indications that utilize antithrombotic or antiplatelet actions such as Kawasaki disease, proteinuria, and cancer metastasis, (5) Endothelial shock, arteriovascular patency, hypotension, Bartter syndrome, male infertility, immunosuppression, and strengthening immunotherapy mainly Indications due to the action are known (Hiroo Imura, Etsuro Ogata, Fumimaru Takaku, Seichiro Darui, `` Latest Internal Medicine, Volume 74 Joint Disease <Bone and
또한, 본 명세서에 있어서 인용된 모든 선행기술문헌은 참조로서 본 명세서에 삽입된다.In addition, all the prior art documents referred to in this specification are integrated in this specification as a reference.
이하, 본 발명에 대해서 실시예를 들어 설명하나, 본 발명은 이것에 의해 한정되는 것은 아니다.Hereinafter, although an Example is given and described about this invention, this invention is not limited by this.
[실시예 1] (카라기닌 발 부종 억제시험, 급성염증에 대한 작용)Example 1 Carrageenan Foot Edema Inhibition Test, Action against Acute Inflammation
본 실시예는 유청 단백질 분리물(WPI) 및 WPI에 함유되는 각종 단백의 카라기닌 유발성 발 부종에 대한 억제효과를 검증하였다. 또한, WPI란 유청을 정밀여 과(MF), 한외여과(UF), 크로스·폴로 정밀여과(CFM), 이온 교환 등으로 처리하여 단백질을 분리하고, 단백질 농도를 높인 것이다.This example demonstrated the inhibitory effect on whey protein isolate (WPI) and carrageenan-induced paw edema of various proteins contained in WPI. WPI is a process in which whey is separated by microfiltration (MF), ultrafiltration (UF), cross-polo microfiltration (CFM), ion exchange, and the like to separate proteins and increase protein concentration.
(방법)(Way)
1주 이상의 순화(馴化)기간을 마친 위스터계 랫트(웅성, 6주령, 1군 6마리, 5군)를 사용하여, 각종 시험물질의 경구 투여를 행하였다. 시험물질로서, 생리식염수에 용해한 유청 단백질 분리물(WPI, 소 유래, Davisco Foods International, Inc.사제) 1 g/㎏[WPI군], α-락토알부민(α-LA, 소 유래, Davisco Foods International, Inc.사제) 250 ㎎/㎏(WPI의 25 w/w%)[aLA군], β-락토글로불린(β-LG, 소 유래, Davisco Foods International, Inc.사제) 500 ㎎/㎏(WPI의 50 w/w%)[bLG군], 락토페린(LF, 소 유래, Murray Goulburn Ingredients사제) 10 ㎎/㎏(WPI의 1 w/w%)[LF군], 및 생리식염수[대조군]를 각각 표기의 용량으로, 4 ㎖/㎏의 용량(容量)으로 투여하였다. 시험물질의 경구 투여로부터 1시간 후, 1 w/w% 카라기닌 용액을 왼쪽 발바닥에 0.1 mL 피내 투여하였다. 카라기닌 투여 3시간 후의 시점에서 발 용적을 측정하여, 그 항염증작용을 평가하였다. 또한, 이후의 실시예에서는, WPI, α-LA, β-LG 및 LF는 여기에 나타내는 것과 동일한 것을 사용하였다.Various test substances were orally administered using Wister rats (male, 6-week-old, six-group, five-group) that had undergone one or more weeks of purification. As a test substance, 1 g / kg of whey protein isolate (WPI, cow derived, manufactured by Davisco Foods International, Inc.) dissolved in physiological saline [WPI group], α-lactoalbumin (α-LA, cow derived, Davisco Foods International , Inc.) 250 mg / kg (25 w / w% of WPI) [aLA group], β-lactoglobulin (β-LG, derived from Bovine, Davisco Foods International, Inc.) 500 mg / kg (WPI 50 w / w%) [bLG group], lactoferrin (LF, cow derived, manufactured by Murray Goulburn Ingredients) 10 mg / kg (1 w / w% of WPI) [LF group], and physiological saline [control] The dose of was administered at a dose of 4 mL / kg. One hour after oral administration of the test substance, 1 w / w% carrageenan solution was administered 0.1 mL intradermally to the left foot. Foot volume was measured at 3 hours after carrageenan administration, and its anti-inflammatory action was evaluated. In addition, in the following Example, WPI, (alpha) -LA, (beta) -LG, and LF used the same thing as what is shown here.
(결과)(result)
WPI 중에는 주된 성분으로서, α-락토알부민(WPI의 25 w/w%), β-락토글로불린(WPI의 50 w/w%), 락토페린(WPI의 1 w/w%)이 존재한다. 이번에는 WPI 중의 활성성분을 검토하기 위해, 그 함유비율에 따라서 투여하였다. 그 결과, α-락토알부민 에만 카라기닌 발 부종을 억제하는 효과가 보였다. 이 결과로부터, WPI의 카라기닌 발 부종 억제효과는 α-락토알부민이 기여하는 것인 것을 알 수 있었다(도 1).Among the WPIs, α-lactoalbumin (25 w / w% of WPI), β-lactoglobulin (50 w / w% of WPI), and lactoferrin (1 w / w% of WPI) are present. This time, in order to examine the active ingredient in WPI, it administered according to the content rate. As a result, only carbo-albumin was shown to inhibit carrageenan edema. From these results, it was found that the inhibitory effect of carpiginous paw edema of WPI was contributed by α-lactoalbumin (FIG. 1).
[실시예 2](애쥬번트 관절염(치료) 모델, 아급성 염증(실험적 만성염증)에 대한 작용)Example 2 (Adjuvant Arthritis (Treatment) Model, Action on Subacute Inflammation (Experimental Chronic Inflammation)
본 실시예에서는 류머티즘성 관절염의 동물 모델인 랫트 애쥬번트 관절염 모델을 제작하여, WPI에 함유되는 각종 단백의 관절염에 대한 치료효과를 검증하였다.In this example, a rat adjuvant arthritis model, which is an animal model of rheumatoid arthritis, was produced, and the therapeutic effect of various proteins contained in the WPI was verified.
(방법)(Way)
1주 이상의 순화기간 종료 후, 위스터계 랫트(웅성, 6주령)의 왼쪽 발바닥에 0.1 mL의 프로인트 완전 애쥬번트를 피하 주사하여 애쥬번트 관절염을 야기하였다. 사용한 프로인트 완전 애쥬번트는 10 mL 중, 유동 파라핀 8.5 mL, 계면활성제 스판 80 1.5 mL 및 인간형 결핵사균 H37Rv 7.5 ㎎을 함유한다. 애쥬번트 투여로부터 14일 후, 충분히 관절염이 발증한 랫트를 선발하여, 왼쪽 발바닥의 발 용적을 토대로 하여 군 분류를 행하였다(1군 6마리, 5군).After the end of one or more weeks of purification, adjuvant arthritis was caused by subcutaneous injection of 0.1 mL of Freund's complete adjuvant into the left paw of the Wister rats (male, 6 week old). Freund's complete adjuvant contains, in 10 mL, 8.5 mL of liquid paraffin, 1.5 mL of surfactant Span 80, and 7.5 mg of humanoid Mycobacterium tuberculosis H37Rv. After 14 days from adjuvant administration, rats with sufficient arthritis were selected and grouped based on the paw volume of the left foot (
생리식염수에 용해한 시험물질(α-락토알부민[aLA군], β-락토글로불린[bLG군], 락토페린[LF군])은 각각 300 ㎎/㎏의 용량으로, 비스테로이드성 소염진통제(NSAIDs)인 디클로페낙(와코 순약 공업사제)[양성 대조군]은 50 ㎎/㎏의 용량으로, 4 ㎖/㎏의 용량(容量)으로 애쥬번트 투여로부터 14~16일째까지의 3일간 연속 경구 투여하였다. 또한, 대조군으로서 동용량의 생리식염수를 애쥬번트 투여로부터 14~16일째까지의 3일간 연속 경구 투여하였다.Test substances dissolved in physiological saline (α-lactoalbumin [aLA group], β-lactoglobulin [bLG group], lactoferrin [LF group]) were doses of 300 mg / kg, respectively, which are nonsteroidal anti-inflammatory drugs (NSAIDs). Diclofenac (manufactured by Wako Pure Chemical Industries, Ltd.) [positive control] was administered orally at a dose of 50 mg / kg for 3 days from adjuvant to 14 to 16 days at a dose of 4 mL / kg. In addition, the same dose of physiological saline was administered orally for three consecutive days from the adjuvant administration to 14-16 days.
애쥬번트 투여로부터 14(피험물질 투여 직후), 15, 17일째에 왼쪽 발바닥의 발 용적을 측정하여, 치료효과를 조사하였다.On the 14th day immediately after administration of the adjuvant, 15 and 17 days, the volume of the foot of the left foot was measured to investigate the therapeutic effect.
(결과)(result)
애쥬번트를 투여한 왼쪽 발의 부종에 대해, α-락토알부민은 부종의 증악(增惡)을 억제하였다. 또한, 락토페린의 투여에서는 발 용적은 감소하여, 치료적 효과가 얻어졌다(도 2).For edema of the left foot, which received the adjuvant, α-lactoalbumin inhibited the swelling of the edema. In addition, in the administration of lactoferrin, the paw volume decreased, and a therapeutic effect was obtained (FIG. 2).
[실시예 3](애쥬번트 관절염(동통) 모델, 만성 동통에 대한 작용)Example 3 (Adjuvant Arthritis (Pain) Model, Action on Chronic Pain)
1주 이상의 순화기간 종료 후, 위스터계 랫트(웅성, 6주령)의 왼쪽 발바닥에, 실시예 2와 동일한 프로인트 완전 애쥬번트 0.1 mL를 피하 주사하여 애쥬번트 관절염을 야기하였다. 애쥬번트 투여로부터 16일 후, 충분히 관절염이 발증한 랫트를 선발하여, 왼쪽 발바닥의 발 용적을 토대로 군 분류를 행하였다(1군 6마리, 5군).After the end of one or more weeks of acclimation, adjuvant arthritis was induced by subcutaneous injection of 0.1 mL of Freund's complete adjuvant as in Example 2, to the left foot of the Wister rat (male, 6 week old). Sixteen days after the adjuvant administration, rats with sufficient arthritis were selected and grouped based on the paw volume of the left paw (6 groups, 6 groups).
생리식염수에 용해한 시험물질(α-락토알부민[aLA군], β-락토글로불린[bLG군], 락토페린[LF군])은 각각 300 ㎎/㎏의 용량으로, 소염진통제인 디클로페낙[양성 대조군]은 50 ㎎/㎏의 용량으로, 4 ㎖/㎏의 용량(容量)으로 경구 투여하였다. 시험물질 투여 1시간 후에, 왼쪽 뒷다리 발관절의 굴곡(屈曲) 신전(伸展) 자극 동통에 대한 명제반응의 유무를 측정하였다. 10회 굴곡 신전했을 때 몇번 명제하는지를 수치화하여, 동통 억제효과를 평가하였다.Test substances dissolved in physiological saline (α-lactoalbumin [aLA group], β-lactoglobulin [bLG group], lactoferrin [LF group]) were doses of 300 mg / kg, respectively, and diclofenac [positive control] It was orally administered at a dose of 50 mg / kg and a dose of 4 ml / kg. One hour after administration of the test substance, the presence or absence of a prognosis response to flexion extension stimulation pain of the left hind limb was measured. The number of propositions for 10 times of flexion was quantified to evaluate the effect of suppressing pain.
(결과)(result)
α-락토알부민 단회 투여, 락토페린 단회 투여에 있어서, 관절염 동통의 억 제효과가 얻어졌다(도 3).In single administration of α-lactoalbumin and single administration of lactoferrin, an inhibitory effect of arthritis pain was obtained (FIG. 3).
[실시예 4](초산 라이징 시험, 동통에 대한 작용)Example 4 Acetic Acid Rising Test, Action on Pain
본 실시예에서는 WPI에 함유되는 각종 단백의 초산 유발성 동통에 대한 치료효과를 검증하였다.In this example, the therapeutic effect of various proteins contained in WPI against acetic acid-induced pain was verified.
1주 이상의 순화기간을 마친 마우스(웅성, 6주령, 1군 6마리, 5군)를 사용하여, 생리식염수에 용해한 유청 단백질 분리물(WPI)[WPI군], α-락토알부민[αLA군], β-락토글로불린[bLG군], 락토페린[LF군]을 각각 300 ㎎/㎏의 용량으로, 소염진통제인 디클로페낙[양성 대조(Dicro)군]은 50 ㎎/㎏의 용량으로, 4 ㎖/㎏의 용량(容量)으로 경구 투여하였다. 또한, 대조(Vehicle)군으로서, 동용량의 생리식염수를 경구 투여하였다. 시험물질의 경구 투여로부터 1시간 후, 0.6 v/v% 초산 용액을 복강내에 0.2 mL 투여하였다. 초산 투여 10분 후부터 30분 후까지의 20분간의 고민동작 횟수를 수치화하여, 동통 억제효과를 평가하였다.Whey protein isolates (WPI) [WPI] and [alpha] -lactoalbumin [αLA group] dissolved in physiological saline using mice that had been purified for at least one week (Woong, 6-week-old,
(결과)(result)
결과를 도 4에 나타낸다. α-락토알부민, 락토페린에 유의(有意)한 진통효과가 보였다.The results are shown in FIG. There were significant analgesic effects on α-lactoalbumin and lactoferrin.
[실시예 5](효소 저해실험)Example 5 (Enzyme Inhibition Experiment)
본 실시예에서는 시험물질(α-락토알부민, WPI)의 염증의 각종 효소에 대한 저해활성을 검증하였다.In this example, the inhibitory activity against various enzymes of inflammation of the test substance (α-lactoalbumin, WPI) was verified.
(방법)(Way)
(1) 시클로옥시게나제-1(COX-1)의 효소 표품(標品)을 사용한 활성 측정(n=2)(1) Activity measurement using the enzyme standard of cyclooxygenase-1 (COX-1) (n = 2)
각종 농도의 시험물질(α-락토알부민 또는 WPI), 및 시클로옥시게나제-1(EC 1.14.99.1, 인간 혈소판 유래)의 효소 표품을, HBSS(Hanks' Balanced Salt Solutions, 15 mM HEPES;pH 7.4) 중에서 37℃ 15분간 프리인큐베이션한 후, 아라키돈산을 최종 농도 100 μM가 되도록 첨가하여 37℃ 15분간 반응시켰다. 반응 후, PGE2의 농도를 EIA(enzyme immuno assay)로 측정하였다. 또한, 시험물질(α-락토알부민 또는 WPI)을 첨가하지 않는 것을 대조군으로서 두었다. 대조군의 측정값의 평균값을 효소 저해율 100%로 하여 α-락토알부민 및 WPI의 효소 저해율을 산출하고, 50% 저해농도를 IC50값으로 하였다.Enzyme samples of various concentrations of test substance (α-lactoalbumin or WPI) and cyclooxygenase-1 (EC 1.14.99.1, derived from human platelets) were prepared by HBSS (Hanks' Balanced Salt Solutions, 15 mM HEPES; pH 7.4). After preincubation at 37 ° C. for 15 minutes, arachidonic acid was added to a final concentration of 100 μM and reacted at 37 ° C. for 15 minutes. After the reaction, the concentration of PGE 2 was measured by an enzyme immunoassay (EIA). In addition, no test substance (α-lactoalbumin or WPI) was added as a control. Using the mean value of the control value as the enzyme inhibition rate of 100%, the enzyme inhibition rate of α-lactoalbumin and WPI was calculated, and the 50% inhibition concentration was set as the IC 50 value.
(2) 시클로옥시게나제-2(COX-2)의 효소 표품을 사용한 활성 측정(n=2)(2) Activity measurement using enzyme standard of cyclooxygenase-2 (COX-2) (n = 2)
각종 농도의 시험물질(α-락토알부민 또는 WPI), 및 시클로옥시게나제-2(EC 1.14.99.1, 인간 재조합;Sf21 곤충세포)의 효소 표품을, 1 mM 글루타티온, 1 μM 헤마틴, 500 μM 페놀을 포함하는 100 mM Tris-HCl buffer(pH 7.7)중에서 37℃ 15분간 프리인큐베이션한 후, 아라키돈산을 최종농도 0.3 μM가 되도록 첨가하여 37℃ 5분간 반응시켰다. 반응 후, PGE2의 농도를 EIA로 측정하였다. 또한, 시험물질(α-락토알부민 또는 WPI)을 첨가하지 않는 것을 대조군으로서 두었다. 대조군의 측정값의 평균값을 효소 저해율 100%로 하여 α-락토알부민 및 WPI의 효소 저해율을 산출하고, 50% 저해농도를 IC50값으로 하였다.Enzyme samples of various concentrations of test substance (α-lactoalbumin or WPI) and cyclooxygenase-2 (EC 1.14.99.1, human recombination; Sf21 insect cells) were prepared using 1 mM glutathione, 1 μM hematin, 500 μM. After preincubation at 37 ° C. for 15 minutes in 100 mM Tris-HCl buffer containing phenol (pH 7.7), arachidonic acid was added to a final concentration of 0.3 μM and allowed to react at 37 ° C. for 5 minutes. After the reaction, the concentration of PGE 2 was measured by EIA. In addition, no test substance (α-lactoalbumin or WPI) was added as a control. Using the mean value of the control value as the enzyme inhibition rate of 100%, the enzyme inhibition rate of α-lactoalbumin and WPI was calculated, and the 50% inhibition concentration was set as the IC 50 value.
(3) 유도형 일산화질소 합성효소(iNOS)의 효소 표품을 사용한 활성 측정(n=2)(3) Activity measurement using enzyme standard of inducible nitric oxide synthase (iNOS) (n = 2)
각종 농도의 시험물질(α-락토알부민 또는 WPI), 및 유도형 일산화질소 합성 효소(EC 1.14.13.39, 마우스 매크로파지 유래)의 효소 표품을, 4 mM NADPH(nicotinamide adenine dinucleotide 환원형), 8 μM(6R)-5,6,7,8-테트라히드로-L-바이오프테린, 8 μM FAD, 6 mM DTT(Dithiothreitol)를 포함하는 100 mM Tris-HCl buffer(pH 7.9) 중에서 37℃ 15분간 프리인큐베이션한 후, 아르기닌을 최종 농도 100 μM가 되도록 첨가하여 37℃ 2시간 반응시켰다. 반응 후, NO2-를 분광광도법으로 정량하였다. 또한, 시험물질(α-락토알부민 또는 WPI)을 첨가하지 않는 것을 대조군으로서 두었다. 대조군의 정량값의 평균값을 효소 저해율 100%로 하여 α-락토알부민 및 WPI의 효소 저해율을 산출하고, 50% 저해농도를 IC50값으로 하였다.Enzyme samples of various concentrations of the test substance (α-lactoalbumin or WPI) and inducible nitric oxide synthase (EC 1.14.13.39, derived from mouse macrophages) were prepared using 4 mM NADPH (reduced nicotinamide adenine dinucleotide), 8 μM ( 6R) -5,6,7,8-tetrahydro-L-biopterin, 8 μM FAD, 6 mM pre-incubation in 100 mM Tris-HCl buffer (pH 7.9) containing 6 mM DTT (Dithiothreitol) for 15 minutes After that, arginine was added to a final concentration of 100 μM and reacted at 37 ° C. for 2 hours. After the reaction, NO 2- was quantified by spectrophotometry. In addition, no test substance (α-lactoalbumin or WPI) was added as a control. The enzyme inhibition rate of α-lactoalbumin and WPI was calculated by making the average value of the quantitative value of the control group 100% enzyme inhibition rate, and 50% inhibition concentration was made into IC 50 value.
(4) 포스포리파제 A2(PLA2)의 효소 표품을 사용한 활성 측정(n=2)(4) Determination of activity using enzyme standard of phospholipase A2 (PLA2) (n = 2)
각종 농도의 시험물질(α-락토알부민 또는 WPI), 및 포스포리파제 A2-I(EC 3.1.1.4, 돼지 췌장 유래) 또는 포스포리파제 A2-II(EC 3.1.1.4, 악질방울뱀 유래)의 효소 표품을, 20 μM EDTA를 포함하는 0.1 M Glycine-NaOH buffer(pH 9.0) 중에서 37℃ 15분간 프리인큐베이션한 후, 1-팔미토일-2-[1-14C]올레오일-L-3-포스파티딜콜린을 최종농도 0.03 μCi가 되도록 첨가하여 37℃ 5분간 반응시켰다. 미반응의 1-팔미토일-2-[1-14C]올레오일-L-3-포스파티딜콜린을 제거한 후, 올레산염 분획의 방사활성을 액체 신틸레이션 카운터(liquid scintillation counter)로 측정하였다. 또한, 시험물질(α-락토알부민 또는 WPI)을 첨가하지 않는 것을 대조군으로서 두었 다. 대조군의 방사활성(Ci)의 평균값을 효소 저해율 100%로 하여 α-락토알부민 및 WPI의 효소 저해율을 산출하고, 50% 저해농도를 IC50값으로 하였다.Enzymes of various concentrations of test substance (α-lactoalbumin or WPI) and phospholipase A2-I (EC 3.1.1.4, derived from porcine pancreas) or phospholipase A2-II (EC 3.1.1.4, derived from venomous rattlesnake) The product was preincubated in 0.1 M Glycine-NaOH buffer containing 20 μM EDTA (pH 9.0) for 15 minutes at 37 ° C., followed by 1-palmitoyl-2- [1- 14 C] oleoyl-L-3-phosphatidylcholine Was added to a final concentration of 0.03 μCi and reacted for 5 minutes at 37 ° C. After removal of unreacted 1-palmitoyl-2- [1- 14 C] oleoyl-L-3-phosphatidylcholine, the radioactivity of the oleate fractions was measured with a liquid scintillation counter. In addition, no control substance (α-lactoalbumin or WPI) was added as a control. The enzyme inhibition rate of α-lactoalbumin and WPI was calculated using the average value of the radioactivity (Ci) of the control group as the enzyme inhibition rate of 100%, and the 50% inhibition concentration was set as the IC 50 value.
(결과)(result)
결과를 표 1 및 표 2에 나타낸다. α-락토알부민은 시클로옥시게나제-2, 포스포리파제 A2-I, 포스포리파제 A2-II에 있어서 높은 활성이 보였다. 특히, 시클로옥시게나제-2에 선택적으로 높은 활성을 발견할 수 있었다. 또한, α-락토알부민은 WPI와 비교해도 높은 시클로옥시게나제-2 활성을 갖는 것을 알 수 있었다.The results are shown in Table 1 and Table 2. α-lactoalbumin showed high activity in cyclooxygenase-2, phospholipase A2-I, and phospholipase A2-II. In particular, selective high activity could be found for cyclooxygenase-2. It was also found that α-lactoalbumin had high cyclooxygenase-2 activity even when compared to WPI.
[실시예 6](월경통(동통)에 대한 인간 시험)Example 6 (Human Test for Dysmenorrhea)
본 실시예에서는 α-락토알부민의 월경통에 대한 개선효과를 랜덤화 더블 블라인드 크로스 오버 시험으로 검증하였다.In this example, the improvement effect of α-lactoalbumin on dysmenorrhea was verified by a randomized double blind crossover test.
(피험자)(Subject)
협력 의뢰의 게시에 협력을 신청한 여성 70명을 대상으로 사전조사를 행하여, 월경 주기가 28일 ± 3일로 안정되고, 최근 월경에 관한 자기식 질문지(표 3: 월경통의 통증 정도, 월경통에 의한 일상생활으로의 영향 정도, 진통제의 사용 정도)의 회답이, 월경통의 통증 정도 1 이상, 월경통 스코어(월경통에 의한 일상생활으로의 영향 정도, 진통제의 사용 정도)의 합계가 2 이상인 여성 30명(22~50세, 평균 36.4세)을 선발하여, 피험자로 하였다.A preliminary survey was conducted on 70 women who applied for cooperation in posting a request for cooperation, and the menstrual cycle stabilized at 28 days ± 3 days, and a magnetic questionnaire about recent menstruation (Table 3: Pain in menstruation and dysmenorrhea) 30 women (degrees of influence on daily life, use of painkiller) 30 or more women (more than pain degree of dysmenorrhea, the sum of menstrual pain score (degree of influence on daily life by dysmenorrhea, use of painkiller) 2 or more 22-50 years old, average 36.4 years old) were selected and were the subjects.
(피험물)(Subject)
외견이 완전히 동일한 정과(錠菓) A, B를 준비하였다. 한쪽은 α-락토알부민 정과(한알 중 α-락토알부민 150 ㎎ 함유)이고, 다른 쪽은 α-락토알부민을 전혀 함유하지 않는 것(플라세보 정과)이다. 피험자, 평가자 모두 평가 종료까지 어느 정과가 α-락토알부민 정과인지를 숨긴 상태에서 시험을 개시하였다.Tablets A and B with identical appearances were prepared. One is an α-lactoalbumin tablet (containing 150 mg of α-lactoalbumin in one tablet), and the other contains no α-lactoalbumin at all (placebo tablet). Both the subject and the evaluator started a test in the state which hidden which tablet was the α-lactoalbumin tablet until the evaluation completion.
(피험물의 섭취방법)(Ingestion method)
2007년 9~12월의 3월경 주기에 있어서 시험을 실시하였다. 최초의 월경 종료부터 다음 월경 종료까지의 1월경 주기를 1회째의 피험물 섭취기로서 두었다. 1회째의 피험물 섭취기에 이어지는 1월경 주기(월경 종료부터 다음 월경 종료까지)는 피험물을 섭취하지 않는 휴식기로 하였다. 또한, 휴식기에 이어지는 1월경 주기(월경 종료부터 다음 월경 종료까지)를 2회째의 피험물 섭취기로 하였다.Tests were conducted during the March-May cycle between September and December 2007. The menstrual cycle from the end of the first menstruation to the end of the next menstruation was placed as the first test subject. The menstrual cycle (from the end of menstruation to the end of the next menstruation) following the first subject intake period was set to rest without ingesting the subject. In addition, the menstrual cycle (from the end of menstruation to the end of the next menstruation) following the rest period was set as the second test subject intake.
피험자를 2개의 군으로 분류하여, 1군(정과 A 섭취기-휴식기-정과 B 섭취기, n=13) 및 2군(정과 B 섭취기-휴식기-정과 A 섭취기, n=17)으로, 각각 정과 A, 정과 B의 섭취 순서를 다르게 설정하였다.Subjects were divided into two groups, group 1 (tablet A intake-rest-table B intake, n = 13) and group 2 (tablet B intake-rest-table A intake, n = 17). The order of intake of tablets and A, tablets and B, respectively, was set differently.
피험물 섭취기는 1회에 두알의 피험물(정과 A 또는 정과 B)을 아침, 점심, 저녁의 3회 계속해서 섭취시켰다.The test subject ingested two tablets (tablet A or tablet B) three times each morning, lunch and dinner.
또한, 시험 개시 전 및 시험기간 중에는 진통제의 사용은 자유롭게 하였다.In addition, the use of analgesics was freed before the start of the test and during the test period.
(평가방법)(Assessment Methods)
시험 개시 전의 1회의 월경기간 중에는 피험자에게 자기식 질문지(표 3)를 기입시켰다. 또한, 피험물 섭취기 및 휴식기 사이에, 피험자에게 1일 1회, 자기식 질문지에 계속 기록시켰다. 자기식 질문지의 내용은 월경통과 QOL에 관한 것이다. 월경기간 중에 자기식 질문지에 기입된 월경통의 정도, 일상생활으로의 영향, 및 진통제의 사용 정도는 VRS(verbal rating scale)를 사용해서 수치화하여, 각 피험자의 기간 중에서의 최대값을 평가에 사용하였다. 또한, 평가대상의 월경통은 요통과 하복부통으로 한정하였다.During one menstrual period prior to commencement of the study, subjects were asked to fill out a magnetic questionnaire (Table 3). In addition, between the subject intake period and the resting period, the subject was continuously recorded in the self-reported questionnaire once a day. The content of the magnetic questionnaire is about dysmenorrhea and QOL. The degree of menstrual pain, the effects on daily life, and the use of analgesics were recorded on the questionnaire during the menstrual period using the VRS (verbal rating scale), and the maximum value during each period was used for evaluation. . In addition, menstrual pain was evaluated as low back pain and lower abdominal pain.
또한, 시험 개시 전의 월경 및 휴식기의 결과의 평균값을 구하여, 이것을 비섭취기의 값으로 하였다.In addition, the average value of the results of menstruation and rest periods before the start of the test was obtained, and this was taken as the value of the non-intake period.
(통계처리)(Statistical processing)
각 측정값에 대해서 평균값과 표준오차를 구하고, 유의차의 검정은 통계 소프트웨어를 사용하여 비모수적방법(nonparametric method)으로 대응이 있는 군으로서 검정을 행하였다(Wilcoxson의 부호 순위합 검정).The mean value and standard error were obtained for each measured value, and the test of the significant difference was performed as a non-parametric method by using statistical software (Wilcoxson's sign rank sum test).
(결과)(result)
월경통의 통증 정도를 측정한 VRS(verbal rating scale)값은, 비섭취기와 비교하면 α-락토알부민 정과의 섭취로 유의(p<0.01)하게 저하되었다(도 5).The VRS (verbal rating scale) value, measured for pain in menstrual pain, was significantly (p <0.01) lowered with the intake of α-lactoalbumin compared to the non-ingested group (FIG. 5).
월경통에 의한 일상생활으로의 영향 정도(QOL)를 평가하는 VRS(verbal rating scale)값은, 비섭취기와 비교하면 α-락토알부민 정과의 섭취로 감소하는 경향(p<0.10)이 있었다(도 6).The VRS (verbal rating scale) value for assessing the effect of daily dysmenorrhea (QOL) on dysmenorrhea tended to decrease (p <0.10) with the intake of α-lactoalbumin compared to the non-ingestion group (Fig. 6). ).
진통제의 사용 정도에 대해서는, 시험 개시 전에 월경통 때문에 진통제를 복용한 사람은 21명(70%)이었으나, α-락토알부민 정과 섭취기와 플라세보 정과 섭취기에서는 10명(전체의 33%)으로 감소하였다. 진통제의 사용 정도를 측정한 VRS(verbal rating scale)값은, 비섭취기와 비교하면 정과 섭취기 모두 유의한 저하가 확인되었다(p<0.01)(도 7).In terms of the use of analgesics, 21 patients (70%) took analgesics for menstrual pain before the start of the test, but decreased to 10 (33% of total) in the α-lactobumin tablets and placebo tablets. The VRS (verbal rating scale) value, which measured the use of analgesics, was found to be significantly lower in both tablets and intakes compared to the non-intake group (p <0.01) (FIG. 7).
이상의 결과로부터, α-락토알부민 300 ㎎을 1일 3회(아침, 점심, 저녁) 섭취함으로써, 진통제의 사용비율을 대폭 감소시키는 동시에, 월경통의 완화, QOL의 개선효과가 명확해졌다.From the above results, by ingesting 300 mg of α-lactoalbumin three times a day (morning, lunch and dinner), the use rate of analgesics was greatly reduced, and the effect of alleviating menstrual pain and improving QOL became clear.
본 발명에 있어서의 유효성분인 α-락토알부민류는 우유 등의 비교적 저렴한 원료로부터 대량생산이 가능하다. 또한, 부작용이 적고, 안전성이 높아, 장기간에 걸쳐서 섭취하는 것이 가능하기 때문에, 의약품에 혼합하거나, 식품으로서 섭취함으로써, 소염진통효과를 향수할 수 있다. 이 뿐 아니라, 일상적으로 투여 또는 섭취함으로써, 충분한 영양관리가 가능해지기 때문에, 저영양상태의 환자에 대한 기능성 식품 등의 제조 등의 용도에 적용하는 것도 가능하다.Α-lactoalbumins, which are the active ingredient in the present invention, can be mass-produced from relatively inexpensive raw materials such as milk. Moreover, since there are few side effects, high safety, and it is possible to ingest over a long period of time, the anti-inflammatory analgesic effect can be enjoyed by mixing with pharmaceuticals or ingesting as a food. Not only this, but it is also possible to apply it to the use, such as manufacture of functional foods for the patient in a low nutrition state, since sufficient nutrition management is possible by daily administration or ingestion.
SEQUENCE LISTING <110> MEIJI DAIRIES CORPORATION <120> A NOVEL ANTIINFLAMMATORY AND ANALGESIC AGENT <130> M1-A0704P <150> JP 2007-127286 <151> 2007-05-11 <160> 2 <170> PatentIn version 3.4 <210> 1 <211> 724 <212> DNA <213> Bos taurus <220> <221> CDS <222> (28)..(456) <220> <221> sig_peptide <222> (28)..(84) <220> <221> mat_peptide <222> (85)..(453) <400> 1 atttcagaat cttggggggt aaccaaa atg atg tcc ttt gtc tct ctg ctc ctg 54 Met Met Ser Phe Val Ser Leu Leu Leu -15 gta ggc atc cta ttc cat gcc acc cag gct gaa cag tta aca aaa tgt 102 Val Gly Ile Leu Phe His Ala Thr Gln Ala Glu Gln Leu Thr Lys Cys -10 -5 -1 1 5 gag gtg ttc cgg gag ctg aaa gac ttg aag ggc tac gga ggt gtc agt 150 Glu Val Phe Arg Glu Leu Lys Asp Leu Lys Gly Tyr Gly Gly Val Ser 10 15 20 ttg cct gaa tgg gtc tgt acc acg ttt cat acc agt ggt tat gac aca 198 Leu Pro Glu Trp Val Cys Thr Thr Phe His Thr Ser Gly Tyr Asp Thr 25 30 35 caa gcc ata gta caa aac aat gac agc aca gaa tat gga ctc ttc cag 246 Gln Ala Ile Val Gln Asn Asn Asp Ser Thr Glu Tyr Gly Leu Phe Gln 40 45 50 ata aat aat aaa att tgg tgc aaa gac gac cag aac cct cac tca agc 294 Ile Asn Asn Lys Ile Trp Cys Lys Asp Asp Gln Asn Pro His Ser Ser 55 60 65 70 aac atc tgt aac atc tcc tgt gac aag ttc ctg gat gat gat ctt act 342 Asn Ile Cys Asn Ile Ser Cys Asp Lys Phe Leu Asp Asp Asp Leu Thr 75 80 85 gat gac att atg tgt gtc aag aag att ctg gat aaa gta gga att aac 390 Asp Asp Ile Met Cys Val Lys Lys Ile Leu Asp Lys Val Gly Ile Asn 90 95 100 tac tgg ttg gcc cat aaa gca ctc tgt tct gag aag ctg gat cag tgg 438 Tyr Trp Leu Ala His Lys Ala Leu Cys Ser Glu Lys Leu Asp Gln Trp 105 110 115 ctc tgt gag aag ttg tgaacacctg ctgtctttgc tgcttctgtc ctctttctgt 493 Leu Cys Glu Lys Leu 120 tcctggaact cctctgcccc gtggctacct cgttttgctt ctttgtaccc ccttgaagct 553 aactcgtctc tgagccctgg gccctgtagt gacaatggac atgtaaggac taatctccag 613 gggtgcatga atggcgctct ggacttttga cccttsstcg atgtccctga tggcgctttt 673 aatgcaacag tacatattcc acttttgtcc cgaataaaaa gcctgatttt g 724 <210> 2 <211> 142 <212> PRT <213> Bos taurus <400> 2 Met Met Ser Phe Val Ser Leu Leu Leu Val Gly Ile Leu Phe His Ala -15 -10 -5 Thr Gln Ala Glu Gln Leu Thr Lys Cys Glu Val Phe Arg Glu Leu Lys -1 1 5 10 Asp Leu Lys Gly Tyr Gly Gly Val Ser Leu Pro Glu Trp Val Cys Thr 15 20 25 Thr Phe His Thr Ser Gly Tyr Asp Thr Gln Ala Ile Val Gln Asn Asn 30 35 40 45 Asp Ser Thr Glu Tyr Gly Leu Phe Gln Ile Asn Asn Lys Ile Trp Cys 50 55 60 Lys Asp Asp Gln Asn Pro His Ser Ser Asn Ile Cys Asn Ile Ser Cys 65 70 75 Asp Lys Phe Leu Asp Asp Asp Leu Thr Asp Asp Ile Met Cys Val Lys 80 85 90 Lys Ile Leu Asp Lys Val Gly Ile Asn Tyr Trp Leu Ala His Lys Ala 95 100 105 Leu Cys Ser Glu Lys Leu Asp Gln Trp Leu Cys Glu Lys Leu 110 115 120 SEQUENCE LISTING <110> MEIJI DAIRIES CORPORATION <120> A NOVEL ANTIINFLAMMATORY AND ANALGESIC AGENT <130> M1-A0704P <150> JP 2007-127286 <151> 2007-05-11 <160> 2 <170> PatentIn version 3.4 <210> 1 <211> 724 <212> DNA <213> Bos taurus <220> <221> CDS <222> (28) .. (456) <220> <221> sig_peptide (222) (28) .. (84) <220> <221> mat_peptide (222) (85) .. (453) <400> 1 atttcagaat cttggggggt aaccaaa atg atg tcc ttt gtc tct ctg ctc ctg 54 Met Met Ser Phe Val Ser Leu Leu Leu -15 gta ggc atc cta ttc cat gcc acc cag gct gaa cag tta aca aaa tgt 102 Val Gly Ile Leu Phe His Ala Thr Gln Ala Glu Gln Leu Thr Lys Cys -10 -5 -1 1 5 gag gtg ttc cgg gag ctg aaa gac ttg aag ggc tac gga ggt gtc agt 150 Glu Val Phe Arg Glu Leu Lys Asp Leu Lys Gly Tyr Gly Gly Val Ser 10 15 20 ttg cct gaa tgg gtc tgt acc acg ttt cat acc agt ggt tat gac aca 198 Leu Pro Glu Trp Val Cys Thr Thr Phe His Thr Ser Gly Tyr Asp Thr 25 30 35 caa gcc ata gta caa aac aat gac agc aca gaa tat gga ctc ttc cag 246 Gln Ala Ile Val Gln Asn Asn Asp Ser Thr Glu Tyr Gly Leu Phe Gln 40 45 50 ata aat aat aaa att tgg tgc aaa gac gac cag aac cct cac tca agc 294 Ile Asn Asn Lys Ile Trp Cys Lys Asp Asp Gln Asn Pro His Ser Ser 55 60 65 70 aac atc tgt aac atc tcc tgt gac aag ttc ctg gat gat gat ctt act 342 Asn Ile Cys Asn Ile Ser Cys Asp Lys Phe Leu Asp Asp Asp Leu Thr 75 80 85 gat gac att atg tgt gtc aag aag att ctg gat aaa gta gga att aac 390 Asp Asp Ile Met Cys Val Lys Lys Ile Leu Asp Lys Val Gly Ile Asn 90 95 100 tac tgg ttg gcc cat aaa gca ctc tgt tct gag aag ctg gat cag tgg 438 Tyr Trp Leu Ala His Lys Ala Leu Cys Ser Glu Lys Leu Asp Gln Trp 105 110 115 ctc tgt gag aag ttg tgaacacctg ctgtctttgc tgcttctgtc ctctttctgt 493 Leu Cys Glu Lys Leu 120 tcctggaact cctctgcccc gtggctacct cgttttgctt ctttgtaccc ccttgaagct 553 aactcgtctc tgagccctgg gccctgtagt gacaatggac atgtaaggac taatctccag 613 gggtgcatga atggcgctct ggacttttga cccttsstcg atgtccctga tggcgctttt 673 aatgcaacag tacatattcc acttttgtcc cgaataaaaa gcctgatttt g 724 <210> 2 <211> 142 <212> PRT <213> Bos taurus <400> 2 Met Met Ser Phe Val Ser Leu Leu Leu Val Gly Ile Leu Phe His Ala -15 -10 -5 Thr Gln Ala Glu Gln Leu Thr Lys Cys Glu Val Phe Arg Glu Leu Lys -1 1 5 10 Asp Leu Lys Gly Tyr Gly Gly Val Ser Leu Pro Glu Trp Val Cys Thr 15 20 25 Thr Phe His Thr Ser Gly Tyr Asp Thr Gln Ala Ile Val Gln Asn Asn 30 35 40 45 Asp Ser Thr Glu Tyr Gly Leu Phe Gln Ile Asn Asn Lys Ile Trp Cys 50 55 60 Lys Asp Asp Gln Asn Pro His Ser Ser Asn Ile Cys Asn Ile Ser Cys 65 70 75 Asp Lys Phe Leu Asp Asp Asp Leu Thr Asp Asp Ile Met Cys Val Lys 80 85 90 Lys Ile Leu Asp Lys Val Gly Ile Asn Tyr Trp Leu Ala His Lys Ala 95 100 105 Leu Cys Ser Glu Lys Leu Asp Gln Trp Leu Cys Glu Lys Leu 110 115 120
Claims (10)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2007127286 | 2007-05-11 | ||
JPJP-P-2007-127286 | 2007-05-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
KR20100017708A true KR20100017708A (en) | 2010-02-16 |
Family
ID=40002237
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020097025589A KR20100017708A (en) | 2007-05-11 | 2008-05-09 | Novel antiphlogistic-analgesic agent |
Country Status (5)
Country | Link |
---|---|
JP (2) | JP5683106B2 (en) |
KR (1) | KR20100017708A (en) |
CN (1) | CN101678077B (en) |
HK (1) | HK1142277A1 (en) |
WO (1) | WO2008140041A1 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103431276A (en) * | 2013-08-31 | 2013-12-11 | 山东卫康生物医药科技有限公司 | Mixed-grain total-nutrition formulation food for patients with inflammatory bowel diseases |
CA2980990A1 (en) * | 2015-04-07 | 2016-10-13 | Meiji Co., Ltd. | Hot flash-suppressing agent |
JP2016204356A (en) * | 2015-04-23 | 2016-12-08 | 株式会社明治 | Hepatic fibrogenesis inhibitor |
AU2016366635A1 (en) * | 2015-12-07 | 2018-06-21 | Benevolentai Cambridge Limited | VAP-1 inhibitors for treating pain |
CN113876944A (en) * | 2021-10-18 | 2022-01-04 | 南京京达生物技术有限公司 | Preparation method of immunologic adjuvant |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4534316B2 (en) * | 2000-07-14 | 2010-09-01 | 株式会社玄米酵素 | Nutritional supplement manufacturing method and nutritional supplement |
JP2003088329A (en) * | 2001-09-19 | 2003-03-25 | Yamagami Chizuko | Analgesic health supplement |
US7144590B2 (en) * | 2003-01-09 | 2006-12-05 | Lipoprotein Technologies, Inc. | Bioactive compositions derived from humulus lupulus |
JP4578821B2 (en) * | 2004-02-19 | 2010-11-10 | 明治乳業株式会社 | Pharmaceutical composition for the treatment of nephritis |
JP2006219458A (en) * | 2005-02-14 | 2006-08-24 | Meiji Milk Prod Co Ltd | Agent for inhibiting ischemic enteropathy |
-
2008
- 2008-05-09 CN CN2008800156559A patent/CN101678077B/en active Active
- 2008-05-09 JP JP2009514147A patent/JP5683106B2/en active Active
- 2008-05-09 WO PCT/JP2008/058631 patent/WO2008140041A1/en active Application Filing
- 2008-05-09 KR KR1020097025589A patent/KR20100017708A/en not_active Application Discontinuation
-
2010
- 2010-09-16 HK HK10108800.1A patent/HK1142277A1/en unknown
-
2013
- 2013-06-25 JP JP2013132166A patent/JP5797234B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
JP2013241418A (en) | 2013-12-05 |
CN101678077B (en) | 2013-02-20 |
CN101678077A (en) | 2010-03-24 |
HK1142277A1 (en) | 2010-12-03 |
JP5797234B2 (en) | 2015-10-21 |
JPWO2008140041A1 (en) | 2010-08-05 |
JP5683106B2 (en) | 2015-03-11 |
WO2008140041A1 (en) | 2008-11-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6026720B2 (en) | Glucose-lowering agent and blood glucose-lowering food and beverage composition | |
Wong et al. | Bovine colostrum enhances natural killer cell activity and immune response in a mouse model of influenza infection and mediates intestinal immunity through toll-like receptors 2 and 4 | |
CN106535915B (en) | Ghrelin secretion promoter | |
Kassem | Future challenges of whey proteins | |
JP5925274B2 (en) | Endometriosis prevention and / or amelioration agent and food and beverage composition comprising the same | |
WO2011096414A1 (en) | Mitochondrial function improver | |
JP5797234B2 (en) | New anti-inflammatory analgesic | |
KR20080108523A (en) | Fat accumulation inhibitor | |
Foisy Sauvé et al. | Glycomacropeptide: A bioactive milk derivative to alleviate metabolic syndrome outcomes | |
JP5273989B2 (en) | Preventive or therapeutic agent for gastrointestinal ulcer | |
Agarwal et al. | A review on anticancer property of colostrum | |
KR101418968B1 (en) | Composition for blood sugar regulation comprising soybean hydrololysate with high chp(cyclo(his-pro)) | |
CN111201026B (en) | Fermented milk and polysaccharides with cancer cachexia inhibiting effect | |
RU2448529C1 (en) | Method for correction of organism digestive system homeostasis disruption | |
JP2019081733A5 (en) | ||
JP2001226289A (en) | Hepatic function ameliorative agent | |
JP7462321B2 (en) | Inhibitor of inflammatory cytokine production | |
WO2013058627A2 (en) | Composition including rebamipide as an active ingredient for preventing or treating obesity | |
JP6038416B1 (en) | Fire suppression agent | |
JP2008115169A (en) | PHARMACEUTICAL AND NUTRITIONAL COMPOSITION FOR INCREASING TOTAL IgA LEVEL AND/OR ANTIGEN-SPECIFIC IgA ANTIBODY TITER IN MOTHER'S MILK | |
JP6823397B2 (en) | Stumbling improver while walking | |
JP2006143652A (en) | Agent for treatment of inflammatory bowel disease | |
JP5995803B2 (en) | Catechol-O-methyltransferase inhibitor | |
JP5752108B2 (en) | Blood uric acid level lowering agent |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A201 | Request for examination | ||
E902 | Notification of reason for refusal | ||
E601 | Decision to refuse application |