CN102149383B - 化合物在制备用于治疗通过抑制血清素再吸收而改善的疾病的医药品或饮食品中的用途 - Google Patents
化合物在制备用于治疗通过抑制血清素再吸收而改善的疾病的医药品或饮食品中的用途 Download PDFInfo
- Publication number
- CN102149383B CN102149383B CN200980132443.3A CN200980132443A CN102149383B CN 102149383 B CN102149383 B CN 102149383B CN 200980132443 A CN200980132443 A CN 200980132443A CN 102149383 B CN102149383 B CN 102149383B
- Authority
- CN
- China
- Prior art keywords
- mtca
- pharmaceuticals
- food
- disease
- microorganism
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 201000010099 disease Diseases 0.000 title claims abstract description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 27
- 235000013305 food Nutrition 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 title claims description 47
- 235000013361 beverage Nutrition 0.000 title abstract description 7
- 230000002401 inhibitory effect Effects 0.000 title abstract description 5
- 230000000697 serotonin reuptake Effects 0.000 title abstract description 4
- 230000001668 ameliorated effect Effects 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 title description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 36
- 235000005911 diet Nutrition 0.000 claims description 28
- 230000037213 diet Effects 0.000 claims description 28
- 230000013016 learning Effects 0.000 claims description 23
- 229940076279 serotonin Drugs 0.000 claims description 17
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 11
- 239000000654 additive Substances 0.000 claims description 7
- 239000004615 ingredient Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 230000000996 additive effect Effects 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 3
- 239000008177 pharmaceutical agent Substances 0.000 abstract 1
- 244000005700 microbiome Species 0.000 description 35
- 239000000047 product Substances 0.000 description 32
- 230000000694 effects Effects 0.000 description 28
- 239000000203 mixture Substances 0.000 description 27
- 238000004519 manufacturing process Methods 0.000 description 26
- 238000000034 method Methods 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 241000186660 Lactobacillus Species 0.000 description 22
- 230000001430 anti-depressive effect Effects 0.000 description 22
- 230000009182 swimming Effects 0.000 description 21
- 229940039696 lactobacillus Drugs 0.000 description 20
- 239000001963 growth medium Substances 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- 239000000463 material Substances 0.000 description 16
- 102000014914 Carrier Proteins Human genes 0.000 description 15
- 108010078791 Carrier Proteins Proteins 0.000 description 15
- 230000013275 serotonin uptake Effects 0.000 description 14
- 240000006024 Lactobacillus plantarum Species 0.000 description 13
- 235000013965 Lactobacillus plantarum Nutrition 0.000 description 13
- 239000000935 antidepressant agent Substances 0.000 description 13
- 229940005513 antidepressants Drugs 0.000 description 13
- 229940072205 lactobacillus plantarum Drugs 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 12
- 239000012228 culture supernatant Substances 0.000 description 12
- 190000032366 miboplatin Chemical compound 0.000 description 11
- 229950002777 miboplatin Drugs 0.000 description 11
- 239000003981 vehicle Substances 0.000 description 11
- ZUPHXNBLQCSEIA-UHFFFAOYSA-N 1-methyl-tetrahydro-beta-carboline-3-carboxylic acid Natural products N1C2=CC=CC=C2C2=C1C(C)NC(C(O)=O)C2 ZUPHXNBLQCSEIA-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- QYMDEOQLJUUNOF-UHFFFAOYSA-N pinoline Chemical compound C1NCCC2=C1NC1=CC=C(OC)C=C12 QYMDEOQLJUUNOF-UHFFFAOYSA-N 0.000 description 9
- 241000589516 Pseudomonas Species 0.000 description 8
- 210000004556 brain Anatomy 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 240000001929 Lactobacillus brevis Species 0.000 description 7
- 235000013957 Lactobacillus brevis Nutrition 0.000 description 7
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 7
- -1 fatty acid ester Chemical class 0.000 description 7
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 7
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 6
- 241001478240 Coccus Species 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000000994 depressogenic effect Effects 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 235000013336 milk Nutrition 0.000 description 6
- 239000008267 milk Substances 0.000 description 6
- 210000004080 milk Anatomy 0.000 description 6
- 208000011580 syndromic disease Diseases 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- 229930006000 Sucrose Natural products 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 238000000108 ultra-filtration Methods 0.000 description 5
- 235000014469 Bacillus subtilis Nutrition 0.000 description 4
- 241000186000 Bifidobacterium Species 0.000 description 4
- 206010013754 Drug withdrawal syndrome Diseases 0.000 description 4
- 241000194033 Enterococcus Species 0.000 description 4
- 241000194036 Lactococcus Species 0.000 description 4
- 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 4
- 241000192132 Leuconostoc Species 0.000 description 4
- 238000012347 Morris Water Maze Methods 0.000 description 4
- 241000192001 Pediococcus Species 0.000 description 4
- 241000194017 Streptococcus Species 0.000 description 4
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 230000003542 behavioural effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000000855 fermentation Methods 0.000 description 4
- 230000004151 fermentation Effects 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 235000015203 fruit juice Nutrition 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 238000010829 isocratic elution Methods 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 235000013599 spices Nutrition 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 235000014101 wine Nutrition 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 244000063299 Bacillus subtilis Species 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 206010029897 Obsessive thoughts Diseases 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 235000013334 alcoholic beverage Nutrition 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 235000013399 edible fruits Nutrition 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 208000024714 major depressive disease Diseases 0.000 description 3
- 238000001225 nuclear magnetic resonance method Methods 0.000 description 3
- 208000019906 panic disease Diseases 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000004904 shortening Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000012549 training Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- PJVXUVWGSCCGHT-ZPYZYFCMSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;(3s,4r,5r)-1,3,4,5,6-pentahydroxyhexan-2-one Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO PJVXUVWGSCCGHT-ZPYZYFCMSA-N 0.000 description 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
- AHOUBRCZNHFOSL-UHFFFAOYSA-N 3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)piperidine Chemical compound C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 241000201860 Abiotrophia Species 0.000 description 2
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 241000422409 Alkalibacterium Species 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 241000193818 Atopobium Species 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- 241000588807 Bordetella Species 0.000 description 2
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 2
- 241000206594 Carnobacterium Species 0.000 description 2
- 241000207199 Citrus Species 0.000 description 2
- 241001672694 Citrus reticulata Species 0.000 description 2
- 240000000560 Citrus x paradisi Species 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- 208000008967 Enuresis Diseases 0.000 description 2
- 241000628997 Flos Species 0.000 description 2
- 241000235796 Granulicatella Species 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- 241001468189 Melissococcus Species 0.000 description 2
- 241000202223 Oenococcus Species 0.000 description 2
- 241000235070 Saccharomyces Species 0.000 description 2
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 2
- 206010041250 Social phobia Diseases 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- 241001537924 Tetracoccus <angiosperm> Species 0.000 description 2
- 241000500334 Tetragenococcus Species 0.000 description 2
- 241001635318 Trichococcus Species 0.000 description 2
- 241000207194 Vagococcus Species 0.000 description 2
- 241000202221 Weissella Species 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 230000006793 arrhythmia Effects 0.000 description 2
- 235000013405 beer Nutrition 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 235000020971 citrus fruits Nutrition 0.000 description 2
- 235000013353 coffee beverage Nutrition 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 239000012531 culture fluid Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003797 essential amino acid Substances 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000003365 glass fiber Substances 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 235000015243 ice cream Nutrition 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 206010022437 insomnia Diseases 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 235000015110 jellies Nutrition 0.000 description 2
- 239000008274 jelly Substances 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000001814 pectin Substances 0.000 description 2
- 235000010987 pectin Nutrition 0.000 description 2
- 229920001277 pectin Polymers 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 235000013555 soy sauce Nutrition 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 210000000225 synapse Anatomy 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013618 yogurt Nutrition 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- ZUPHXNBLQCSEIA-CPCISQLKSA-N (1s,3s)-1-methyl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylic acid Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C)N[C@H](C(O)=O)C2 ZUPHXNBLQCSEIA-CPCISQLKSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- XPQOARAAVQVKOK-CBAPKCEASA-N 1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid Natural products C[C@@H]1NC[C@H](C(=O)O)c2c1[nH]c3ccccc23 XPQOARAAVQVKOK-CBAPKCEASA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 1
- GLQPTZAAUROJMO-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)benzaldehyde Chemical compound C1=C(OC)C(OC)=CC=C1C1=CC=C(C=O)C=C1 GLQPTZAAUROJMO-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- KFYRPLNVJVHZGT-UHFFFAOYSA-N Amitriptyline hydrochloride Chemical compound Cl.C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KFYRPLNVJVHZGT-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 238000011814 C57BL/6N mouse Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000555678 Citrus unshiu Species 0.000 description 1
- UNPLRYRWJLTVAE-UHFFFAOYSA-N Cloperastine hydrochloride Chemical compound Cl.C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)OCCN1CCCCC1 UNPLRYRWJLTVAE-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 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
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- LFMYNZPAVPMEGP-PIDGMYBPSA-N Fluvoxamine maleate Chemical compound OC(=O)\C=C/C(O)=O.COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 LFMYNZPAVPMEGP-PIDGMYBPSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010060891 General symptom Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010029216 Nervousness Diseases 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 1
- 241000927544 Olsenella Species 0.000 description 1
- 229940087098 Oxidase inhibitor Drugs 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 240000004885 Quercus rubra Species 0.000 description 1
- 235000009135 Quercus rubra Nutrition 0.000 description 1
- 241000209051 Saccharum Species 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 description 1
- QTENRWWVYAAPBI-YZTFXSNBSA-N Streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@H]1[C@H](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@H]1[C@H](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O QTENRWWVYAAPBI-YZTFXSNBSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 244000290333 Vanilla fragrans Species 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- 240000001417 Vigna umbellata Species 0.000 description 1
- 235000011453 Vigna umbellata Nutrition 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000005862 Whey Substances 0.000 description 1
- 102000007544 Whey Proteins Human genes 0.000 description 1
- 108010046377 Whey Proteins Proteins 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000012271 agricultural production Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940087168 alpha tocopherol Drugs 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
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960005119 amitriptyline hydrochloride Drugs 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 229940125713 antianxiety drug Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 229940046011 buccal tablet Drugs 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical class [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 1
- 229960002079 calcium pantothenate Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000013736 caramel Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- 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 1
- 235000021240 caseins Nutrition 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000000498 cooling water Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000013345 egg yolk Nutrition 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229960002107 fluvoxamine maleate Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 235000020400 fruit nectar Nutrition 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910001410 inorganic ion Inorganic materials 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 239000011785 micronutrient Substances 0.000 description 1
- 235000013369 micronutrients Nutrition 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 229940126569 noradrenaline reuptake inhibitor Drugs 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000004798 organs belonging to the digestive system Anatomy 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 229960005183 paroxetine hydrochloride Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 208000022821 personality disease Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 235000011962 puddings Nutrition 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000013606 secretion vector Substances 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 229940126570 serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 1
- 229960003660 sertraline hydrochloride Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000009329 sexual behaviour Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- 239000004320 sodium erythorbate Substances 0.000 description 1
- 235000010352 sodium erythorbate Nutrition 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 description 1
- 229940013618 stevioside Drugs 0.000 description 1
- 235000019202 steviosides Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 239000008400 supply water Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 238000004454 trace mineral analysis Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 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 1
- 239000002076 α-tocopherol Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/12—Fermented milk preparations; Treatment using microorganisms or enzymes
- A23C9/13—Fermented milk preparations; Treatment using microorganisms or enzymes using additives
- A23C9/1307—Milk products or derivatives; Fruit or vegetable juices; Sugars, sugar alcohols, sweeteners; Oligosaccharides; Organic acids or salts thereof or acidifying agents; Flavours, dyes or pigments; Inert or aerosol gases; Carbonation methods
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23F—COFFEE; TEA; THEIR SUBSTITUTES; MANUFACTURE, PREPARATION, OR INFUSION THEREOF
- A23F5/00—Coffee; Coffee substitutes; Preparations thereof
- A23F5/24—Extraction of coffee; Coffee extracts; Making instant coffee
- A23F5/243—Liquid, semi-liquid or non-dried semi-solid coffee extract preparations; Coffee gels; Liquid coffee in solid capsules
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
- A23G9/00—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor
- A23G9/32—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor characterised by the composition containing organic or inorganic compounds
-
- 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
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/02—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation containing fruit or vegetable juices
-
- 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
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12G—WINE; PREPARATION THEREOF; ALCOHOLIC BEVERAGES; PREPARATION OF ALCOHOLIC BEVERAGES NOT PROVIDED FOR IN SUBCLASSES C12C OR C12H
- C12G3/00—Preparation of other alcoholic beverages
- C12G3/04—Preparation of other alcoholic beverages by mixing, e.g. for preparation of liqueurs
- C12G3/05—Preparation of other alcoholic beverages by mixing, e.g. for preparation of liqueurs with health-improving ingredients, e.g. flavonoids, flavones, polyphenols or polysaccharides
- C12G3/055—Preparation of other alcoholic beverages by mixing, e.g. for preparation of liqueurs with health-improving ingredients, e.g. flavonoids, flavones, polyphenols or polysaccharides extracted from plants
-
- 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)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- General Health & Medical Sciences (AREA)
- Nutrition Science (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- General Engineering & Computer Science (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Botany (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明提供医药品或饮食品,其含有临床上有效量的(1S,3S)-1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸,用于治疗或预防通过抑制血清素再吸收而改善的疾病或病症。
Description
技术领域
本发明涉及用于预防或治疗抑郁症或其并发症的组合物或用于改善学习积极性的组合物,其以(1S,3S)-1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸((1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylicacid)为有效成分,具有血清素转运蛋白抑制活性。
背景技术
抑郁症已成为巨大的社会问题。美国的调查估计,抑郁性障碍的终生患病率女性为26%,男性为12%(非专利文献1)。此外,日本进行的大规模调查报道了终生患病率为14%。而且抑郁症患者中,84%患有并发症,61%患有其他的精神疾病,30%患有人格障碍,58%患有身体疾病的并发症(非专利文献2)。
抑郁症的一般症状为心情郁闷、乏力、抑郁的思维方式、自杀念头、焦躁感、失眠、食欲降低、性欲降低、身体不适等涉及多方面。病情较重的抑郁症称为重性抑郁症。有关重性抑郁症,报道了如下实验数据,初次发病到40周时大多为急速恢复,之后恢复到达了极限。还有如下报道,对重性抑郁症患者进行20年跟踪调查的结果,15~19%的患者残留有就业困难等的慢性后遗症(非专利文献3)。
对于抑郁症的原因提出了各种假说。最早提出且至今仍具有说服力的假说是脑内单胺功能的降低与抑郁症有关(也被称为脑内单胺假说)。这是根据如下事实提出的假说,通过阻断单胺的细胞内再吸收而具有强化脑内单胺功能作用的三环类抗抑郁药对抑郁症的缓解有效。
目前人们对于作为脑内单胺之一的血清素的功能特别关注,通过在使血清素神经细胞体中存在的血清素-1受体致敏之前使神经突触细胞中的游离血清素量增加,从而具有抗抑郁作用的假说被视为有说服力(非专利文献4)。该思 考方法与经典的脑内单胺假说基本一致。认为不管怎样抑郁症均起因于脑内血清素功能的降低。
作为针对抑郁症的药剂治疗,首先为约40年前开发出的三环类抗抑郁药米帕明和单胺氧化酶抑制剂。这些药物所具有的特性之一是使血清素、去甲肾上腺素在神经突触间隙增加,该作用为抗抑郁效果的中心,基于这一想法,此后又开发出许多抗抑郁药。近年来,在临床上已开始使用选择性血清素再吸收抑制剂(SSRI)和血清素/去甲肾上腺素再吸收抑制剂(SNRI),其更有选择性地抑制通过血清素转运蛋白进行的这些单胺的再吸收。在日本,目前已被认可的抗抑郁药有三环类·四环类抗抑郁药、SSRI、SNRI等,达到了17种(非专利文献5)。
这些抗抑郁药除了抑郁症以外,还对各种病状有疗效,根据医药品医疗器械综合机构出示的各医药品的附加说明文章,例如作为SSRI的马来酸氟伏沙明对强迫症及社交焦虑障碍有效,作为SSRI的盐酸帕罗西汀对恐慌症及强迫症有效,作为SSRI的盐酸舍曲林对恐慌症有效。此外,三环类的SNRI盐酸阿米替林对遗尿症有效。
另一方面,有报道指出这些抗抑郁药存在副作用。例如可例举SSRI会引起恶心、头痛、神经过敏等,SNRI会引起震颤、心动过速、勃起·射精障碍等。还报道了很多在投给多种抗抑郁药时与投给单种药剂相比副作用增加的例子(非专利文献6)。
也有如下报道,中止服用抗抑郁药时,有时会产生戒断症状。作为三环类·四环类抗抑郁药的戒断症状,报道有乏力、呕吐及头痛等伴随焦虑、焦躁的消化器官症状及身体不适感;失眠及多梦等的睡眠障碍;北美红栎及帕金森病症状等的运动障碍;发展为类似躁狂状态的行为活动增多;心律不齐等。这些症状除心律不齐以外,也同样被认为是SSRI的戒断症状(非专利文献7)。作为SSRI的特征性戒断症状,报道有平衡障碍、感觉异常及攻击性·冲动性行为等(非专利文献8)。
如上所述,已有报道指出目前广泛使用的抗抑郁药中具有副作用,因而期待开发出可替代这些抗抑郁药的而适用的具有饮食经验的安全的食品材料及 食品成分。有报道指出,作为来自具有抗抑郁作用的食品的组合物有来自蜂王浆的组合物(专利文献1)、以啤酒花提取物为主要成分的组合物(专利文献2)。
1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸(1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid(MTCA))为柠檬、葡萄柚、柑橘、宽皮柑桔等的水果(非专利文献9)、啤酒、葡萄酒(非专利文献10)、酱油(非专利文献11)等中含有的化合物,已知有(1S,3S)及(1R,3S)的2种非对映异构体。已知MTCA在色氨酸和乙醛的存在下非发酵性生成,已知特别是(1S,3S)-MTCA(也称为(1S,3S)-2,3,4,9-四氢-1-甲基-1H-吡啶并[3,4-b]-吲哚-3-羧酸)由酿酒酵母(S.cerevisiae)发酵生成(非专利文献12)。此外,还已知(1S,3S)-MTCA具有抗氧化作用,防止通过使用γ晶体蛋白的FeCl3的芬顿反应引起的自聚合反应,防止γ晶体蛋白的光聚合反应(非专利文献13)。且有如下记载,咔啉化合物松香烃(6-甲氧基-1,2,3,4-四氢-β-咔啉)(Pinolin、6-methoxy-1,2,3,4-tetrahydro-beta-carboline)抑制单胺氧化酶A的活性,且抑制脑内的血清素吸收(非专利文献14)。此外有报道指出在使用大鼠的强制游泳试验中,松香烃缩短了大鼠的不动时间,其与三环类抗抑郁药具有同样的作用(非专利文献15)。
但是,对于MTCA的血清素吸收抑制作用、抗抑郁效果、学习积极性改善效果却全然不知。
现有技术文献
专利文献
专利文献1日本特开2004-131407号公报
专利文献2日本特开2002-58450号公报
非专利文献
非专利文献1APA:Am J Psychiatry 157(Suppl 4):1-20,2000
非专利文献2Pincus HA,et al:Arch Gen Psychiatry 56:442-449,1999
非专利文献3野村总一郎:平成13年度厚生劳动省,有关灾害科学的委托研究报告书,2001(日语原名:野村総一郎:平成13年度厚生労働省,災害科学に関する委託研究報告書,2001)
非专利文献4野村总一:别册 日本临床 精神医学综合征I 38:236-239,2003(日语原名:野村総一:別冊 日本臨床 精神医学症候群I 38:236-239,2003)
非专利文献5田中辉明等:别册 日本临床 精神医学综合征I 38:362-365,2003(日语原名:田中輝明ら:別冊 日本臨床精神医学症候群I 38:362-365,2003)
非专利文献6山肋成人等:别册 日本临床 精神医学综合征I 38:370-373,2003(日语原名:山脇成人ら:別冊 日本臨床精神医学症候群I 38:370-373,2003)
非专利文献7 Tamam L,et al:Adv Ther 19:17-26,2002
非专利文献8 Haddad P:J Psychopharmacol 12:305-313,1996
非专利文献9 T.Herraiz:J.Agric.Food Chem,47 4883-4887,1999
非专利文献10 T.Herraiz:J.Agric.Food Chem,44 3057-3065,1996
非专利文献11 Shuichi M,et al:Biosci.Biotechnol.Biochem,69 2232-2235,2005
非专利文献12 Tomas H,et al:J.Agric.Food Chem,41 959-964,1993
非专利文献13 Koteppa P,et al:J.Biol.Chem,275 2455-2462,2000
非专利文献14 Pahkla R,et al:Pharmacol Toxicol,80 122-126,1997
非专利文献15 Pahkla R,et al:Pharmacol Research,3473-78,1996
发明内容
以往,抑郁症或其并发症的预防或治疗药及学习积极性改善药很难兼顾其效果和低副作用及高安全性。而且,还有一大问题就是在医药品的合成中需要经过多道工序,成本高。综上所述,强烈希望通过简单工序即可从来自食品的物质中获得抗抑郁活性物质以及学习积极性改善物质。本发明的课题在于提供有效且安全性高的、用于预防或治疗抑郁症或其并发症的医药品或食品以及用于改善学习积极性的医药品或食品。
本发明者为解决上述课题进行了锐意研究,从乳酸菌的培养上清中分离· 鉴定了(1S,3S)-MTCA。而后发现了(1S,3S)-MTCA具有作为体外(in vitro)的抗抑郁效果指标的血清素转运蛋白抑制活性。
而且,为评价(1S,3S)-MTCA的抗抑郁效果,通过制作在开场游泳实验(open space swimming)中积极性呈降低状态的小鼠,使用该小鼠,调查投给(1S,3S)-MTCA时对Morris水迷宫试验中到达逃生平台的时间(也称为逃避潜伏期)的缩短效果,从而判定(1S,3S)-MTCA的抗抑郁效果。其结果确认了(1S,3S)-MTCA具有缩短到达逃生平台的时间的效果,该物质具有抗抑郁效果。而且,在Morris水迷宫试验中,由于通过基于对空间认识的学习而缩短了到达逃生平台的时间,因而可认为本发明中的缩短到达逃生平台的时间的效果为改善开场游泳实验(open space swimming)中降低了的学习积极性的效果,也可确认为(1S,3S)-MTCA具有学习积极性改善效果。
即本发明如下。
1.一种医药品或饮食品,其特征在于,含有临床上有效量的(1S,3S)-1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸,用于治疗或预防通过抑制血清素再吸收而改善的疾病或病症。
2.一种医药品或饮食品,其特征在于,含有具有生产(1S,3S)-1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸能力的微生物或其加工品,用于治疗或预防通过抑制血清素再吸收而改善的疾病或病症。
3.一种医药品或饮食品,其特征在于,含有具有生产(1S,3S)-1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸能力的微生物的培养上清或其加工品,用于治疗或预防通过抑制血清素再吸收而改善的疾病或病症。
4.根据上述1~3中任一项所述的医药品或饮食品,其特征在于,进一步含有允许添加在医药品或食品中的添加剂。
5.根据上述2或3所述的医药品或饮食品,其特征在于,所述微生物为乳酸菌。
6.根据上述5所述的医药品或饮食品,其特征在于,所述乳酸菌属于链球菌属(Streptococcus)、乳杆菌属(Lactobacillus)、明串珠菌属(Leuconostoc)、片球菌属(Pediococcus)、双歧杆菌属(Bifidobacterium)、 四联球菌属(Tetragenococcus)、魏斯氏菌属(Weissella)、肠球菌属(Enterococcus)、蜜蜂球菌属(Melissococcus)、乳球菌属(Lactococcus)、肉食杆菌属(Carnobacterium)、漫游球菌属(Vagococcus)、奇异菌属(Atopobium)、乳球形菌属(Lactosphaera)、酒球菌属(Oenococcus)、乏养菌属(Abiotrophia)、Paralactobacillus、颗粒链菌属(Granulicatella)、Atopobactor、嗜盐嗜碱菌属(Alkalibacterium)、或O1senella。
7.根据上述2或3所述的医药品或饮食品,其特征在于,所述微生物属于植物乳杆菌或短乳杆菌。
8.根据上述1~3中任一项所述的医药品或饮食品,其特征在于,通过抑制血清素再吸收而改善的疾病或病症为抑郁症。
9.根据上述1~3中任一项所述的医药品或饮食品,其特征在于,通过抑制血清素再吸收而改善的疾病或病症为抑郁症的并发症。
10.根据上述1~3中任一项所述的医药品或饮食品,其特征在于,通过抑制血清素再吸收而改善的疾病或病症为学习积极性减退。
11.一种制造方法,其是上述1~3中任一项所述的医药品或饮食品的制造方法,其特征在于,包括在培养基中培养具有生产(1S,3S)-1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸能力的微生物的工序。
12.-种血清素再吸收抑制剂,其特征在于,含有(1S,3S)-1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸。
根据本发明,可提供具有抗抑郁效果以及学习积极性改善效果的医药品或饮食品。已知作为本发明的医药品或饮食品中的有效成分使用的(1S,3S)-MTCA存在于食品中,与具有其他同种活性的化合物、例如非专利文献14中记载的脑内物质松香烃(6-甲氧基-1,2,3,4-四氢-β-咔啉)等相比,可以说安全性极高,对副作用等的担心程度小。且本发明的医药品或饮食品还具有可简单制造的优点。
附图说明
图1表示从乳酸菌培养上清中得到的组分(Develosil C-30组分)的质 谱分析结果
图2表示组合开场游泳实验和Morris水迷宫试验的行为科学药理试验中,单次给药时(1S,3S)-MTCA的抗抑郁效果以及学习积极性改善效果
图3表示组合开场游泳实验和Morris水迷宫试验的行为科学药理试验中,持续给药时(1S,3S)-MTCA的抗抑郁效果以及学习积极性改善效果。
具体实施方式
本发明的医药品或饮食品含有作为有效成分的(1S,3S)-MTCA。本发明中使用的(1S,3S)-MTCA为下式表示的化合物:
含有(1S,3S)-MTCA的医药品或饮食品(本说明书中也仅称为“组合物”。)具有血清素转运蛋白抑制活性,对抑郁症或其并发症的治疗、学习积极性改善、强迫症、社交焦虑障碍、恐慌症、遗尿症等有效。
(1S,3S)-MTCA可使用合成物,也可使用作为试剂的市售品。作为试剂,例如可为和光纯药工业株式会社销售的(1S,3S)-2,3,4,9-四氢-1-甲基-1H-吡啶并[3,4-b]-吲哚-3-羧酸市售品。且也可使用从乳酸菌的培养上清、柠檬、葡萄柚、柑橘、宽皮柑桔等的水果、啤酒、葡萄酒、酱油等的食品材料中提取的(1S,3S)-MTCA。
在制造大量含有(1S,3S)-MTCA的食品时,可使(1S,3S)-MTCA在食品中生成,也可从外界添加到食品中。使(1S,3S)-MTCA在食品中生成时,可通过在食品中加入色氨酸和乙醛,静置数日,根据情况加热到80℃左右,而使(1S,3S)-MTCA在食品中非发酵性生成。或者也可如以下说明通过发酵生成。
而且,本发明者还发现如后述实施例中所述,在培养乳酸菌(植物乳杆菌(Lactobacillus plantarum)SAM2446株(FERM BP-10438))之后的培养基上 清中含有(1S,3S)-MTCA。
从上述的食品材料、培养上清等中分离(1S,3S)-MTCA时,可对该食品材料等直接进行分离操作,或也可以在分离操作之前进行冷冻干燥或使用有机溶剂进行液液分配萃取等,从而浓缩该材料中的(1S,3S)-MTCA。作为分离操作,可使用任何方法,例如可在用超滤处理等进行粗分离后,使用反相色谱柱等进行分离。上述的液液分配萃取、超滤处理及反相色谱柱处理可使用本领域技术人员通常使用的方法进行。
根据上述方法,例如可通过测定MS光谱、NMR光谱,来确认是否得到了(1S,3S)-MTCA。
本发明的组合物中所含有的(1S,3S)-MTCA例如可使用如盐酸盐那样的药学上允许的盐的形态,也可使用在体内转化成(1S,3S)-MTCA的盐(前体药物)的形态。另外,因为只要含有一定量的(1S,3S)-MTCA即可,所以也可使用外消旋体。
本发明还提供含有具有生产(1S,3S)-MTCA能力的微生物或其加工品或含有该微生物的培养上清或其加工品的所述医药组合物或饮食物。
在本说明书中,“具有生产(1S,3S)-MTCA能力的微生物”指在有效条件下培养时生产(1S,3S)-MTCA的微生物。此处所述的有效条件,只要是本领域技术人员均可适当确定。微生物的生产(1S,3S)-MTCA能力可如下确认,将微生物(也包含微生物自身、微生物的干燥物、微生物的培养液、微生物的提取物等)例如使用液相色谱法(LC)、质谱分析法(MS)、核磁共振法(NMR)等根据规定方法进行分析时,通过检测出(1S,3S)-MTCA等来确认。具有此生产能力的微生物中,也包含在将培养条件(培养基的组成、培养时的温度条件、培养时的pH条件、培养密度等)进行适当调整时,可具有生产(1S,3S)-MTCA能力的微生物。
上述微生物可从天然获取,或也可为设计成具有生产(1S,3S)-MTCA能力的突变体及/或重组体。此种突变体及/或重组体也包含有意地设计成使用相 同组成的培养基进行培养时,与野性株相比,可提高生产(1S,3S)-MTCA的能力的突变体及/或重组体。
此种具有生产(1S,3S)-MTCA能力的微生物例如可以为乳酸菌、酵母、枯草芽孢杆菌等。作为乳酸菌,例如可例举属于链球菌属(Streptococcus)、乳杆菌属(Lactobacillus)、明串珠菌属(Leuconostoc)、片球菌属(Pediococcus)、双歧杆菌属(Bifidobacterium)、四联球菌属(Tetragenococcus)、魏斯氏菌属(Weissella)、肠球菌属(Enterococcus)、蜜蜂球菌属(Melissococcus)、乳球菌属(Lactococcus)、肉食杆菌属(Carnobacterium)、漫游球菌属(Vagococcus)、奇异菌属(Atopobium)、乳球形菌属(Lactosphaera)、酒球菌属(Oenococcus)、乏养菌属(Abiotrophia)、Paralactobacillus、颗粒链菌属(Granulicatella)、Atopobactor、嗜盐嗜碱菌属(Alkalibacterium)、或Olsenella的微生物;作为酵母,例如可例举属于念珠菌属(Candida)或酵母属(Saccharomyces)的微生物;作为枯草芽孢杆菌,可例举枯草芽孢杆菌(B.subtilis)。
特别是优选的微生物为属于植物乳杆菌(Lactobacillus plantarum)(更加特定地说,为植物乳杆菌SAM2446株(FERM BP-10438))及短乳杆菌(Lactobacillus brevis)(更加特定地说为短乳杆菌SAM2447株(FERM BP-10439))的乳酸菌。
植物乳杆菌SAM2446株及短乳杆菌SAM2447株均由独立行政法人产业技术综合研究所、专利生物保藏中心(日本国茨城县筑波市东1丁目1番地1中央第6)于2005年10月26日接受并进行国际保藏,被分别赋予FERM BP-10438及FERM BP-10439的保藏号。植物乳杆菌SAM2446株(FERM BP-10438)的菌学特性如表1所示,短乳杆菌SAM2447株(FERM BP-10439)的菌学特性如表2所示。
表1
植物乳杆菌SAM2446株
(FERM BP-10438)
表2
短乳杆菌SAM2447株
(FERM BP-10439)
本发明还提供包含在培养基中培养所述具有生产(1S,3S)-MTCA能力的微生物的工序的医药品或饮食品的制造方法。该微生物的培养可通过在适当的培养基中接种微生物,根据微生物的种类采用本领域技术人员公知的方法培养微生物来进行。
微生物为乳酸菌时的培养例如下所述。作为培养基,例如可使用琼脂培养基及/或液体培养基。培养基中可以所需浓度添加碳源及氮源,而且可根据需要添加无机离子、维生素类等的微量营养源。更加简便地说,例如可使用MRS 培养基等的市售培养基,根据需要,可进一步在其中添加添加剂来使用。制备培养基后,可使用适当的酸或碱,将pH调节在6.0~7.0的范围内,使用高压灭菌器等进行灭菌。
而且,以增强(1S,3S)-MTCA的产生量为目的,例如也可将适量的色氨酸和乙醛添加到培养基中。
其后,在培养基中接种乳酸菌,在培养温度10℃~45℃下,通常进行1~2天的振荡培养、静置培养或在发酵罐中进行工业化培养等,使微生物在培养基中增殖。培养条件根据所使用的微生物不同而不同,例如使用植物乳杆菌(Lactobacillus plantarum)时,可使用pH6.5左右的MRS培养基,在37℃左右静置培养1天。可将如此培养的微生物根据需要离心分离,再根据需要进行过滤,得到培养上清。
(1S,3S)-MTCA在后述实施例中被证实具有血清素转运蛋白抑制活性,而且具有抗抑郁效果、学习积极性改善效果。在本说明书中,治疗疾病或病症包括防止该疾病或病症的恶化、改善该疾病或病症以及预防该疾病或病症。
本发明的组合物含有临床上有效量的(1S,3S)-MTCA。临床上有效量为用于发挥抗抑郁效果、学习积极性改善效果等的临床上有效的量。(1S,3S)-MTCA的给药量不特别存在上限,但从经济性上考虑,通常优选不超过100mg/kg左右的量。
本发明的组合物为充分发挥其效果,希望含有如下量的(1S,3S)-MTCA,每次服用(1S,3S)-MTCA为1μg/kg~100mg/kg(优选为2μg/kg~50mg/kg,更优选为4μg/kg~25mg/kg),更加具体地说,以成人为对象时,每次服用(1S,3S)-MTCA为60μg~6000mg(优选为120μg~3000mg,更优选为240μg~1500mg)。
本发明的组合物中,可直接含有以下物质,含有(1S,3S)-MTCA的食品材料等的原料、具有产生(1S,3S)-MTCA能力的微生物、该微生物的培养上清以及含有该微生物的培养物自身等,或也可含有将这些物质进行提取·分离操作,将(1S,3S)-MTCA进行分离·纯化后的产物。且可以使用将这些进行通常的杀菌处理后的产物,也可以使其含有通过减压浓缩及冷冻干燥等而加工成 浓缩物、干燥粉体等的加工品。在制造干燥粉体时,也可使用糊精、高分子淀粉水解物或高分子肽等的常用的赋形剂来制造干燥粉体。本发明的组合物从操作性及保存性的观点来看,优选制成粉末。
本发明的组合物根据目的不同,可以为饮食品(食品、饮料、调味料、酒精饮料、功能性食品等)及医药品的形态。
作为适用于本发明的饮食品,可例举糖、含片、口香糖、酸奶、冰淇淋、布丁、果冻、水羊羹、酒精饮料、咖啡饮料、果汁、果实饮料、碳酸饮料、清凉水饮料、牛奶、乳清饮料、乳酸菌饮料等各种饮食品。可将上述饮食品根据通常方法制造。
在这些饮食品中,也可根据需要配合各种添加剂。具体地说,例如可将葡萄糖、果糖、蔗糖、麦芽糖、山梨糖醇、甜菊苷、甜茶素、玉米糖浆、乳糖、柠檬酸、酒石酸、苹果酸、琥珀酸、乳酸、L-抗坏血酸、d1-α-生育酚、异抗坏血酸钠、甘油、丙二醇、甘油脂肪酸酯、聚甘油脂肪酸酯、蔗糖脂肪酸酯、山梨糖醇酐脂肪酸酯、丙二醇脂肪酸酯、阿拉伯胶、卡拉胶、酪蛋白、明胶、果胶、琼脂、维生素B类、烟酸胺、泛酸钙、氨基酸类、钙盐类、色素、香料、防腐剂等作为食品原料通常使用的原料根据通常方法配合。
而且,在制备本发明的医药品时,可根据需要配合各种添加剂,根据通常方法制备成各种剂形。例如可制成片剂、胶囊剂、颗粒剂、散剂、糖浆剂、精华素等的口服医药品;或软膏、眼膏、洗液、霜剂、贴附剂、栓剂、眼药水、滴鼻药、注射剂等的非口服医药品。使用的添加剂无特别限制,可使用通常所使用的添加剂。例如淀粉、乳糖、白糖、甘露糖醇、羧甲基纤维素、玉米淀粉、无机盐等的固体载体;蒸馏水、生理盐水、葡萄糖水溶液、乙醇等的醇类、丙二醇、聚乙二醇等的液体载体;各种的动植物油、白色凡士林、石蜡、蜡类等的油性载体等。
本发明的组合物不仅可含有作为有效成分的(1S,3S)-MTCA,还可根据需要进一步含有已知抗抑郁效果等的其他有效成分。此种其他有效成分在与(1S,3S)-MTCA并用时,必须是安全的成分。
例如,本发明的组合物可含有1种或多种组合含有本领域技术人员公知的 物质,其为SSRI及SNRI等的抗抑郁剂、抗焦虑剂及贯叶连翘等。
而且,本发明的组合物在含有具有生产(1S,3S)-MTCA能力的微生物或其加工品或其培养上清或加工品时,也可含有来自该微生物的已知上述抗抑郁效果等的物质。
而且,本发明的医药品或饮食品也可在其包装等上注明其具体用途(例如用于抗抑郁、用于预防抑郁症的并发症、用于改善学习积极性、用于维持健康等)及/或其具体的使用方法(例如摄取量、摄取次数及摄取方法等)。
实施例
以下根据实施例详细说明本发明,但本发明不限于这些实施例。
在以下实施例中,确认了(1S,3S)-MTCA的血清素转运蛋白抑制活性。且分析了(1S,3S)-MTCA对小鼠的抗抑郁效果及学习积极性改善效果。进而制造了含有(1S,3S)-MTCA的医药品及饮食品。
实施例1
乳酸菌培养上清中的(1S,3S)-MTCA的分离·鉴定
(1)乳酸菌的培养
将市售的MRS培养基(Difco制)55g溶解于水1L中,用1当量盐酸或1当量氢氧化钠溶液中将pH值调节为pH6.5后,用高压灭菌器进行杀菌。在此,接种乳酸菌(植物乳杆菌(Lactobacillus plantarum)SAM2446株(FERMABP-10438)),在培养温度37℃下进行1天静置培养。将所得到的培养物进行8000rpm、5分钟离心分离,将所得到的离心上清用具有0.45μm孔径的过滤器过滤,得到培养上清1L。
(2)乳酸菌培养上清的超滤
使所得到的培养上清235mL通过超滤膜(分子量为10000截留分子量、Amicon-YM10、MILLIPORE制),将通过的组分作为超滤组分(165ml)。
(3)使用Develosil C-30-UG-5的色谱法确认(1S,3S)-MTCA的峰
使用分析色谱柱Develosil C-30-UG-5(150mm x 4.6mm)(野村化学制),用以下的测定条件确认超滤组分中含有(1S,3S)-MTCA。作为流动相,使用以下2种溶液:含有0.1%甲酸的蒸馏水(Buf.A)、含有0.1%甲酸的80%乙腈/20%蒸馏水(Buf.B)。流动相的流速为1mL/分钟,使用以下梯度条件进行洗脱:10%Buf.B/90%Buf.A等度洗脱8.3分钟,10%Buf.B/90%Buf.A~16%Buf.B/84%Buf.A线性梯度19.92分钟,16%Buf.B/84%Buf.A~100%Buf.B线性梯度1.66分钟,100%Buf.B等度洗脱4.98分钟。注入将超滤组分使用Buf.A稀释2倍后的产物200μL。检测波长为215nm。可在保留时间17分钟附近检测出相当于(1S,3S)-MTCA的峰。
(4)使用CHP20P(三菱化学制)色谱法的粗纯化
在预先用2.5L的Buf.A平衡的三菱化学公司制色谱柱CHP20P(500mL)中,加入(2)中得到的超滤组分165mL,之后依次使用750mL的Buf.A、500mL的10%Buf.B/90%Buf.A及500mL的20%Buf.B/80%Buf.A,用流速300mL/小时洗脱。在用20%Buf.B/80%Buf.A洗脱时,每次取样50mL。将所得到的馏分用(3)的方法进行分析时,因在第5~7馏分中可检测出(1S,3S)-MTCA的峰,所以将第5~7的馏分作为含有(1S,3S)-MTCA的组分回收,作为CHP20P组分。所得到的CHP20P组分的用量为150mL,冷冻干燥后的重量为133mg。
(5)使用Develosil C-30-UG-5色谱法的纯化·制备·鉴定
作为分析试样,使用将(4)中得到的CHP20P组分的冷冻干燥物10mg溶解在Buf.A中的产物2000μL。分析色谱柱使用Develosil C-30-UG-5(200mm x20mm)(野村化学制)。流速为2.5mL/分钟,使用以下梯度条件进行洗脱:5%Buf.B/95%Buf.A等度洗脱42.48分钟,5%Buf.B/95%Buf.A~30%Buf.B/70%Buf.A线性梯度127.44分钟,100%Buf.B等度洗脱42.48分钟。检测波长为215nm。将在保留时间84~90分钟附近检测出的峰作为Develosil C-30组分。重复10次该操作,从合计为100mg的CHP20P组分中得到3.4mg的Develosil C-30组分。将所得到的Develosil C-30组分根据(3)进行分析时,可确认出相当于 (1S,3S)-MTCA的峰。而后,将该Develosil C-30组分作为结构分析用试样进行NMR及MS分析时,可确认为含有(1S,3S)-MTCA。Develosil C-30组分的MS分析结果如图1所示。
实施例2
(1S,3S)-MTCA的血清素转运蛋白抑制效果的确认
将市售的(1S,3S)-2,3,4,9-四氢-1-甲基-1H-吡啶并[3,4-b]-吲哚-3-羧酸试剂(和光纯药制)作为被检物质((1S,3S)-MTCA)使用,使用Masahiko T,et al:Europian Journal of Pharmacology 368 277-283,1999中记载的方法分析(1S,3S)-MTCA的血清素转运蛋白抑制效果。
(1)细胞匀浆的制备
使整合了人体血清素转运蛋白的cDNA的分泌载体pRc/CMV通过磷酸钙法转染到CHO细胞中。而后,将该CHO细胞在150mm的培养皿中的17.5ml DME培养基(Dulbecco’s Modified Eagles’s Medium、Mediatech制)(含有0.1mM MEM用非必需氨基酸溶液(Non-Essential Amino Acid Solution For MEM、Mediatech制)、5%(V/V)胎牛血清(Fetal Clone Bovine serum product、Hyclone Laboratories制)及1U/μL青霉素/链霉素溶液(Mediatech制))中培养。且培养在10%CO2及90%air的环境下、温度37℃及湿度100%下进行。
而后,为制备细胞匀浆,吸除培养基。将细胞用4mL的改性Puck’s D1液(溶液1)洗涤后,加入溶液1及100mM EGTA(乙二醇-双(β-氨基乙基醚)N,N,N’,N’-四乙酸)10mL,37℃下孵育5分钟。而后,使用橡皮刮刀剥离·回收细胞,移入离心管中,4℃下、110xg离心5分钟。将所得到的菌球悬浮于含有50mM Tris-HCl(pH7.4)、120mM NaCl、5mM KCl及0.1%BSA的溶液(溶液2)中,用匀浆机(Polytron)(Brinkmann Instruments制)用setting6进行10秒匀浆。将所得到的匀浆在4℃下、35600xg离心10分钟。将所得到的菌球悬浮于等容的溶液2中再次在4℃下、35600xg离心10分钟。除去离心上清,将所得到的菌球悬浮于溶液2中,作为细胞匀浆,-80℃下保存以备检测。
将所得到的细胞匀浆的蛋白质浓度以牛血清白蛋白(BSA)为标准用Lowry法测定。
(2)检测
而后,在96孔酶标板中,添加溶解于生理盐水中的(1S,3S)-MTCA溶液(100μg/mL)25μL和含有2nM[3H]米帕明的溶液2(225μL),在此,加入(1)中得到的细胞匀浆(蛋白质量15μg),22℃下孵育60分钟。且已知在该检测中使用的米帕明的作用为通过与血清素转运蛋白结合,来抑制血清素转运蛋白进行的血清素再吸收,是三环类抗抑郁药之一。作为对照,对于不含有(1S,3S)-MTCA的样品同样进行孵育。使用10μM米帕明分析[3H]米帕明与细胞匀浆的非特异性结合。
孵育之后,将试样使用预先浸在0.3%PEI中的内置有玻璃纤维滤纸(GF/G、Packard制)的96孔细胞收集器(Unifilter、Packard制)迅速过滤,而后,使用冰冷的50mM Tris-HCl(pH7.4)及150mM NaCl数次洗涤,除去未结合的[3H]米帕明。将洗涤后的玻璃纤维滤纸干燥后,通过加入闪烁液(scintillation cocktail)(Microscint 0、Packard制),使用闪烁计数器(Topcount、Packard制)测定试样的放射活性,来测定[3H]米帕明与细胞匀浆的结合量。
在本检测中,将作为对照的[3H]米帕明与细胞匀浆的特异性结合量作为100时,可知100μg/mL的(1S,3S)-MTCA样品与细胞匀浆的特异性结合量保留在69。该结果表明(1S,3S)-MTCA竞争性抑制米帕明与血清素转运蛋白的结合,因此,可表明(1S,3S)-MTCA与米帕明同样与血清素转运蛋白结合。如果(1S,3S)-MTCA与血清素转运蛋白结合,即可推断(1S,3S)-MTCA也与米帕明同样具有血清素转运蛋白抑制作用(即血清素再吸收抑制作用)。
实施例3
通过使用小鼠的行为科学药理试验评价(1S,3S)-MTCA的抗抑郁效果及学习积极性改善效果
被验体
将无实验经验的雄性C57BL/6N小鼠90只作为被验体。被验体在实验开始时平均为约12周龄,平均体重为24.9g(SD=3.30)。被验体在室温23℃、湿度50~60%的动物饲养室内在丙烯酸树脂制笼中饲养。将动物饲养室内的明期和暗期设定为12小时交替的周期(明期:上午8时~下午8时)。本实验在每天明期的相同时间带实施。作为食饵,投喂干燥固体饲料(日本农产工业株式会社制Labo MR)。饲料食用·供水无限制。
被验体分为3组,分别命名为noOS-Vehicle组(正常小鼠组)(n=10)、OS-(1S,3S)-MTCA给药组(n=10)及OS-Vehicle组(抑郁小鼠组)(n=10)。
实验装置
使用内径为95cm、深度为35cm的圆形泳池。泳池用高度为120cm、宽度为150cm的白色屏风将四面围住。逃生平台为在直径11.5cm、厚度0.5cm的圆盘上安装台座,高度为21cm。逃生平台仅设置在后述Phase 2中的泳池内。设置位置为将圆形水面均分为4个扇形象限(Quadrant 1~4)的各扇形象限的中央部,并对每个被验体进行规定。水位在距逃生平台表面约0.5cm处。逃生平台的边缘与泳池内壁的最短距离为20cm。用氧化钛使水为白浊状态,水温维持在24±1℃。除被验体用于记忆逃生平台位置的装置之外,将可用作抓手的刺激极力从泳池周围去除。实验时,从实验装置的设置区域外通过荧光灯照明,水面上的照度为约240lux。
实验
Phase 1:开场游泳处理期(Day 1~5)
对于除noOS-Vehicle组以外的2组被验体全部,每天进行5分钟开场游泳处理(OS),连续进行5天。将被验体从池壁边缘投入,使其自由游泳。通过设置在泳池水面上约2m位置的摄像机拍摄游泳的姿态,使用行动跟踪·分析用视频跟踪系统,对假定在泳池水面的4个象限(Quadrant 1~4)内的各滞留时间和游泳距离进行分析。
Phase 2:水迷宫学习训练期(Day 6~15)
对于OS-(1S,3S)-MTCA给药组的被验体,将(1S,3S)-2,3,4,9-四氢-1-甲基-1H-吡啶并[3,4-b]-吲哚-3-羧酸(和光纯药制)((1S,3S)-MTCA)按照每1kg体重20mg的量制成10mL水溶液,使用顶端安装有硅胶球(直径2mm)的特富龙(Teflon)(注册商标)制饲管(粗度为1.2mm,长度为38mm),在每天进行水迷宫学习训练的60分钟之前口服给药。制备(1S,3S)-MTCA的水溶液时使用蒸馏水。对于noOS-Vehicle组及OS-Vehicle组的被验体,使用同样方法投给蒸馏水。在各试行试验中,将被验体从泳池的假想4象限(Quadrant 1~4)中的任一池壁边缘按照随机顺序将头朝向池壁投入泳池,将两前肢接触逃生平台的时间作为到达逃生平台的时间(逃避潜伏期)来计算。当被验体爬上逃生平台并停留10秒间后,再次用同样的方法投入泳池。该试行试验为1天重复5次。在投入泳池后60秒以内被验体未到达逃生平台时,实验者将被验体诱导到逃生平台上,在逃生平台上停留10秒后再次重复进行实验。此时,逃避潜伏期记录为60秒,定义为失败试行试验。试行试验的间隔为30秒。水迷宫学习训练连续进行10天。
结果
noOS-Vehicle组(正常小鼠组)、OS-(1S,3S)-MTCA给药组及OS-Vehicle组(抑郁小鼠组)的第1天的平均逃避潜伏期(秒、5次试行试验的平均值)如图2所示。OS-Vehicle组(抑郁小鼠组)的平均逃避潜伏期为52.6秒,而OS-(1S,3S)-MTCA给药组为42.7秒。且noOS-Vehicle组(正常小鼠组)为44.1秒(图2)。该结果表明OS-(1S,3S)-MTCA给药组从给药第1天开始,即显示与OS-Vehicle组(抑郁小鼠组)相比,到达逃生平台的时间缩短。由此,可确认出(1S,3S)-MTCA在单次给药时的抗抑郁作用以及学习积极性改善作用。
此外,到给药第10天的各天的平均逃避潜伏期的变化如图3所示。可确认出在实验期间内,与OS-Vehicle组(抑郁小鼠组)相比,OS-(1S,3S)-MTCA给药组具有到达逃生平台的时间显著缩短的效果(图3)。由此可确认出(1S,3S)-MTCA在持续给药时的抗抑郁作用以及学习积极性改善作用。
实施例4
制造例1:含有(1S,3S)-MTCA的医药品片剂:
将(1S,3S)-MTCA20g与乳糖278.7g及硬脂酸镁1.3g混合,用单冲压片机压片,制造直径为10mm、重量为300mg的片剂。
制造例2:含有(1S,3S)-MTCA的颗粒剂:
将(1S,3S)-MTCA 20g再加上乳糖278.7g及硬脂酸镁1.3g进行压缩、粉碎、制粒、筛选,得到20~50目的颗粒剂。
实施例5
制造例3:含有(1S,3S)-MTCA的饮食物
根据以下表3~表8中记载的配合,根据通常方法制造含有(1S,3S)-MTCA的各种食品。
表3
冰淇淋:
(组成) (重量份)
鲜奶油(45%脂肪) 33.8
脱脂奶粉 11.0
精制白砂糖 14.8
加糖蛋黄 0.3
香草提取物 0.1
水 39.98
(1S,3S)-MTCA 0.02
总量 100.00
表4
果汁:
(组成) (重量份)
冷冻浓缩温州蜜柑果汁 5.0
果糖葡萄糖液糖 11.0
柠檬酸 0.2
L-抗坏血酸 0.02
(1S,3S)-MTCA 0.02
香料 0.2
色素 0.1
水 83.46
总量 100.00
表5
乳酸菌饮料:
(组成) (重量份)
乳固体成分21%发酵乳 14.76
果糖葡萄糖液糖 13.31
果胶 0.5
柠檬酸 0.08
香料 0.15
水 71.18
(1S,3S)-MTCA 0.02
总量 100.00
表6
酸奶:
(组成) (重量份)
生乳(3.4%脂肪) 80.0
鲜奶油(50%脂肪) 8.0
脱脂奶粉 1.5
水 7.48
乳酸菌(starter) 3.0
(1S,3S)-MTCA 0.02
总量 100.00
表7
咖啡饮料:
(组成) (重量份)
精制白砂糖 8.0
脱脂奶粉 5.0
焦糖 0.2
咖啡提取物 2.0
香料 0.1
聚甘油脂肪酸酯 0.05
食盐 0.05
水 84.58
(1S,3S)-MTCA 0.02
总量 100.00
表8
酒精饮料:
(组成) (重量份)
50容量%乙醇 32.0
砂糖 8.4
果汁 2.4
(1S,3S)-MTCA 0.02
纯水 57.18
总量 100.0
Claims (2)
1.临床上有效量的(1S,3S)-1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸作为有效成分在制备用于治疗或预防通过抑制血清素再吸收而改善的疾病或病症的医药品或饮食品中的用途,其中,所述疾病或病症为抑郁症、抑郁症的并发症或学习积极性减退。
2.根据权利要求1所述的用途,其特征在于,所述医药品或饮食品进一步含有允许添加在医药品或食品中的添加剂。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008212789 | 2008-08-21 | ||
JP2008-212789 | 2008-08-21 | ||
PCT/JP2009/063934 WO2010021247A1 (ja) | 2008-08-21 | 2009-08-06 | セロトニントランスポーター阻害活性を有する医薬品又は飲食品 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102149383A CN102149383A (zh) | 2011-08-10 |
CN102149383B true CN102149383B (zh) | 2014-08-20 |
Family
ID=41707125
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200980132443.3A Active CN102149383B (zh) | 2008-08-21 | 2009-08-06 | 化合物在制备用于治疗通过抑制血清素再吸收而改善的疾病的医药品或饮食品中的用途 |
Country Status (6)
Country | Link |
---|---|
US (1) | US8669267B2 (zh) |
EP (1) | EP2332539A4 (zh) |
JP (1) | JP5400779B2 (zh) |
CN (1) | CN102149383B (zh) |
TW (1) | TWI496574B (zh) |
WO (1) | WO2010021247A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106822114A (zh) * | 2016-12-12 | 2017-06-13 | 中国科学院西北高原生物研究所 | Mtca在制备降血糖或降血脂的药物中的用途 |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FI126711B (fi) * | 2011-10-12 | 2017-04-13 | Gut Guide Oy | Serotoniinivajeeseen liittyvän terveysriskin arvioiminen |
JP6066466B2 (ja) * | 2012-03-27 | 2017-01-25 | 国立大学法人九州大学 | 腸管機能制御剤 |
CN104284592A (zh) * | 2012-05-10 | 2015-01-14 | 雀巢产品技术援助有限公司 | 乳饮料及其制备方法 |
ES2624673T3 (es) * | 2014-04-23 | 2017-07-17 | National Yang-Ming University | Bacteria ácido láctica, composición que la contiene y su uso |
US10188684B2 (en) | 2015-04-20 | 2019-01-29 | National Yang-Ming University | Method for preventing or treating functional gastrointestinal disorder by lactic acid bacterium |
ES2929100T3 (es) * | 2014-10-28 | 2022-11-24 | Medlab Ip Pty Ltd | Tratamiento para la depresión y los trastornos depresivos |
KR20180019474A (ko) * | 2016-08-16 | 2018-02-26 | 주식회사 엠디헬스케어 | 락토바실러스 플란타룸 유래 소포를 포함하는 정신질환 예방 또는 치료용 조성물 |
TWI725464B (zh) * | 2018-07-03 | 2021-04-21 | 大江生醫股份有限公司 | 減脂之益生菌株及其組合物與用途 |
US20220264903A1 (en) * | 2019-08-18 | 2022-08-25 | Nikolai Tcherniakovski | Method of producing coffee tablets for making coffee |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL65809A (en) * | 1981-06-01 | 1986-07-31 | Merrell Toraude & Co | Aminoacid derivatives,their preparation and pharmaceutical compositions containing them |
EP1083913A4 (en) * | 1998-06-05 | 2004-03-17 | Regent Court Technologies | MONOAMINE OXIDASE (MAO) INHIBITORS AND USES THEREOF |
JP2002058450A (ja) | 2000-08-17 | 2002-02-26 | (有)日本バイオメディカル研究所 | 抗うつ病用食品 |
JP2004131407A (ja) | 2002-10-09 | 2004-04-30 | Yamada Bee Farm | ローヤルゼリー又はその水溶性画分を有効成分とする抗うつ性組成物 |
-
2009
- 2009-08-06 JP JP2010525657A patent/JP5400779B2/ja active Active
- 2009-08-06 US US13/059,819 patent/US8669267B2/en active Active
- 2009-08-06 EP EP09808183A patent/EP2332539A4/en not_active Withdrawn
- 2009-08-06 CN CN200980132443.3A patent/CN102149383B/zh active Active
- 2009-08-06 WO PCT/JP2009/063934 patent/WO2010021247A1/ja active Application Filing
- 2009-08-14 TW TW098127393A patent/TWI496574B/zh active
Non-Patent Citations (1)
Title |
---|
T. herratz.Identification and occurrence of beta-carboline alkaloids in raisins and inhibition of monoamine oxidase(MAO).《J Agric Food Chem》.2007,第55卷(第21期),8534-8540. * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106822114A (zh) * | 2016-12-12 | 2017-06-13 | 中国科学院西北高原生物研究所 | Mtca在制备降血糖或降血脂的药物中的用途 |
CN106822114B (zh) * | 2016-12-12 | 2020-08-07 | 中国科学院西北高原生物研究所 | Mtca在制备降血糖或降血脂的药物中的用途 |
Also Published As
Publication number | Publication date |
---|---|
TW201010701A (en) | 2010-03-16 |
EP2332539A1 (en) | 2011-06-15 |
JPWO2010021247A1 (ja) | 2012-01-26 |
CN102149383A (zh) | 2011-08-10 |
EP2332539A4 (en) | 2012-05-09 |
JP5400779B2 (ja) | 2014-01-29 |
US8669267B2 (en) | 2014-03-11 |
TWI496574B (zh) | 2015-08-21 |
WO2010021247A1 (ja) | 2010-02-25 |
US20110152309A1 (en) | 2011-06-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102149383B (zh) | 化合物在制备用于治疗通过抑制血清素再吸收而改善的疾病的医药品或饮食品中的用途 | |
US20110319497A1 (en) | Ampk activator | |
US8492442B2 (en) | Medicinal composition, food or drink having effect of enhancing parasympathetic nervous activity | |
CN108367033A (zh) | 使用长双歧杆菌治疗或预防抑郁症状的方法和组合物 | |
KR101600940B1 (ko) | 식물성유산균 발효액을 포함하는 당뇨 및 고혈압 예방 및 치료용 조성물 | |
JP5592640B2 (ja) | 乳酸菌発酵ローヤルゼリーを含有する抗ストレス剤、その製造方法、視床下部−下垂体−副腎皮質系の活動抑制剤、及び交感神経−副腎髄質系の活動抑制剤 | |
KR20110041050A (ko) | 발효차 추출물을 함유하는 혈액 순환 개선 및 수족 냉증 개선용 조성물 | |
CN102669761A (zh) | 一种苦瓜饮料及其制备方法 | |
CN109554435A (zh) | 细菌组胺的产生和应用 | |
AU2016230139B2 (en) | Fermented tea product | |
CN105012349A (zh) | 一种防治血管性痴呆的益生菌制剂及其制备方法 | |
TW200911775A (en) | Pharmaceutical composition, food or beverage capable of enhancing sympathetic nerve activity | |
KR101614929B1 (ko) | 인지장애 및 기억장애 치료용 약학 조성물 | |
KR101770036B1 (ko) | 오미자 추출물을 유효성분으로 포함하는 IL-1β에 의한 관절염의 예방 또는 개선용 조성물 | |
KR102041847B1 (ko) | 물푸레나무 추출물을 유효성분으로 포함하는 우울증 및 불안장애의 예방, 개선 또는 치료용 조성물 | |
KR101354370B1 (ko) | 기억력 증진 또는 집중력 향상용 조성물 | |
CN106666746B (zh) | 具有调节神经递质平衡功能的芦笋组合物及其制备方法、芦笋组合物粉剂 | |
CN103191106B (zh) | 京尼平氨基酸衍生物作为NF-κB抑制剂的用途 | |
KR101266328B1 (ko) | 지방세포 분화 유도에 관여하는 유전자의 발현을 억제함으로써 지방세포 분화 억제 효능을 갖는 락토바실러스 가세리 에이치와이7021 및 이를 유효성분으로 함유하는 제품 | |
Song et al. | Acanthopanax senticosus extract alleviates radiation‐induced learning and memory impairment based on neurotransmitter‐gut microbiota communication | |
US20140148385A1 (en) | Composition for preventing or treating erectile dysfunction comprising angiopoietin-4 protein | |
US20210023105A1 (en) | Composition for promoting increase in androgen | |
JP2005206462A (ja) | 不安障害の緩和用又は消失用組成物 | |
TWI797600B (zh) | 用以提升腦組織能力之組合物及其用途 | |
CN108553526A (zh) | 一种用生物法制备改善睡眠质量的组合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |