CN1317961A - 用于预防或治疗与血脂水平升高相关的疾病的含有肉桂酸衍生物的组合物 - Google Patents
用于预防或治疗与血脂水平升高相关的疾病的含有肉桂酸衍生物的组合物 Download PDFInfo
- Publication number
- CN1317961A CN1317961A CN99810928A CN99810928A CN1317961A CN 1317961 A CN1317961 A CN 1317961A CN 99810928 A CN99810928 A CN 99810928A CN 99810928 A CN99810928 A CN 99810928A CN 1317961 A CN1317961 A CN 1317961A
- Authority
- CN
- China
- Prior art keywords
- compositions
- acid
- cinnamic acid
- acid derivative
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001851 cinnamic acid derivatives Chemical class 0.000 title claims abstract description 51
- 210000004369 blood Anatomy 0.000 title claims abstract description 43
- 239000008280 blood Substances 0.000 title claims abstract description 43
- 201000010099 disease Diseases 0.000 title claims abstract description 33
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 33
- 150000002632 lipids Chemical class 0.000 title claims abstract description 27
- 239000000203 mixture Substances 0.000 claims abstract description 46
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 10
- 208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 10
- 241000124008 Mammalia Species 0.000 claims abstract description 8
- 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- NGSWKAQJJWESNS-UHFFFAOYSA-N 4-coumaric acid Chemical compound OC(=O)C=CC1=CC=C(O)C=C1 NGSWKAQJJWESNS-UHFFFAOYSA-N 0.000 claims description 92
- DZAUWHJDUNRCTF-UHFFFAOYSA-N 3-(3,4-dihydroxyphenyl)propanoic acid Chemical compound OC(=O)CCC1=CC=C(O)C(O)=C1 DZAUWHJDUNRCTF-UHFFFAOYSA-N 0.000 claims description 52
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 claims description 22
- 235000013305 food Nutrition 0.000 claims description 22
- MCGBIXXDQFWVDW-UHFFFAOYSA-N 4,5-dihydro-1h-pyrazole Chemical compound C1CC=NN1 MCGBIXXDQFWVDW-UHFFFAOYSA-N 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 19
- 208000004930 Fatty Liver Diseases 0.000 claims description 12
- 206010019708 Hepatic steatosis Diseases 0.000 claims description 12
- 208000010706 fatty liver disease Diseases 0.000 claims description 12
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 12
- 230000037396 body weight Effects 0.000 claims description 9
- 235000013336 milk Nutrition 0.000 claims description 9
- 239000008267 milk Substances 0.000 claims description 9
- 210000004080 milk Anatomy 0.000 claims description 9
- 208000006011 Stroke Diseases 0.000 claims description 7
- 201000005577 familial hyperlipidemia Diseases 0.000 claims description 7
- 235000014347 soups Nutrition 0.000 claims description 7
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 6
- 235000008960 ketchup Nutrition 0.000 claims description 6
- 235000007688 Lycopersicon esculentum Nutrition 0.000 claims description 5
- 240000003768 Solanum lycopersicum Species 0.000 claims description 5
- 235000014510 cooky Nutrition 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 235000013361 beverage Nutrition 0.000 claims description 4
- 235000013372 meat Nutrition 0.000 claims description 4
- 235000013555 soy sauce Nutrition 0.000 claims description 4
- 229940088594 vitamin Drugs 0.000 claims description 4
- 239000011782 vitamin Substances 0.000 claims description 4
- 235000013343 vitamin Nutrition 0.000 claims description 4
- 229930003231 vitamin Natural products 0.000 claims description 4
- 244000046052 Phaseolus vulgaris Species 0.000 claims description 3
- 235000010627 Phaseolus vulgaris Nutrition 0.000 claims description 3
- 235000008429 bread Nutrition 0.000 claims description 3
- 235000012970 cakes Nutrition 0.000 claims description 3
- 235000013351 cheese Nutrition 0.000 claims description 3
- -1 compound vitamin Chemical class 0.000 claims description 3
- 235000012777 crisp bread Nutrition 0.000 claims description 3
- 235000015203 fruit juice Nutrition 0.000 claims description 3
- 235000015243 ice cream Nutrition 0.000 claims description 3
- 235000012149 noodles Nutrition 0.000 claims description 3
- 235000015192 vegetable juice Nutrition 0.000 claims description 3
- 235000013618 yogurt Nutrition 0.000 claims description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 244000269722 Thea sinensis Species 0.000 claims description 2
- 235000013334 alcoholic beverage Nutrition 0.000 claims description 2
- 235000015218 chewing gum Nutrition 0.000 claims description 2
- 229940112822 chewing gum Drugs 0.000 claims description 2
- 235000019219 chocolate Nutrition 0.000 claims description 2
- 235000009508 confectionery Nutrition 0.000 claims description 2
- 230000003628 erosive effect Effects 0.000 claims description 2
- 235000013402 health food Nutrition 0.000 claims description 2
- 235000013550 pizza Nutrition 0.000 claims description 2
- 235000011888 snacks Nutrition 0.000 claims description 2
- 235000013616 tea Nutrition 0.000 claims description 2
- 235000013339 cereals Nutrition 0.000 claims 2
- 239000000428 dust Substances 0.000 claims 2
- 208000019423 liver disease Diseases 0.000 abstract description 7
- 208000031226 Hyperlipidaemia Diseases 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 239000003937 drug carrier Substances 0.000 abstract description 2
- 235000013376 functional food Nutrition 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 235000020510 functional beverage Nutrition 0.000 abstract 1
- 208000023516 stroke disease Diseases 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 67
- 235000012000 cholesterol Nutrition 0.000 description 31
- 230000000694 effects Effects 0.000 description 26
- 241000283973 Oryctolagus cuniculus Species 0.000 description 20
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 16
- 108010023302 HDL Cholesterol Proteins 0.000 description 12
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 12
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 12
- 241000700159 Rattus Species 0.000 description 12
- 230000003098 cholesteric effect Effects 0.000 description 11
- 235000019197 fats Nutrition 0.000 description 11
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 230000002265 prevention Effects 0.000 description 11
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 210000004185 liver Anatomy 0.000 description 10
- 210000002381 plasma Anatomy 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- BZFBDUQOBQHBSZ-DLCQERRASA-N (3s,8r,9s,10r,13s,14s,17s)-17-[3-(dimethylamino)propyl-methylamino]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-ol;dihydrochloride Chemical compound Cl.Cl.C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](N(C)CCCN(C)C)[C@@]1(C)CC2 BZFBDUQOBQHBSZ-DLCQERRASA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000002440 hepatic effect Effects 0.000 description 7
- 229960004844 lovastatin Drugs 0.000 description 7
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 7
- 230000000630 rising effect Effects 0.000 description 7
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 6
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 210000001589 microsome Anatomy 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 210000000709 aorta Anatomy 0.000 description 5
- 229940093797 bioflavonoids Drugs 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 210000003038 endothelium Anatomy 0.000 description 5
- 235000021251 pulses Nutrition 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 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 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 4
- 235000015220 hamburgers Nutrition 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 3
- 241000209140 Triticum Species 0.000 description 3
- 235000021307 Triticum Nutrition 0.000 description 3
- 235000009392 Vitis Nutrition 0.000 description 3
- 241000219095 Vitis Species 0.000 description 3
- 235000015278 beef Nutrition 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 238000004043 dyeing Methods 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000013312 flour Nutrition 0.000 description 3
- 210000000497 foam cell Anatomy 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 235000013882 gravy Nutrition 0.000 description 3
- 210000002216 heart Anatomy 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 230000003908 liver function Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- KJTLQQUUPVSXIM-ZCFIWIBFSA-N (R)-mevalonic acid Chemical compound OCC[C@](O)(C)CC(O)=O KJTLQQUUPVSXIM-ZCFIWIBFSA-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
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 description 2
- 108010061846 Cholesterol Ester Transfer Proteins Proteins 0.000 description 2
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 2
- KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 2
- 229930182558 Sterol Natural products 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 2
- 239000005516 coenzyme A Substances 0.000 description 2
- 229940093530 coenzyme a Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 229960002855 simvastatin Drugs 0.000 description 2
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 2
- 150000003432 sterols Chemical class 0.000 description 2
- 235000003702 sterols Nutrition 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- SPSSULHKWOKEEL-UHFFFAOYSA-N 2,4,6-trinitrotoluene Chemical compound CC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O SPSSULHKWOKEEL-UHFFFAOYSA-N 0.000 description 1
- RPERJPYDELTDMR-UHFFFAOYSA-K 2-hydroxyethyl(trimethyl)azanium;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound C[N+](C)(C)CCO.C[N+](C)(C)CCO.C[N+](C)(C)CCO.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O RPERJPYDELTDMR-UHFFFAOYSA-K 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 102000011690 Adiponectin Human genes 0.000 description 1
- 108010076365 Adiponectin Proteins 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 101000856500 Bacillus subtilis subsp. natto Glutathione hydrolase proenzyme Proteins 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000004420 Creatine Kinase Human genes 0.000 description 1
- 108010042126 Creatine kinase Proteins 0.000 description 1
- 235000019750 Crude protein Nutrition 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
- 101710107035 Gamma-glutamyltranspeptidase Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 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
- 101710173228 Glutathione hydrolase proenzyme Proteins 0.000 description 1
- 108010010234 HDL Lipoproteins Proteins 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 229930195722 L-methionine Natural products 0.000 description 1
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- 102000000853 LDL receptors Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 208000000501 Lipidoses Diseases 0.000 description 1
- 206010024585 Lipidosis Diseases 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 240000008790 Musa x paradisiaca Species 0.000 description 1
- RJECHNNFRHZQKU-UHFFFAOYSA-N Oelsaeurecholesterylester Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCC=CCCCCCCCC)C2 RJECHNNFRHZQKU-UHFFFAOYSA-N 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 240000000851 Vaccinium corymbosum Species 0.000 description 1
- 235000003095 Vaccinium corymbosum Nutrition 0.000 description 1
- 235000017537 Vaccinium myrtillus Nutrition 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
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 238000002835 absorbance 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
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 210000001765 aortic valve Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000009455 aseptic packaging Methods 0.000 description 1
- 235000021015 bananas Nutrition 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
- 230000033228 biological regulation Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 235000021014 blueberries Nutrition 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 235000014121 butter Nutrition 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
- 235000012241 calcium silicate Nutrition 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
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001840 cholesterol esters Chemical class 0.000 description 1
- RJECHNNFRHZQKU-RMUVNZEASA-N cholesteryl oleate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)C1 RJECHNNFRHZQKU-RMUVNZEASA-N 0.000 description 1
- 229960003257 choline citrate Drugs 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 235000019784 crude fat Nutrition 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000007937 eating Effects 0.000 description 1
- 235000005686 eating Nutrition 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 235000021149 fatty food Nutrition 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 239000004459 forage Substances 0.000 description 1
- 238000009432 framing Methods 0.000 description 1
- 102000006640 gamma-Glutamyltransferase Human genes 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
- 235000009569 green tea Nutrition 0.000 description 1
- 235000001497 healthy food Nutrition 0.000 description 1
- 238000003898 horticulture Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 238000011889 obduction Methods 0.000 description 1
- XDUHQPOXLUAVEE-BPMMELMSSA-N oleoyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CCCCCCC\C=C/CCCCCCCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 XDUHQPOXLUAVEE-BPMMELMSSA-N 0.000 description 1
- 235000015205 orange juice Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000013997 pineapple juice Nutrition 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- LZFIOSVZIQOVFW-UHFFFAOYSA-N propyl 2-hydroxybenzoate Chemical compound CCCOC(=O)C1=CC=CC=C1O LZFIOSVZIQOVFW-UHFFFAOYSA-N 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000003044 randomized block design Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000021003 saturated fats Nutrition 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- PTLRDCMBXHILCL-UHFFFAOYSA-M sodium arsenite Chemical compound [Na+].[O-][As]=O PTLRDCMBXHILCL-UHFFFAOYSA-M 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000012192 staining solution Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 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
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 235000015193 tomato juice Nutrition 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 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
- 239000000015 trinitrotoluene Substances 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- 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
- A23G3/00—Sweetmeats; Confectionery; Marzipan; Coated or filled products
- A23G3/34—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof
- A23G3/346—Finished or semi-finished products in the form of powders, paste or liquids
-
- A—HUMAN NECESSITIES
- A21—BAKING; EDIBLE DOUGHS
- A21D—TREATMENT, e.g. PRESERVATION, OF FLOUR OR DOUGH, e.g. BY ADDITION OF MATERIALS; BAKING; BAKERY PRODUCTS; PRESERVATION THEREOF
- A21D2/00—Treatment of flour or dough by adding materials thereto before or during baking
- A21D2/08—Treatment of flour or dough by adding materials thereto before or during baking by adding organic substances
- A21D2/14—Organic oxygen compounds
- A21D2/145—Acids, anhydrides or salts thereof
-
- 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
- A23G9/52—Liquid products; Solid products in the form of powders, flakes or granules for making liquid products ; Finished or semi-finished solid products, frozen granules
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- A23G2200/00—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF containing organic compounds, e.g. synthetic flavouring agents
-
- 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)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Nutrition Science (AREA)
- Organic Chemistry (AREA)
- Mycology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Emergency Medicine (AREA)
- Urology & Nephrology (AREA)
- Gastroenterology & Hepatology (AREA)
- Vascular Medicine (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
本发明涉及用于治疗或预防哺乳动物中与血脂水平升高相关的疾病如高血脂、动脉硬化、心绞痛、中风或肝病的药物组合物,其含有效量的如式(Ⅰa)或(Ⅰb)表示的肉桂酸衍生物或其药学可接受的盐、以及药学可接受的赋形剂、载体或稀释剂。本发明还涉及用于此等疾病的功能性食品或饮料组合物,其含有效量的如式(Ⅰa)或(Ⅰb)表示的肉桂酸衍生物。式中:R1、R2、R3、R4和R5独立地是H、OH、或C1-4烷氧基,而R6是H、C1-4烷基或具有一个或多个选自于OH、烷氧基和羧基组成的组中的取代基的C5-7环烷基。
Description
发明领域
本发明涉及一种用于治疗或预防哺乳动物中与血脂水平升高相关的疾病如高脂血症、动脉硬化、心绞痛、中风和肝疾病的药物组合物,该组合物含有有效量的作为活性成分的肉桂酸衍生物以及药学可接受的载体;本发明还涉及用于治疗或预防此类疾病的功能性食品或饮料组合物,其含有有效量的肉桂酸衍生物。
发明背景
已有报导,血脂、特别是胆甾醇和甘油三酯与各种疾病如冠状心循环性疾病,如动脉硬化和高胆甾醇血症以及脂肪肝密切相关。胆甾醇作为一种脂肪甾醇,是在肝脏中由饱和脂肪产生的血脂。甘油三酯是另一类血脂,已知其会增加各种疾病的危险。也已有报导,血或血浆胆甾醇水平升高引起脂肪、巨噬细胞和泡沫细胞在血管壁上沉积,而这种沉积导致形成斑块,然后导致动脉硬化(参见Ross,R.,Nature,362,801-809(1993))。降低血浆胆甾醇水平的方法之一是降低胆甾醇和脂质摄取的饮食疗法。另一种方法是通过抑制胆甾醇的吸收涉及的酶来抑制胆甾醇的吸收。
酰基CoA-胆甾醇-o-酰基转移酶(ACAT)促进血液中胆甾醇的酯化作用。泡沫细胞是通过ACAT的作用形成的,而且含有大量的由血液中的低密度脂蛋白携带的胆甾醇酯。泡沫细胞在动脉壁上的形成随ACAT活性而增加,因而ACAT的抑制剂也可以是预防动脉硬化的药剂。另外,已有报导,通过抑制ACAT活性可以降低血液LDL-胆甾醇的水平(参见Witiak,D.T.和D.R.Feller(编辑),Anti-LipidemicDrugs:Medicinal,Chemical and Biochemical Aspects,Elsevier,第159-195页(1991))。
此外,已有报导,通过抑制介导脂蛋白间胆甾醇转移的胆甾醇酯转移蛋白(CETP)或抑制介导甲羟戊酸(一种生物合成甾醇或类异戊二烯的中间体)合成的3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶而降低胆甾醇的生物合成速率,可有效地治疗高胆甾醇血症(参见Cardiovascular Pharmacology,William W.Parmley和Kanu Chatterjee Ed.,Wolfe Publishing,第8.6-8.7页,1994)。
因此,人们已进行了许多努力来开发抑制HMG-CoA还原酶的药物;而且其结果是,已有从青霉属和曲霉属衍生而来的几种化合物被商品化。具体而言,由美国的Merck公司开发的洛伐他汀和辛伐他汀,以及由日本的Sankyo公司开发的普伐他汀已被商品化(参见C.D.R.Dunn,Stroke:Trends,Treatment and Markets,SCRIPTReport,PJB Publications Ltd.,1 995)。
但是,这些药物非常昂贵,而且已知其长期给药会在中枢神经系统引起不利的副作用。此外,虽然洛伐他汀和辛伐他汀可通过增强肝中LDL受体的活性来降低血浆LDL胆甾醇水平,但它们引起诸如肝中肌酸激酶增加和横纺肌溶解症等副作用(参见Farmer,J.A.,等,Baillers-clin.Endocrinol.Metal.,9,825-847(1995))。因而,仍需要开发便宜且无毒的HMG-CoA还原酶抑制剂。
与血脂水平升高相关的疾病的另一个例子是脂肪肝。具体而言,过度摄取含脂肪的食物以及酒精导致脂肪肝,其中大量的脂质沉积于肝组织中,而且血清GOT(谷氨酸-草酰乙酸转氨酶)、GPT(谷氨酸-丙酮酸转氨酶)和γ-GTP(γ-谷氨酰基转肽酶)水平升高(参见T.Banciu等,Med.Interne.,20,69-71(1982)和A.Par等,Acta.Med Acad.Sci.Hung.,33,309-319(1976))。Hayashi等已报导,绿茶的提取物可通过防止血清GOT和GPT的升高来改善大鼠的肝功能(M.Hayashi等,Nippon Yakuri gaku Zasshi,100,391-399(1992))。
脂肪在肝脏中主要以甘油三酯和脂肪酸的形式积聚,同时少量地以胆甾醇的形式积聚。另外,已有报导,脂肪肝的主要迹象之一是高血胆甾醇和/或甘油三酯含量。因而,脂肪肝与血液中胆甾醇和/或甘油三酯含量密切相关。
生物类黄酮是广泛存在于自然界、特别是存在于蔬菜、水果、葡萄酒等中的多酚类抗氧剂。已有报道,生物类黄酮显示出诸如抗炎、毛细管增强、抗氧化、抗癌、抗病毒和抗血小板凝聚活性等各种有用的药理学活性(参见O.Benavente-Garcia等人,Uses andproperties of citrus flavonoids,J.Agr.Food Chem.,45,4506-4515,1997)。
本发明的发明者致力于开发生物类黄酮的新药理学用途,这种物质在草本植物、食品、蔬菜和水果中含量丰富。结果发现,肉桂酸和氢化肉桂酸衍生物在治疗或预防与血脂水平升高相关的疾病中有效,这些肉桂酸衍生物在生物类黄酮的生物合成中被用作前体并形成生物类黄酮的骨架结构。具体而言,其可大大降低血浆胆甾醇水平;抑制HMG-CoA还原酶和ACAT的活性;抑制巨噬细胞-脂质复合物在动脉的内皮壁上的积聚;以及预防哺乳动物肝功能不良。
发明概述
因而,本发明的目的是提供一种用于治疗或预防与血脂水平升高相关的疾病并含有肉桂酸衍生物的药物组合物。
本发明的另一个目的是提供一种用于治疗或预防与血脂水平升高相关的疾病并含有肉桂酸衍生物的食品或饮料组合物。
附图简述
结合以下附图,通过以下本发明的说明将更为明了本发明的以上和其它的目的及特征,其中:
图1A、1B、1C、1D和1E显示了分别给药1%胆甾醇、1%胆甾醇加1mg/kg洛伐他汀、1%胆甾醇加0.1%4-羟基肉桂酸、1%胆甾醇加0.1%3,4-二羟基肉桂酸、以及1%胆甾醇加0.1%3,4-二羟基氢化肉桂酸的兔的动脉内皮;以及
图2A、2B、2C、2D和2E给出分别给药1%胆甾醇、1%胆甾醇加1mg/kg洛伐他汀、1%胆甾醇加0.1%4-羟基肉桂酸、1%胆甾醇加0.1%3,4-二羟基肉桂酸、以及1%胆甾醇加0.1%3,4-二羟基氢化肉桂酸的兔的肝脏的显微特征子。
发明详述
在整个说明书中,术语“血脂”是指存在于血液中的脂质。血脂以血液中携带的胆甾醇和甘油三酯为代表。
术语血脂“高或升高的水平”是指高于正常水平,正常水平随患者的具体情况如年龄、性别和体重而改变。高血脂水平通常被认为是有害于健康的。
术语“与血脂水平升高相关的疾病”是指由于血脂水平高或升高而引起的疾病,和/或其症状包括血脂水平高或升高的疾病。这些疾病的实例包括高脂血症、动脉硬化、心绞痛、中风、肝脏疾病如脂肪肝等。
本发明的优选肉桂酸衍生物包括如下的式Ⅰa或Ⅰb化合物:其中R1、R2、R3和R5独立地是H或OH;R4是H、OH或OCH3;而R6是H或被一个或多个羟基和羧基取代的环烷基。
肉桂酸衍生物可容易地从植物如苹果、茶叶、马铃薯、咖啡、葡萄、坚果、草莓、李子、樱桃和越桔(blueberry)中提取,或者根据常规方法合成。
肉桂酸衍生物对与血脂水平升高相关的疾病发挥抑制及治疗作用,这些疾病例如是高脂血症、动脉硬化、心绞痛、中风以及肝脏疾病。另外,尽管它们效力强,当以1000mg/kg的剂量将肉桂酸衍生物口服给药于小鼠时,它们未显示毒性。此外,它们对肝功能没有不利影响。
本发明提供一种用于治疗或预防与血脂水平升高相关的疾病的药物组合物,该组合物包括有效量的肉桂酸衍生物以及药学可接受的赋形剂、载体或稀释剂。
药物制剂可按照任何常规方法制备。在制备制剂时,活性成分优选与载体混合或用载体稀释,或包封在载体内,载体可为胶囊、小药囊或其他容器形式。当载体用作稀释剂时,其可为固体、半固体或液体物质,对活性成分起载体、赋形剂或介质作用。因此,制剂可为片剂、丸剂、散剂、小药囊、酏剂、混悬剂、乳剂、溶液、糖浆剂、气溶胶、软和硬明胶胶囊、无菌注射溶液、无菌包装粉末等剂型。
适宜的载体、赋形剂和稀释剂的实例为乳糖、葡萄糖、蔗糖、山梨醇、甘露糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、水杨酸甲酯、水杨酸丙酯、滑石、硬脂酸镁和矿物油。制剂还可选择性地包含:充填剂、抗凝结剂、润滑剂、润湿剂、矫味剂、乳化剂、防腐剂等。可采用任一种公知的方法将本发明的组合物配制成在将其给药于哺乳动物后快速、持续或迟延释放活性成分的制剂。
进而,本发明的药物组合物可经各种途径给药,包括:口服、经皮给药、皮下给药、静脉内给药和肌内给药。对于人来说,肉桂酸衍生物的每日剂量一般为0.1-500mg/kg体重,优选1-100mg/kg体重,可以单次剂量给药或分多次剂量给药。
但应理解的是,活性成分的实际给药量应根据各种因素确定,包括待治疗的疾病、所选的给药途径、患者的年龄、性别和体重以及患者病症的严重程度;因而,上述剂量不应看作是对本发明范围的限制。
进而,肉桂酸衍生物可有利地掺入食品或饮料中用于治疗或预防与血脂水平升高相关的疾病。食品或饮料可包括:肉;汁液如蔬菜汁(例如,胡萝卜汁和西红柿汁)和果汁(如,橙汁、葡萄汁、菠萝汁、苹果汁和香蕉汁);巧克力;小吃;糖果;比萨饼;由谷物制成的食品,如面包、蛋糕、薄脆饼干、曲奇饼、饼干、面条等;口香糖;奶制品,如奶、干酪、酸乳和冰淇淋;汤;肉汤;酱(paste)、蕃茄酱(ketchup)和酱油;茶;酒精饮料;碳酸饮料;复合维生素;和各种保健食品。
肉桂酸衍生物在食品或饮料中的含量可为0.01-20 wt%,优选0.1-5 wt%。
如上所述,肉桂酸衍生物可用作有效且无毒的药物,用于治疗或预防与血脂水平升高相关的疾病,如高脂血症、动脉硬化和肝病。
下述实施例用于进一步说明本发明,但它们并非对本发明范围的限制。
进而,如下在固体混合物中对固体,在液体中对液体和在液体中对固体给出的百分数分别基于wt/wt、vol/vol和wt/vol,除非另有说明,所有的反应均在室温下进行。实施例1:口服给药4-羟基肉桂酸的毒性
将12只7周龄无特异病原体的ICR雌性小鼠,其中6只体重为约25-29g的雌性小鼠和6只体重为约34-38g的雄性小鼠,保持在环境温度22±1℃,相对湿度55±5%及光周期12L/12D下。将饲料(Cheiljedang Co.,鼠和兔子饲料)和水消毒并喂给小鼠。
将商购自Aldrich-Sigma Chemical Co.(St.Louis,MO,U.S.A)的4-羟基肉桂酸溶解于0.5%吐温80中至浓度为100 mg/ml,然后将该溶液口服给药于小鼠,用量为0.2ml/20 g小鼠体重。将溶液一次给药于小鼠,按照下述程序对有害作用的迹象或死亡情况观察10天:给药后1、4、8和12小时,此后每隔12小时,记录小鼠重量的变化以检查4-羟基肉桂酸的作用。另外,在第10天时将小鼠处死,目视观察内部器官。
所有的小鼠在第10天均存活,在剂量为1000mg/kg下,4-羟基肉桂酸均无毒。尸体解剖表明,小鼠并未产生任何病理学的异常,而且在10天的试验期内,未观察到体重减少。因而,可以得出结论,当口服给药于动物时,4-羟基肉桂酸无毒。实施例2:肉桂酸衍生物对血浆胆甾醇、HDL-胆甾醇和中性脂质水平的影响步骤1:将肉桂酸衍生物给药于大鼠
将30只3周龄的白色Sprague-Dawley大鼠(Taihan laboratoryanimal center,韩国)(每只体重大约为90-110 g)通过随机区组设计平衡地分成四个组。四组的大鼠分别用四种不同的高胆甾醇含量的饲料喂养,即、包含1%胆甾醇的AIN-76实验室动物食物(ICNBiochemicals,Cleveland,OH,美国)(对照组)、1%胆甾醇+0.1%4-羟基肉桂酸(4-羟基肉桂酸组)、1%胆甾醇+0.1%3,4-二羟基肉桂酸(3,4-二羟基肉桂酸组)、和1%胆甾醇+0.1%3,4-二羟基氢化肉桂酸(3,4-二羟基氢化肉桂酸组)。给四组大鼠进食的食物的组成如表Ⅰ所示:表Ⅰ
*1商购自TEKLAD Premier Co.(Madison,WI,美国)*2商购自Sigma Chemical Co.(St.Louis,MO,美国)
饮食组组分 | 对照组(n=10) | 4-羟基肉桂酸组(N=10) | 3,4-二羟基肉桂酸组(n=10) | 3,4-二羟基氢化肉桂酸组(n=10) |
酪蛋白 | 20 | 20 | 20 | 20 |
D,L-蛋氨酸 | 0.3 | 0.3 | 0.3 | 0.3 |
玉米淀粉 | 15 | 15 | 15 | 15 |
蔗糖 | 49 | 48.9 | 48.9 | 48.9 |
纤维素粉末*1 | 5 | 5 | 5 | 5 |
矿物质混合物*1 | 3.5 | 3.5 | 3.5 | 3.5 |
维生素混合物*1 | 1 | 1 | 1 | 1 |
柠檬酸胆碱 | 0.2 | 0.2 | 0.2 | 0.2 |
玉米油 | 5 | 5 | 5 | 5 |
胆甾醇 | 1 | 1 | 1 | 1 |
4-羟基肉桂酸*2 | - | 0.1 | - | - |
3,4-二羟基肉桂酸*2 | - | - | 0.1 | - |
3,4-二羟基氢化肉桂酸*2 | - | - | - | 0.1 |
总计(%) | 100 | 100 | 100 | 100 |
在6个星期内,使大鼠自由进食所规定的食物及水,记录每日的摄取量,每7天对大鼠称重,然后对记录进行分析。所有的大鼠均显示出正常的生长速度,而且在食物摄取量和体重增加方面,四个组间没有显著差异。步骤2:测定血液中的总胆甾醇、HDL-胆甾醇和中性脂质含量
如下测量向大鼠给药肉桂酸衍生物对血浆胆甾醇和中性脂质含量的影响。
将在步骤1中获得的四组规定食物组的大鼠处死,取得血样。将血液放置2小时,在3,000 rpm下离心15分钟,分离出上清液,并在使用前贮藏于深冷冷冻机中。采用血液化学分析仪(CIBACorning 550 Express,美国)对血液进行化学分析,测定总胆甾醇和HDL-胆甾醇水平的变化。结果如表Ⅱ所示。表Ⅱ
*TC:总胆甾醇*HDL-C:HDL-胆甾醇
组脂质浓度 | 对照组 | 4-羟基肉桂酸组 | 3,4-二羟基肉桂酸组 | 3,4-二羟基氢化肉桂酸组 |
TC(mg/dl) | 135±6 | 102±6 | 118±6 | 127±4 |
HDL-C(mg/dl) | 38±2 | 57±3 | 39±3 | 45±4 |
HDL-C/TC(%) | 28 | 56 | 33 | 35 |
从表Ⅱ可以看出,与对照组相比,4-羟基肉桂酸、3,4-二羟基肉桂酸和3,4-二羟基氢化肉桂酸组中的总血浆胆甾醇水平分别降低24%、13%和6%。另外与对照组相比,4-羟基肉桂酸、3,4-二羟基肉桂酸和3,4-二羟基氢化肉桂酸组中的HDL-C/TC比值分别增加100%、18%和25%。实施例3:肉桂酸衍生物在抑制ACAT中的活性步骤1:制备微粒体
为测定进食肉桂酸衍生物给大鼠对ACAT活性的作用,从准备使用的肝组织中分离出微粒体作为酶源。
将来自实施例2每一组大鼠的各1g肝在5ml的匀化介质(0.1MKH2PO4,pH7.4,0.1mM EDTA和10mMβ-巯基乙醇)中匀化。将匀浆在3,000×g及4℃下离心15分钟,将所获得的上清液在15,000×g及4℃下离心15分钟,获得上清液。将该上清液放入超离心机管(Beckman)中,并在100,000×g及4℃下离心以获得微粒体沉淀物,然后,将其悬浮于3 ml的匀化介质中并在100,000×g及4℃下离心1小时。将所获得的沉淀物悬浮于1ml的匀浆介质中。用Lowry的方法测量在所得悬浮液中的蛋白质浓度,然后调节至4-8mg/ml。将形成的悬浮液在深冷冷冻机(Biofreezer,Forma Scientific Inc.)中贮藏。步骤2:ACAT分析
将6.67μl的1mg/ml胆甾醇的丙酮溶液与6μl的10%三硝基甲苯WR-1339(Sigma Co.)的丙酮溶液混合,然后,通过在氮气氛下进行蒸发,从混合物中除去丙酮。向形成的混合物中加入蒸馏水,调节胆甾醇的浓度为30mg/ml。
向10μl形成的胆甾醇水溶液中加入10μl的1M KH2PO4(pH7.4)、5μl的0.6 mM牛血清白蛋白(BSA)、10μl上述步骤1中获得的微粒体溶液和55μl蒸馏水(总共90μl)。将混合物在37℃的水浴中预培养30分钟。
向经过预培养的混合物中加入10μl的(1-14C)油酰基-CoA溶液(0.05μCi,最终浓度:10μM),然后将形成的混合物在37℃的水浴中预培养30分钟。再向混合物中加入500μl的异丙醇∶庚烷混合物(4∶1(v/v))、300μl的庚烷和200μl的0.1M KH2PO4(pH 7.4),将混合物用涡旋混合机剧烈混合,然后使其在室温下放置2分钟。
将200μl形成的上清液放置在闪烁瓶中,并向其中加入4ml的闪烁流体(Lumac)。采用1450 Microbeta液体闪烁计数器(Wallacoy,芬兰)进行放射活性分析。以每分钟每mg的蛋白质合成的微微摩尔的胆甾醇油酸酯(pmol/min/mg蛋白质)来计算ACAT活性。结果如下表Ⅲ所示。表Ⅲ
组 | 对ACAT活性的抑制率% |
对照 | 0 |
4-羟基肉桂酸 | 17 |
3,4-二羟基肉桂酸 | 7 |
3,4-二羟基氢化肉桂酸 | 20 |
从表Ⅲ看出,在4-羟基肉桂酸、3,4-二羟基肉桂酸和3,4-二羟基氢化肉桂酸组中观察到的ACAT活性分别比在对照组中观察到的ACAT活性低7-20%。实施例4:肉桂酸衍生物在HMG-CoA还原酶抑制中的活性
为了测定HMG-CoA还原酶的活性,采用Hulcher所述方法但进行了一些改进(参见J.Lipid Res.,14,625-641(1973))。在该方法中,通过光谱测量辅酶-A(CoA-SH)的浓度,辅酶-A(CoA-SH)是在HMG-CoA还原酶作用下,当HMG-CoA还原成甲羟戊酸盐时产生的,从而计算出HMG-CoA还原酶活性。步骤1:制备微粒体
将取自实施例2每一组大鼠的肝组织3g依次用100ml的冷盐水(0.15M NaCl)和100ml的冷缓冲液A(0.1M三乙醇胺,HCl/0.2M EDTA/2mM二硫苏糖醇(DTT))洗涤。向肝组织中加入冷的缓冲液,用量为2ml/1g肝组织,将混合物用匀化器匀化。将匀浆在15,000×g下离心15分钟,然后,将上清液在100,000×g下超离心60分钟,得到微粒体沉淀。将所获得的沉淀用冷的缓冲液A洗涤,并将其保持在-70℃下的1.5ml管中。步骤2:HMG-CoA还原酶活性实验
用于HMG-CoA还原酶活性实验中的反应底物如下:ⅰ)缓冲液B:0.1M三乙醇胺,HCl/0.02M EDTA(pH7.4),ⅱ)HMG-CoA溶液:150μmmol/培养介质,以及ⅲ)NADPH溶液:2μmol/培养介质。
将悬浮液(微粒体)与反应底物混合,将混合物放置在离心管中,在37℃下反应30分钟。将反应混合物用20μl的0.01M亚砷酸钠处理,使其放置1分钟,然后使其与100μl的柠檬酸盐缓冲液(2M柠檬酸盐/3%钨酸钠,pH 3.5)在37℃下反应10分钟,随后在25,000×g下离心15分钟以除去蛋白质。将所获得的1ml的上清液转移至带盖的管中,向其中加入0.1ml的2M tris-HCl溶液(pH 10.6)和0.1ml的2M tris-HCl溶液(pH 8.0),以调节反应物的pH值至8.0。
然后,将反应物与20μl的DTNB缓冲液(3mM DTNB/0.1M三乙醇胺/0.2M EDTA,pH 7.4)混合,测量在412nm下混合物的吸光度值以计算CoA-SH的量(HMG-CoA还原酶的活性)。
根据上述结果计算肉桂酸衍生物对HMG-CoA还原酶活性的抑制率。结果如表Ⅳ所示。
表Ⅳ
组 | HMG-CoA还原酶活性的抑制率(%) |
对照组 | 0 |
4-羟基肉桂酸 | 31 |
3,4-二羟基肉桂酸 | 44 |
3,4-二羟基氢化肉桂酸 | 70 |
从表Ⅳ可以看出,在4-羟基肉桂酸、3,4-二羟基肉桂酸和3,4-二羟基氢化肉桂酸组中观察到的HMG-CoA还原酶的活性比在对照组中的活性分别低31-70%。实施例5:肉桂酸衍生物在兔子中的作用步骤1:将肉桂酸衍生物给药于兔子
将30只3月龄雄性新西兰白兔(Yeonam Horticulture and AnimalHusbandry College,韩国)(每只重约2.5-2.6kg)在下述条件下饲养:温度20±2℃,相对湿度55±5%和光周期12L/12D。将兔子分成五组,五组兔子用不同的食物喂养,即包含1%胆甾醇的RC4食物(Oriental Yeast Co.,日本)(对照组);1%胆甾醇+1mg/kg洛伐他汀(Merck,美国)(洛伐他汀组);1%胆甾醇+0.1%4-羟基肉桂酸(4-羟基肉桂酸组);1%胆甾醇+0.1%3,4-二羟基肉桂酸(3,4-二羟基肉桂酸组);以及1%胆甾醇+0.1%3,4-二羟基氢化肉桂酸(3,4-二羟基氢化肉桂酸组)。RC4食物包含7.6%的水分,22.8%的粗蛋白,2.8%的粗脂肪,8.8%的粗灰分,14.4%粗纤维素和43.6%的可溶性无氮物质。肉桂酸衍生物均商购自SigmaChemical Co.(St.Louis,MO)。
将兔子喂养8周,期间使其自由进食食物和水。步骤2:血液的化学分析
在8周后,用在股骨区肌内注射氯胺酮(50mg/kg)的方法将兔子麻醉并处死。从每只兔子的心脏取得血样,并使其放置2小时,在3,000rpm下离心15分钟,分离出上清液血清,使用前将其贮藏于冰箱内。
采用血液化学分析仪(CIBA Corning 550 Express,美国)对血液进行化学分析,测定GOT、GPT、总胆甾醇、HDL-胆甾醇和甘油三酯水平的变化。结果如表Ⅴ所示。步骤3:对主动脉中脂肪条纹的分析
将步骤2处死的每只兔子的胸部切开。将主动脉瓣膜上方1cm位置处的主动脉向下部分切开,长度为约5cm,将围绕主动脉的脂肪除去。沿纵轴在中部将主动脉切开,用针别在盘中。将湿的动脉进行照相,然后按照下述方法进行脂肪条纹的染色:Esper,E.等(J.Lab.Clin.Med.,121,103-110(1993))。
将一部分切下的主动脉用无水丙二醇在2分钟内洗涤3次,用油性红O在丙二醇中的饱和溶液(ORO,Sigma Co.)染色30分钟。此后,将动脉用85%的丙二醇在3分钟内洗涤两次,以除去残余的染色溶液,然后再用生理盐水洗涤。对动脉照相,追踪照片。采用图像分析仪(LEICA,Q-600,德国)测定染色区域的面积(脂肪条纺区域),计算其与总动脉面积的比值(%)。结果如表Ⅴ所示。
图1A、1B、1C、1D和1E分别显示了对照组、洛伐他汀组、4-羟基肉桂酸组、3,4-二羟基肉桂酸组和3,4-二羟基氢化肉桂酸组的兔子的动脉。如图1A、1B、1C、1D和1E所示,在对照组的兔子的动脉内皮上观察到一厚层的巨噬细胞-脂质复合物,而在洛伐他汀组、4-羟基肉桂酸组、3,4-二羟基肉桂酸组和3,4-二羟基氢化肉桂酸组的兔子的动脉内皮上未观察到或只有非常薄的巨噬细胞-脂质复合物层。
因而,可以得出结论,即使当血胆甾醇水平较高时,肉桂酸衍生物仍可强烈地抑制巨噬细胞在动脉内皮上的沉积。步骤4:器官的组织学观察
从每只步骤2中处死的兔子取出一部分主动脉、心脏、肺、肝、肾和肌肉,目视检测以确认未发现致病性异常。将这些器官每部分的一半进行深冷冻,而另一半固定于10%中性缓冲福尔马林中超过24小时。将固定的器官片段充分用自来水洗涤,逐步用70%、80%、90%和100%的乙醇脱水,然后采用SHANDONHistocentre 2(美国)将其包埋于石蜡中。将包埋的器官片段用切片机(LSICA,RM2045,德国)切成4μm厚度,并用苏木精和曙红进行染色。将染色后的器官样本用二甲苯制成透明的,用permount进行封固,然后在显微镜下进行观察以寻找存在的损害。在任一种器官样本中都未观察到损害。步骤5:预防肝病
为了评价进食含肉桂酸衍生物的高胆甾醇食物对肝组织的影响,从步骤2处死的兔子中取得的肝样本按照以下文献所述的方法进行处理:Fogt F.和Nanji A.,毒理学和应用药理学,136,87-93,1996;以及Keegan A.等,Journal of Hepatology 23:591-600,1995,并在显微镜下进行观察分类成四个等级,即1+(0-25%)、2+(26-50%)、3+(51-75%)、4+(76-100%),其是基于肝腺泡中围绕中央静脉的异常含脂肪细胞的比例。结果如表Ⅴ所示。
图2A、2B、2C、2D和2E给出了对照组、洛伐他汀组、4-羟基肉桂酸组、3,4-二羟基肉桂酸组和3,4-二羟基氢化肉桂酸组的兔子肝脏的显微镜特征。在图2A和2B中,观察到含过量脂肪的许多细胞围绕着中央静脉。与此相对照,在图2C、2D和2E中,几乎所有的肝细胞均具有正常的形状,这表明肉桂酸衍生物可显著地抑制脂肪肝的形成。
从以上说明可以看出,给药肉桂酸衍生物可改善兔子的脂质代谢和肝功能,并抑制在主动脉的内皮中斑块的形成和形成脂肪肝,如表Ⅴ所示。结果采用Microsoft excel(7.0版)程序通过学生t-检验进行了检验。表Ⅴ
*TC:总胆甾醇*TG:甘油三酯*HDL-C:高密度脂蛋白-胆甾醇A:含异常脂肪的肝细胞比例
组 | 对照 | 洛伐他汀 | 4-羟基肉桂酸 | 3,4-二羟基肉桂酸 | 3,4-二羟基氢化肉桂酸 |
TC(mg/dl) | 1995±472 | 1446±263 | 1517±417 | 1559±347 | 1256±150 |
TG(mg/dl) | 170±30 | 153±95 | 167±43 | 139±46 | 108±22 |
HDL-C(mg/dl ) | 50±11 | 58±23 | 57±28 | 53±13 | 80±23 |
HDL/TC(%) | 2.5±0.4 | 4.9±2.6 | 3.7±1.3 | 3.4±0.4 | 6.3±1.6 |
GOT(IU/l) | 161±71 | 43±12 | 59±45 | 99±49 | 55±20 |
GPT(IU/l) | 96±46 | 81±44 | 74±49 | 40±27 | 90±83 |
脂肪条纹(%) | 80±8 | 15±3 | 24±11 | 13±5 | 16±1 |
A | 3.2±0.3 | 3.4±0.5 | 2.7±0.3 | 2.6±0.3 | 2.6±0.3 |
从表Ⅴ可以看出,与对照组相比,给药4-羟基肉桂酸、3,4-二羟基肉桂酸和3,4-二羟基氢化肉桂酸可降低血清中甘油三酯水平22-37%。进而与对照组相比,给药肉桂酸衍生物可分别降低血清GOT和GPT水平10-36%和6-58%。此外,与对照组和洛伐他汀组相比,给药肉桂酸衍生物显著地抑制了脂肪肝的形成。
因此,肉桂酸衍生物可用作有效的无毒药物,治疗或预防与血脂水平升高相关的疾病,如高脂血症、动脉硬化和肝疾病。实施例6:肉桂酸衍生物在兔中对ACAT抑制作用的活性
根据实施例3所述的方法,在实施例5的步骤1中准备的兔子中检查肉桂酸衍生物在ACAT抑制作用中的活性。结果见表Ⅵ所示。表Ⅵ
组 | 对ACAT活性的抑制率% |
对照 | 0 |
4-羟基肉桂酸 | 9 |
3,4-二羟基肉桂酸 | 33 |
3,4-二羟基氢化肉桂酸 | 37 |
从表Ⅵ可以看出,在4-羟基肉桂酸、3,4-二羟基肉桂酸和3,4-二羟基氢化肉桂酸组中观察到的ACAT活性分别比在对照组中观察到的ACAT活性低9-37%。实施例7:向人给药4-羟基肉桂酸对血浆脂代谢的影响
二位55岁左右的男性,患有高血脂症,血液中胆甾醇的浓度为230-270mg/dl,甘油三酯的浓度为200-220mg/dl。向他们给药4-羟基肉桂酸胶囊剂,每日口服剂量为10mg/kg,共进行60天。在给药之前和之后测量血浆胆甾醇和甘油三酯含量。
给药4-羟基肉桂酸将血浆胆甾醇和甘油三酯的含量分别降低25%和20%。制剂1:制备药物制剂采用下述成分制备硬明胶胶囊:
量(mg/胶囊)活性成分(4-羟基肉桂酸) 200维生素C 50乳糖(载体) 150总计 400将上述成分充分混合,然后填充入硬明胶胶囊中。制剂2:含肉桂酸衍生物的食品
按照下述过程制备肉桂酸衍生物的食品:(1)制备蕃茄酱和酱油
将足够量的4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸加至蕃茄酱或酱油中,以获得改善健康的蕃茄酱或酱油,其包含0.1-5wt%的4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸。(2)制备含小麦粉的食品
将足够量的4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸加至小麦粉中,制得包含0.1-5wt%的4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸的小麦粉混合物,并采用该混合物制备面包、蛋糕、曲奇饼、薄脆饼干和面条,获得改善健康的食品。(3)制备汤和肉汁
将足够量的4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸加至汤和肉汁中,获得改善健康的汤和肉汁,其包含0.1-5wt%的4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸。(4)制备牛肉馅
将足够量的4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸加至牛肉馅中,获得改善健康的牛肉馅,其包含0.1-5wt%的4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸。(5)制备奶制品
将足够量的4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸加至奶中,得到包含0.1-5wt%的4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸的奶,然后由其制备各种奶制品如奶油和冰淇淋。
在制备干酪时,将4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸加至凝固乳蛋白中;而在制备酸奶时,则将4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸加至发酵后获得的凝固乳蛋白中。(6)包含肉桂酸衍生物的汉堡包调味料
用以下物质根据常规方法制备汉堡包调味料:20%番茄、20%洋葱、7%大蒜、10%枣、10%葡萄干粉、20%燕麦粉、10%马铃薯粉以及3%4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸。
将10g由此制得的汉堡包调味料放在汉堡包上。制剂3:包含肉桂酸衍生物的饮料
将4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸加至用于制备蔬菜或果汁的原料中,获得改善健康的汁液,其包含0.01-20wt%的4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸。
以上本发明由具体的实施方案进行了描述,但应当理解,本领域的技术人员可以做出各种仍在本发明范围内的变化和改进。
Claims (18)
1、一种用于治疗或预防哺乳动物中与血脂水平升高相关的疾病的药物组合物,该组合物包含有效量的式(Ⅰa)或(Ⅰb)表示的肉桂酸衍生物或其药学可接受的盐、以及药学可接受的赋形剂、载体或稀释剂:式中:R1、R2、R3、R4和R5独立地是H、OH、或C1-4烷氧基,而R6是H、C1-4烷基或具有一个或多个选自于OH、烷氧基和羧基组成
的组中的取代基的C5-7环烷基。
2、如权利要求1所述的组合物,其中,所述疾病是高脂血症、动脉硬化、心绞痛、中风或脂肪肝。
3、如权利要求1所述的组合物,其中,哺乳动物是人。
4、如权利要求1所述的组合物,其中,有效量的肉桂酸衍生物的范围为0.1-500 mg/kg体重/天。
5、如权利要求1所述的组合物,其中,R1、R2、R3和R5独立地是H或OH,R4是H、OH或OCH3,而R6是H或被一个或多个羟基和羧基取代的环烷基。
6、如权利要求1所述的组合物,其中,肉桂酸衍生物是4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸。
8、如权利要求7所述的组合物,其中,所述疾病是高脂血症、动脉硬化、心绞痛、中风或脂肪肝。
9、如权利要求7所述的组合物,其中,其中,R1、R2、R3和R5独立地是H或OH,R4是H、OH或OCH3,而R6是H或被一个或多个羟基和羧基取代的环烷基。
10、如权利要求7所述的组合物,其中,肉桂酸衍生物是4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸。
11、如权利要求7所述的组合物,其中,所述食品为肉、巧克力、小吃、糖果、比萨饼、由谷物粉制备的保健食品或食品、口香糖、奶制品、汤、肉汤、酱、蕃茄酱、酱油或复合维生素。
12、如权利要求11所述的组合物,其中,由谷物粉制成的食品是面包、蛋糕、薄脆饼干、曲奇饼、饼干或面条。
13、如权利要求11所述的组合物,其中,奶制品为奶、冰淇淋、干酪或酸奶。
15、如权利要求14所述的组合物,其中,所述疾病是高脂血症、动脉硬化、心绞痛、中风或脂肪肝。
16、如权利要求14所述的组合物,其中,其中,R1、R2、R3和R5独立地是H或OH,R4是H、OH或OCH3,而R6是H或被一个或多个羟基和羧基取代的环烷基。
17、如权利要求14所述的组合物,其中,肉桂酸衍生物是4-羟基肉桂酸、3,4-二羟基肉桂酸或3,4-二羟基氢化肉桂酸。
18、如权利要求14所述的组合物,其中,饮料为蔬菜汁、果汁、茶、酒精饮料或碳酸饮料。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1998/37960 | 1998-09-15 | ||
KR19980037960 | 1998-09-15 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1317961A true CN1317961A (zh) | 2001-10-17 |
CN1148176C CN1148176C (zh) | 2004-05-05 |
Family
ID=19550603
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB998109282A Expired - Fee Related CN1148176C (zh) | 1998-09-15 | 1999-09-15 | 用于预防或治疗与血脂水平升高相关的疾病的含有肉桂酸衍生物的组合物 |
Country Status (7)
Country | Link |
---|---|
US (1) | US6313171B1 (zh) |
EP (1) | EP1113790B1 (zh) |
JP (1) | JP2002524505A (zh) |
CN (1) | CN1148176C (zh) |
CA (1) | CA2344053C (zh) |
DE (1) | DE69916632T2 (zh) |
WO (1) | WO2000015215A1 (zh) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4119629B2 (ja) * | 2001-09-06 | 2008-07-16 | 花王株式会社 | 高血圧症予防・改善・治療剤 |
US7867525B2 (en) * | 2002-08-14 | 2011-01-11 | Bionutrigen Co., Ltd. | Powder or extracts of plant leaves with anti-obesity effects and anti-obesity food comprising them |
EP1559421B1 (en) * | 2002-11-06 | 2016-07-27 | Kao Corporation | Blood circulation promoting agent |
KR100728055B1 (ko) * | 2005-02-24 | 2007-06-13 | (주)바이오뉴트리젠 | 비만증 및 고지혈증 예방용 식품 |
US7985689B2 (en) * | 2006-06-16 | 2011-07-26 | Applied Matrials, Inc. | Patterning 3D features in a substrate |
FR2904935A1 (fr) * | 2006-08-18 | 2008-02-22 | Centre Nat Rech Scient | Composition antidiabetique apte a stimuler la secretion d'insuline et destinee au traitement du diabete de type 2 (diabete non insulino-dependant). |
WO2008099448A1 (ja) * | 2007-02-09 | 2008-08-21 | Masayoshi Yamaguchi | 糖尿病性疾患の予防・治療剤 |
JP5417727B2 (ja) * | 2007-03-28 | 2014-02-19 | 大正製薬株式会社 | 網膜保護剤 |
JP5985138B2 (ja) * | 2009-03-18 | 2016-09-06 | 花王株式会社 | エネルギー消費促進剤 |
FR2951085B1 (fr) * | 2009-10-09 | 2012-05-18 | Inst Substances Vegetales | Utilisation de composes phenoliques pour la deglycation des proteines |
AT509045B1 (de) * | 2010-01-29 | 2011-06-15 | Planta Naturstoffe Vertriebsges M B H | Verbindungen zur behandlung von asthma bronchiale |
MX370090B (es) | 2013-02-01 | 2019-10-25 | Centro De Investig En Alimentacion Y Desarrollo A C | Un método y un sistema para el tratamiento integral de aguas residuales de una industria del maíz. |
JP6051257B2 (ja) * | 2015-04-15 | 2016-12-27 | ライオン株式会社 | 脂質異常症への罹患しやすさを試験する方法 |
JP6708376B2 (ja) * | 2015-07-10 | 2020-06-10 | 株式会社山田養蜂場本社 | IFN−γ及び/又はIL−17の産生抑制剤、並びにTh1細胞及び/又はTh17細胞の分化抑制剤 |
WO2018227170A1 (en) * | 2017-06-09 | 2018-12-13 | Sheth Hetal | Food compositions for mammals |
EP4069208A4 (en) * | 2019-12-05 | 2024-01-10 | Flagship Pioneering Innovations V Inc | ACYLATED ACTIVE INGREDIENTS AND METHODS FOR THE USE THEREOF FOR THE TREATMENT OF METABOLIC DISEASES AND NON-ALCOHOLIC FATTY LIVER |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2728971A (en) | 1970-04-13 | 1972-10-05 | Sumitomo Chemical Company, Limited | Production of cinnamic acid and its derivatives |
US3739015A (en) | 1970-09-04 | 1973-06-12 | Tanabe Seiyaku Co | Esters of p-phenoxy and p-alkoxy cinnamic acid |
-
1999
- 1999-09-15 WO PCT/KR1999/000551 patent/WO2000015215A1/en active IP Right Grant
- 1999-09-15 JP JP2000569799A patent/JP2002524505A/ja active Pending
- 1999-09-15 DE DE69916632T patent/DE69916632T2/de not_active Expired - Lifetime
- 1999-09-15 CA CA002344053A patent/CA2344053C/en not_active Expired - Fee Related
- 1999-09-15 US US09/396,312 patent/US6313171B1/en not_active Expired - Fee Related
- 1999-09-15 CN CNB998109282A patent/CN1148176C/zh not_active Expired - Fee Related
- 1999-09-15 EP EP99944893A patent/EP1113790B1/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
DE69916632D1 (de) | 2004-05-27 |
US6313171B1 (en) | 2001-11-06 |
CN1148176C (zh) | 2004-05-05 |
EP1113790B1 (en) | 2004-04-21 |
DE69916632T2 (de) | 2005-04-21 |
EP1113790A1 (en) | 2001-07-11 |
WO2000015215A1 (en) | 2000-03-23 |
CA2344053A1 (en) | 2000-03-23 |
JP2002524505A (ja) | 2002-08-06 |
CA2344053C (en) | 2007-04-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1317972A (zh) | 用于预防或治疗与血脂水平升高相关的疾病的含有芸香苷和五羟黄酮的组合物 | |
US6133311A (en) | Method for preventing or treating elevated blood lipid level-related diseases by administering natural phenolic compounds | |
CN1148176C (zh) | 用于预防或治疗与血脂水平升高相关的疾病的含有肉桂酸衍生物的组合物 | |
CN1124134C (zh) | 柚苷和柚苷配基作为肝病的预防或治疗剂的应用 | |
US6455577B2 (en) | Flavanone derivatives and composition for preventing or treating blood lipid level-related diseases comprising same | |
CN1124133C (zh) | 橙皮苷和橙皮素作为肝病的预防或治疗剂的应用 | |
JPWO2006082743A1 (ja) | 治療剤 | |
CN1317938A (zh) | 用于治疗或预防与血脂和血糖水平升高相关的疾病的含有新橙皮苷双氢查尔酮的组合物 | |
WO2020262703A1 (ja) | タキシフォリンを含有する肝線維化抑制剤及び褐色脂肪細胞活性化剤 | |
KR100291144B1 (ko) | 디오스민을 포함하는 동맥경화증 및 고지혈증의 예방 및치료용 조성물 | |
KR20030024111A (ko) | 감잎 추출물을 포함하는 혈중 지질농도 저하용 조성물 | |
US20090292012A1 (en) | Therapeutic Agent | |
KR100479736B1 (ko) | 천연 식물체 유래의 혼합분말 또는 추출물을 포함하는 지방간 예방용 식품 | |
KR20000019719A (ko) | 디오스민을 포함하는 동맥경화증 및 고지혈증의 예방 및 치료용조성물 | |
KR100365388B1 (ko) | 신남산 유도체를 포함하는 고농도 혈중 지질-관련 질환의 예방 및 치료용 조성물 | |
KR20030020714A (ko) | 지골피 추출물을 포함하는 혈중 지질농도 저하용 조성물 | |
KR20010015495A (ko) | 루틴 및 쿼세틴을 포함하는 고지혈증, 동맥경화증 및 간질환의 예방 및 치료용 조성물 |
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 | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20040505 Termination date: 20140915 |
|
EXPY | Termination of patent right or utility model |