CN106420688A - Idhp制备预防和治疗冠状动脉粥样硬化疾病药物的应用 - Google Patents
Idhp制备预防和治疗冠状动脉粥样硬化疾病药物的应用 Download PDFInfo
- Publication number
- CN106420688A CN106420688A CN201610876752.3A CN201610876752A CN106420688A CN 106420688 A CN106420688 A CN 106420688A CN 201610876752 A CN201610876752 A CN 201610876752A CN 106420688 A CN106420688 A CN 106420688A
- Authority
- CN
- China
- Prior art keywords
- idhp
- application
- preparing
- isopropyl ester
- coronary atherosclerosis
- 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
- 239000003814 drug Substances 0.000 title claims abstract description 20
- 208000029078 coronary artery disease Diseases 0.000 title claims abstract description 16
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 title claims abstract description 14
- 208000026758 coronary atherosclerosis Diseases 0.000 title claims abstract description 12
- 229940079593 drug Drugs 0.000 title abstract description 7
- ZYFWDUKUSGLMGL-UHFFFAOYSA-N Isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate Chemical compound CC(C)OC(=O)C(O)CC1=CC=C(O)C(O)=C1 ZYFWDUKUSGLMGL-UHFFFAOYSA-N 0.000 title abstract 2
- 230000033115 angiogenesis Effects 0.000 claims abstract description 17
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 230000036541 health Effects 0.000 claims abstract description 13
- 201000004810 Vascular dementia Diseases 0.000 claims abstract description 4
- 230000001737 promoting effect Effects 0.000 claims abstract description 4
- PAFLSMZLRSPALU-QMMMGPOBSA-N Danshensu Natural products OC(=O)[C@@H](O)CC1=CC=C(O)C(O)=C1 PAFLSMZLRSPALU-QMMMGPOBSA-N 0.000 claims description 28
- PAFLSMZLRSPALU-UHFFFAOYSA-N Salvianic acid A Natural products OC(=O)C(O)CC1=CC=C(O)C(O)=C1 PAFLSMZLRSPALU-UHFFFAOYSA-N 0.000 claims description 28
- -1 danshensu isopropyl ester Chemical class 0.000 claims description 24
- 230000002265 prevention Effects 0.000 claims description 13
- 230000002490 cerebral effect Effects 0.000 claims description 6
- 210000002216 heart Anatomy 0.000 claims description 6
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 5
- 208000006011 Stroke Diseases 0.000 claims description 5
- 108010035532 Collagen Proteins 0.000 abstract description 9
- 102000008186 Collagen Human genes 0.000 abstract description 9
- 229920001436 collagen Polymers 0.000 abstract description 9
- 201000010099 disease Diseases 0.000 abstract description 7
- 210000002889 endothelial cell Anatomy 0.000 abstract description 4
- 210000003606 umbilical vein Anatomy 0.000 abstract 1
- 229920000936 Agarose Polymers 0.000 description 12
- 238000001042 affinity chromatography Methods 0.000 description 12
- 239000008280 blood Substances 0.000 description 10
- 210000004204 blood vessel Anatomy 0.000 description 10
- 241000252212 Danio rerio Species 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 108010082117 matrigel Proteins 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 239000003292 glue Substances 0.000 description 4
- 230000000302 ischemic effect Effects 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- PAFLSMZLRSPALU-MRVPVSSYSA-N (2R)-3-(3,4-dihydroxyphenyl)lactic acid Chemical compound OC(=O)[C@H](O)CC1=CC=C(O)C(O)=C1 PAFLSMZLRSPALU-MRVPVSSYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010018910 Haemolysis Diseases 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 210000001367 artery Anatomy 0.000 description 3
- 230000003143 atherosclerotic effect Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 230000008588 hemolysis Effects 0.000 description 3
- 210000001161 mammalian embryo Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- WTPPRJKFRFIQKT-UHFFFAOYSA-N 1,6-dimethyl-8,9-dihydronaphtho[1,2-g][1]benzofuran-10,11-dione;1-methyl-6-methylidene-8,9-dihydro-7h-naphtho[1,2-g][1]benzofuran-10,11-dione Chemical compound O=C1C(=O)C2=C3CCCC(=C)C3=CC=C2C2=C1C(C)=CO2.O=C1C(=O)C2=C3CCC=C(C)C3=CC=C2C2=C1C(C)=CO2 WTPPRJKFRFIQKT-UHFFFAOYSA-N 0.000 description 2
- 206010008092 Cerebral artery thrombosis Diseases 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010061216 Infarction Diseases 0.000 description 2
- 102000004882 Lipase Human genes 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- 239000004367 Lipase Substances 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 238000011047 acute toxicity test Methods 0.000 description 2
- 238000013176 antiplatelet therapy Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 239000006059 cover glass Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000007574 infarction Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 235000019421 lipase Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 210000004681 ovum Anatomy 0.000 description 2
- 235000010603 pastilles Nutrition 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 244000132619 red sage Species 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 229950000578 vatalanib Drugs 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010006100 Bradykinesia Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- QSMTUAJDOTXEDZ-UHFFFAOYSA-N N1C=CC=C1.[Cl] Chemical compound N1C=CC=C1.[Cl] QSMTUAJDOTXEDZ-UHFFFAOYSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000034038 Pathologic Neovascularization Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 240000007164 Salvia officinalis Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 208000030451 Vascular dementia disease Diseases 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000036978 cell physiology Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 231100000132 chronic toxicity testing Toxicity 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 239000009524 danshen dripping Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 231100000567 intoxicating Toxicity 0.000 description 1
- 230000002673 intoxicating effect Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 235000005412 red sage Nutrition 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 238000004879 turbidimetry Methods 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- 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
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
- A23L29/035—Organic compounds containing oxygen as heteroatom
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- 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
-
- 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
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
-
- 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
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/326—Foods, ingredients or supplements having a functional effect on health having effect on cardiovascular health
-
- 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
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/3262—Foods, ingredients or supplements having a functional effect on health having an effect on blood cholesterol
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Emergency Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Hospice & Palliative Care (AREA)
- Polymers & Plastics (AREA)
- Urology & Nephrology (AREA)
- Psychiatry (AREA)
- Vascular Medicine (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Mycology (AREA)
- Dispersion Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
本发明涉及IDHP制备预防和治疗冠状动脉粥样硬化疾病药物的应用。发明人研究发现IDHP可分别显著抑制ADP或胶原诱导的人血小板聚集,同时发现IDHP可显著促进原代人脐带静脉内皮细胞血管新生,这说明IDHP可用于制备预防和治疗冠状动脉粥样硬化相关性疾病药物和保健品的应用,同时IDHP可用于开发抗血小板聚集、促进血管新生、以及治疗老年血管性痴呆药物和保健品。
Description
技术领域
本发明涉及丹参素异丙酯(IDHP)的新应用,具体涉及IDHP用于制备预防和治疗冠状动脉粥样硬化相关性疾病药物和保健品的应用。
背景技术
β-(3,4-二羟基苯基)-α-羟基丙酸异丙酯(丹参素异丙酯,IDHP)是发明人应用代谢物组学研究技术,采用HPLC-MS、GC-MS、GC-FTIR、MS、NMR等技术手段,在复方丹参滴丸、冠心丹参片、丹参饮等复方丹参方和“君-使”对药的研究过程中,从众多的代谢产物及其系列的改性物中,筛选并合成的活性化合物。
发明内容
发明人探索IDHP在抑制血小板聚集、促进血管新生等方面的作用,为预防和治疗冠状动脉粥样硬化相关性疾病新药及保健品开发提供有价值的理论依据。
冠状动脉硬化疾病是冠状动脉血管发生动脉粥样硬化病变而引起血管腔狭窄或阻塞,造成缺血、缺氧或坏死而导致一类疾病,常见冠心病、脑卒中及心肌梗塞(心梗)。冠心病主要发病机制与冠状动脉粥样硬化斑块不稳定及血栓形成密切相关,血小板聚集是导致血栓形成的重要因素,抗血小板治疗在冠心病预防及治疗方面起着重要作用。脑卒中是指脑血管疾病的病人,因各种诱发因素引起脑内动脉狭窄,闭塞或破裂,而造成急性脑血液循环障碍的一种高危疾病,临床上表现为一过性或永久性脑功能障碍,抗血小板治疗在脑卒中的一级和二级预防中起着重要作用,是目前临床公认的三大治疗手段(手术、抗凝和抗血小板聚集)之一。同时,冠状动脉硬化相关性疾病分发生、治疗又与血管新生息息相关。动脉粥样硬化斑块内常出现病理性新生血管,它们可以促进粥样硬化病变的发展,甚至诱发斑块内出血和斑块破裂及其并发症。发生缺血性脑卒中梗死部位周围新生血管的密度与缺血性脑卒中患者的存活率直接相关,促进缺血性脑卒中后血管新生,有利于挽救缺血半暗带。血管新生也是冠状动脉再灌注及缺血心肌修复的关键过程。此外,促血管新生在心梗的愈后方面作用显著。发明人研究发现IDHP可分别显著抑制ADP或胶原诱导的人血小板聚集,同时发现IDHP可显著促进原代人脐带静脉内皮细胞(HUVEC)血管新生,这说明IDHP可用于制备预防和治疗冠状动脉粥样硬化疾病药物的应用。
发明人研究发现IDHP可分别显著抑制ADP及胶原诱导的人血小板聚集,该发现为将IDHP用于开发抗血小板聚集药物奠定了基础。
发明人研究发现IDHP可显著促进原代人脐带静脉内皮细胞(HUVEC)血管新生,同时IDHP对斑马鱼节间血管和背部纵侧血管的生长具有显著地促进作用,这说明IDHP可用于制备促进血管新生的药物。
IDHP可显著抑制人血小板聚集和促进血管新生,改善血运,从而可以治疗老年血管性痴呆。
经过小鼠急性、慢性毒性试验以及溶血实验,发明人发现IDHP具有较高安全性,结合上述相关活性研究发现,说明IDHP可用于开发预防和治疗冠状动脉粥样硬化相疾病保健品、抗血小板聚集保健品、促进血管新生保健品、预防和治疗老年血管性痴呆保健品。
发明人研究发现IDHP为人体内源性物质,进一步说明通过摄入IDHP,调节体内平衡状态,以达到预防、保健与治疗冠状动脉粥样硬化相关性疾病、老年血管性痴呆的目的。
附图说明
图1为不同浓度IDHP对人脐带静脉内皮细胞增殖的影响;
图2为不同浓度IDHP对人脐带静脉内皮细胞迁移的影响;
图3为不同浓度IDHP对人脐带静脉内皮细胞管腔形成的影响;
图4为IDHP对斑马鱼节间血管生长的影响;其中:A,PTK 787;B,0.01μM IDHP;C,0.1μM IDHP;D,1.0μM IDHP;E,10.0μM IDHP;F,10nM VEGF;
图5为IDHP促斑马鱼节间血管生长的测定结果图;
图6为IDHP对ADP及胶原诱导的正常人血小板聚集的影响(n=16);
图7为丹参素异丙酯质谱鉴定;
图8为丹参素异丙酯液相鉴定。
具体实施方式
本发明IDHP化合物的结构式如下式所示,其制备方法可参见CN 200410026205.3,但不限于该文献记载的范围。
本发明所述的保健品可以是软胶囊、滴丸、乳剂、片剂或喷雾等。
实施例1:IDHP促进体外培养的人脐带静脉内皮细胞(HUVEC)血管新生
1.1 IDHP促进人脐带静脉内皮细胞(HUVEC)增殖—CCK-8法
人脐带静脉内皮细胞接种于96孔板中,密度约2,500个/孔。种板24h后,换取新鲜含药培养基,100μl/孔,继续培养48h;药物处理结束前2小时,避光条件下在培养液中加入CCK-8试剂,每孔10μl。继续培养2h后,用酶标仪测定450nm处吸光值,计算细胞增殖率。图1结果显示,与空白对照组相比,IDHP在10-9-10-7M时显著促进血管内皮细胞增殖(P<0.01)。
1.2 IDHP促进人脐带静脉内皮细胞(HUVEC)的迁移—划痕法
将内皮细胞接种于24孔板内由明胶预包被的盖玻片上使之爬片,接种密度约105个/孔,待细胞贴壁并融合后,撤血清饥饿4h,用被实验室特制的多通道损伤工具进行划痕损伤,PBS清洗两遍盖玻片,并加入含药培养基,600μl/孔,0小时对照组立刻用冰甲醇固定,其余组细胞继续培养16h后,用冰甲醇固定,显微镜下观察拍照并统计。结果显示(图2),IDHP在10-10-10-7M时,可剂量依赖性的促进人脐带静脉内皮细胞(HUVEC)的迁移。
1.3 IDHP促进人脐带静脉内皮细胞(HUVEC)的管腔形成—Matrigel胶法
将枪头和96孔板于-20℃预冷,将Matrigel胶放冰上使之融化,取Matrigel胶(60μL/孔)加入到预冷的96孔板中,避免形成气泡,冰上放置5min,使Matrigel液面水平,然后放入细胞培养箱30min使之凝固;取内皮细胞(细胞数5×104/孔)加入到含Matrigel胶的孔中,再加入含不同浓度的药物的新鲜培养基,37℃培养8h;在显微镜下观察,每孔选取0,3,6,9点钟及正中心共5个视野,观察小管数目及管状结构完整性并拍照统计。结果显示,与Ctrl对照组相比,IDHP可显著促进原代人脐带静脉内皮细胞(HUVEC)的管腔形成,说明IDHP在体外具有促进血管新生的活性。
实施例2:IDHP促进转基因斑马鱼的血管新生
转基因Tg(VEGFR2:GFP)系斑马鱼在照明14h/黑暗10h、28℃标准条件下饲养,用卵时,取健康性成熟的斑马鱼,按雌雄1/1或1/2的比例放入交配缸内,次日9~10时获得受精卵。对受精卵进行消毒和清洗后,移入斑马鱼胚胎培养水中,28℃下培养。
将药物溶液加入到24孔培养板中,将24hpf的胚胎小心转移至孔中,每孔8-10个,用培养水加至总体积为2ml。保证DMSO的终浓度不高于1%。药物处理24h后,采用荧光显微镜观察胚胎,计数躯干与尾部的节间血管总数,计算各给药组的ISV相对生成率。采用SPSS软件进行各组间方差分析。
结果显示,浓度分别为0.01,0.1和1.0μM的IDHP对斑马鱼节间血管和背部纵侧血管的生长具有显著地促进作用(图4),血管总数和长度明显增加(表1)。根据公式:相对生成率(%)=(给药组血管总长-PTK787对照组血管总长)÷正常对照组血管总长×100计算相对生成率,药物间呈现良好的剂量依赖关系(图5)。
表1 IDHP对斑马鱼ISV生长的促进作用
注:***代表与对照相比,p<0.001
实施例3:IDHP抑制ADP及胶原诱导的人血小板聚集
采集志愿者全血加入抗凝管中,室温800g离心5min,取淡黄色上清即为富含血小板血浆(PRP),将余液继续以4000g室温离心10min,取上清即为贫血小板血浆(PPP)。
以PPP调节PRP至3×105/μL,取300μL调节后的PRP加入30μL的PBS或不同浓度的IDHP于血液凝聚仪中37℃温育3min后,加入终浓度为3μmol/L的ADP或胶原,启动血小板的凝聚反应。采用比浊法测定IDHP及氯吡格雷对血小板聚集的抑制作用。图6结果显示,氯吡格雷在所测浓度范围内,可显著抑制ADP诱导的血小板聚集(p<0.001);与ADP或胶原单独作用组(Ctrl)相比,IDHP可分别显著抑制ADP及胶原诱导的人血小板聚集,且对胶原诱导的血小板聚集的抑制作用更为显著(P<0.001)。
实施例4:丹参素异丙酯(IDHP)毒理学研究
4.1快速给药小鼠急性毒性试验
选小白鼠60只,♀♂各半,随机分为6组。将丹参素异丙酯用生理盐水配成6种浓度的溶液:3.145%、2.68%、2.4%、2%、1.875%和1.6%。各浓度间的间距为1:0.9。动物禁食12h后,各组分别iv给药,容积20mL/kg,每只动物5s内完成给药。6个组的剂量分别为629mg/kg、530mg/kg、480mg/kg、400mg/kg、375mg/kg和320mg/kg。iv后,动物呼吸急促、心跳加快、跳跃、抽搐,随后运动迟缓、卧地。中毒现象随给药剂量的增加而增加;死亡动物基本在给药后1min内死亡,未死的动物在10min后恢复正常。对死亡小鼠进行尸检,肉眼观察,小鼠的心、肝、脾、肺、肾、脑、胃、肠等重要脏器均未见异常。Bliss法测定LD50为424±58mg/kg,95%可信区间为370~486mg/kg,见表2。
表2 丹参素异丙酯的LD50测定(Bliss’s)法本底死亡率:0%
显著性指数:G=0.1760 X50=-0.3722 Sx=0.0158 G较小,省略
异质性检查:Chi2=6.90 Chi2.05=9.64 Sb=2.7993 无异质性
回归方程式为:Y(Probit)=9.8687+13.0795×log(D) r=0.8716
LD50=424.4±39.7(mg/kg)
Feiller异质性校正:Sx=0.0229 Sb=3.6778
LD50=424.4±57.9(mg/kg)
95%可信区间为370.4~486.2mg/kg
4.2慢速给药小鼠急性毒性试验
试验用小鼠在实验室饲养1天后挑选体重合格者,按体重和性别随机分组,每组10只,雌雄各半,根据预摸结果,全死剂量为2.4g/kg。小鼠采用尾静脉给药,小鼠按体重计算给药量,给药剂量依次为2.4g/kg、2.2g/kg、2.0g/kg、1.8g/kg,并计算给药速度,在10分钟内给药完毕,给药后观察小鼠反应情况并记录14天内小鼠死亡率。
静脉给药后主要毒性反应为中枢抑制,呼吸衰竭等表现。死亡多在给药期间内发生,死亡解剖未见内脏有异常改变,观察14天,再计算小鼠死亡率,Bliss法测定LD50=2.048g/kg±0.085g/kg,95%可信限=1.965~2.135g/kg,结果见表3,
表3小鼠尾静脉给药丹参素异丙酯的LD50测定(Bliss法)
4.3溶血试验
家兔动脉取血,去纤维蛋白,用生理盐水洗涤红细胞后配制成2%的红细胞生理盐水溶液。按表4进行操作每组平行试管4支。
表4
操作完成后,37±0.5℃水浴,于0.5h、1h、2h、3h每组分别各取一支试管,3000rpm离心15min,观察红细胞的溶血情况,同时,光镜下观察红细胞形态。
试验结果表明,红细胞形态完整,无明显的溶血现象,提示丹参素异丙酯无溶血作用。
实施例5:丹参素异丙酯内源性研究
脂肪酶催化丹参素与异丙醇合成丹参素异丙酯:
具体实施可参考以下方案,但不限于该方案:
丹参素(5.0毫克,0.025毫摩尔),异丙醇(0.3毫克,0.005毫摩尔),水(1.5毫升),脂肪酶(5毫克),密闭37℃摇床(220转/分钟)温浴24小时,取100微升反应液,加入100微升乙酸乙酯,振摇20秒,取有机相做液相与质谱分析。质谱结果([M-1]=239.0965)见图7;液相结果见图8。
液相检测条件:甲醇:0.2%甲酸水=3:7;流速:0.6毫升/分钟;色谱柱:C18(zorbax),250毫米,5微米,4.6毫米(内径);柱温:25℃。
结合发明人前期研究发现丹参素为人体内源性物质,同时,脂肪酶广泛存在于含有脂肪的动、植物和微生物(如霉菌、细菌等)组织中,且人体内含有异丙醇,从而可以说明丹参素异丙酯为人体内源性物质。
实施例6:丹参素异丙酯乳剂:
乳剂配方为:丹参素异丙酯:10.0g,维生素E:3.0g,精制大豆:200.0g,油酸:15.0g,精制蛋白卵磷脂:25.0g,注射用水:约900ml,甘油:2.0g。
实施例8:丹参素异丙酯滴丸:
丹参素异丙酯:10.4g,淀粉:6.3g,羧甲基淀粉钠:1.8g,聚乙二醇(分子量6000):26.5g,制备时取处方量丹参素异丙酯与聚乙二醇6000加热至80℃熔化,加入淀粉和羧甲基淀粉钠,混合均匀,滴入液体石蜡冷却剂中(1~5℃),制成1000丸,丸重45mg,除去表面油迹,即得。
Claims (10)
1.丹参素异丙酯用于制备预防和治疗冠状动脉粥样硬化疾病药物的应用。
2.如权利要求1所述的应用,其特征在于,所述的冠状动脉粥样硬化疾病包括脑卒中、冠心病和心梗。
3.丹参素异丙酯用于制备预防和治疗冠状动脉粥样硬化疾病保健品的应用。
4.如权利要求3所述的应用,其特征在于,所述的冠状动脉粥样硬化疾病包括脑卒中、冠心病和心梗。
5.丹参素异丙酯用于制备抗血小板聚集药物的应用。
6.丹参素异丙酯用于制备抗血小板聚集保健品的应用。
7.丹参素异丙酯用于制备促进血管新生药物的应用。
8.丹参素异丙酯用于制备促进血管新生保健品的应用。
9.丹参素异丙酯用于制备预防和治疗老年血管性痴呆药物的应用。
10.丹参素异丙酯用于制备预防和治疗老年血管性痴呆保健品的应用。
Priority Applications (17)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610876752.3A CN106420688B (zh) | 2016-10-08 | 2016-10-08 | Idhp制备预防和治疗冠状动脉粥样硬化疾病药物的应用 |
PL17857834.0T PL3524241T3 (pl) | 2016-10-08 | 2017-09-29 | Zastosowanie idhp do wytwarzania leku lub produktu leczniczego do zapobiegania i leczenia miażdżycy naczyń wieńcowych |
PCT/CN2017/104278 WO2018064953A1 (zh) | 2016-10-08 | 2017-09-29 | Idhp在制备预防和治疗冠状动脉粥样硬化疾病药物或保健品中的应用 |
JP2019518211A JP6851652B2 (ja) | 2016-10-08 | 2017-09-29 | Idhpの冠状動脈アテローム性硬化症の予防及び治療のための薬物又は健康補助食品の調製における応用 |
BR112019006957A BR112019006957A2 (pt) | 2016-10-08 | 2017-09-29 | uso de idhp na preparação de fármaco ou produto de saúde para a prevenção e tratamento de doença de aterosclerose coronária |
SG11201902987SA SG11201902987SA (en) | 2016-10-08 | 2017-09-29 | Use of idhp in preparation of drug or health product for prevention and treatment of coronary atherosclerosis disease |
HUE17857834A HUE063053T2 (hu) | 2016-10-08 | 2017-09-29 | IDHP vérlemezke-aggregáció terápiás gátlásában, angiogenezis terápiás célú elõsegítésében és vaszkuláris demencia megelõzésében vagy kezelésében való alkalmazásra |
KR1020197013111A KR102286297B1 (ko) | 2016-10-08 | 2017-09-29 | 관상동맥 죽상경화증 질환의 예방 및 치료용 약물 또는 건강 제품의 제조에 있어서 idhp의 용도 |
US16/338,801 US10993926B2 (en) | 2016-10-08 | 2017-09-29 | Use of IDHP in preparation of drug or health product for prevention and treatment of coronary atherosclerosis disease |
RU2019113518A RU2719391C1 (ru) | 2016-10-08 | 2017-09-29 | Применение idhp в получении лекарственного средства или медицинского продукта для профилактики и лечения коронарного атеросклероза |
MYPI2019001888A MY195760A (en) | 2016-10-08 | 2017-09-29 | Use of IDHP in Preparation of Drug or Health Product for Prevention and Treatment of Coronary Atherosclerosis Disease |
CA3039287A CA3039287C (en) | 2016-10-08 | 2017-09-29 | Use of idhp in preparation of drug or health product for prevention and treatment of coronary atherosclerosis disease |
NZ752717A NZ752717B2 (en) | 2016-10-08 | 2017-09-29 | Use of idhp in preparation of drug or health product for prevention and treatment of coronary atherosclerosis disease |
EP17857834.0A EP3524241B1 (en) | 2016-10-08 | 2017-09-29 | Idhp for use in the therapeutic inhibition of platelet formation, the therapeutic promotion of angiogenesis and the prevention or treatment of vascular dementia |
AU2017340305A AU2017340305B2 (en) | 2016-10-08 | 2017-09-29 | Use of IDHP in preparation of drug or health product for prevention and treatment of coronary atherosclerosis disease |
IL265753A IL265753B2 (en) | 2016-10-08 | 2019-04-01 | Use of idhp in the preparation of a medicine or health product for the prevention and treatment of coronary arteriosclerosis |
CY20231100274T CY1126073T1 (el) | 2016-10-08 | 2023-06-13 | Idhp για χρηση στην θεραπευτικη αναστολη σχηματισμου αιμοπεταλιων, στην θεραπευτικη υποκινηση αγγειογενεσης και στην αποτροπη ή θεραπεια αγγειακης ανοιας |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610876752.3A CN106420688B (zh) | 2016-10-08 | 2016-10-08 | Idhp制备预防和治疗冠状动脉粥样硬化疾病药物的应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106420688A true CN106420688A (zh) | 2017-02-22 |
CN106420688B CN106420688B (zh) | 2017-11-10 |
Family
ID=58172355
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610876752.3A Active CN106420688B (zh) | 2016-10-08 | 2016-10-08 | Idhp制备预防和治疗冠状动脉粥样硬化疾病药物的应用 |
Country Status (16)
Country | Link |
---|---|
US (1) | US10993926B2 (zh) |
EP (1) | EP3524241B1 (zh) |
JP (1) | JP6851652B2 (zh) |
KR (1) | KR102286297B1 (zh) |
CN (1) | CN106420688B (zh) |
AU (1) | AU2017340305B2 (zh) |
BR (1) | BR112019006957A2 (zh) |
CA (1) | CA3039287C (zh) |
CY (1) | CY1126073T1 (zh) |
HU (1) | HUE063053T2 (zh) |
IL (1) | IL265753B2 (zh) |
MY (1) | MY195760A (zh) |
PL (1) | PL3524241T3 (zh) |
RU (1) | RU2719391C1 (zh) |
SG (1) | SG11201902987SA (zh) |
WO (1) | WO2018064953A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018064953A1 (zh) * | 2016-10-08 | 2018-04-12 | 西北大学 | Idhp在制备预防和治疗冠状动脉粥样硬化疾病药物或保健品中的应用 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102529594B1 (ko) | 2021-06-23 | 2023-05-09 | 재단법인 아산사회복지재단 | 대동맥판막 협착증 진단 및 예후 예측을 위한 바이오마커로서 항-시트룰린화 펩티드 항체의 용도 |
KR102643120B1 (ko) | 2021-11-12 | 2024-03-05 | 재단법인 아산사회복지재단 | 대동맥판막 협착증의 진단을 위한 미토콘드리아 바이오마커 및 미토콘드리아 활성화제를 포함하는 대동맥판막 협착증의 예방 또는 치료용 약학적 조성물 |
KR20240020754A (ko) | 2022-08-08 | 2024-02-16 | 재단법인 아산사회복지재단 | Pad 저해제를 포함하는 퇴행성 판막 질환의 예방 또는 치료용 조성물 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1583710A (zh) * | 2004-06-03 | 2005-02-23 | 西安交通大学 | β-(3,4-二羟基苯基)-α-羟基丙酸异丙酯及其合成方法 |
CN101596196A (zh) * | 2008-06-02 | 2009-12-09 | 北京科士蓝医药技术有限公司 | 川芎嗪和丹参素的组合物及其药理活性研究 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997035579A1 (en) * | 1996-03-27 | 1997-10-02 | Merck & Co., Inc. | A method for inhibiting clot formation |
KR20040044514A (ko) | 2001-09-14 | 2004-05-28 | 미쯔비시 웰 파마 가부시키가이샤 | 항혈전약과 피라졸론 유도체의 조합 약제 |
JP3895228B2 (ja) * | 2002-05-07 | 2007-03-22 | 松下電器産業株式会社 | 無線通信装置および到来方向推定方法 |
CN106420688B (zh) | 2016-10-08 | 2017-11-10 | 西北大学 | Idhp制备预防和治疗冠状动脉粥样硬化疾病药物的应用 |
-
2016
- 2016-10-08 CN CN201610876752.3A patent/CN106420688B/zh active Active
-
2017
- 2017-09-29 AU AU2017340305A patent/AU2017340305B2/en active Active
- 2017-09-29 BR BR112019006957A patent/BR112019006957A2/pt active Search and Examination
- 2017-09-29 SG SG11201902987SA patent/SG11201902987SA/en unknown
- 2017-09-29 JP JP2019518211A patent/JP6851652B2/ja active Active
- 2017-09-29 PL PL17857834.0T patent/PL3524241T3/pl unknown
- 2017-09-29 RU RU2019113518A patent/RU2719391C1/ru active
- 2017-09-29 EP EP17857834.0A patent/EP3524241B1/en active Active
- 2017-09-29 MY MYPI2019001888A patent/MY195760A/en unknown
- 2017-09-29 KR KR1020197013111A patent/KR102286297B1/ko active IP Right Grant
- 2017-09-29 WO PCT/CN2017/104278 patent/WO2018064953A1/zh unknown
- 2017-09-29 CA CA3039287A patent/CA3039287C/en active Active
- 2017-09-29 HU HUE17857834A patent/HUE063053T2/hu unknown
- 2017-09-29 US US16/338,801 patent/US10993926B2/en active Active
-
2019
- 2019-04-01 IL IL265753A patent/IL265753B2/en unknown
-
2023
- 2023-06-13 CY CY20231100274T patent/CY1126073T1/el unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1583710A (zh) * | 2004-06-03 | 2005-02-23 | 西安交通大学 | β-(3,4-二羟基苯基)-α-羟基丙酸异丙酯及其合成方法 |
CN101596196A (zh) * | 2008-06-02 | 2009-12-09 | 北京科士蓝医药技术有限公司 | 川芎嗪和丹参素的组合物及其药理活性研究 |
Non-Patent Citations (1)
Title |
---|
JINGWEI TIAN 等: "ND-309, a novel compound, ameliorates cerebral infarction in rats by antioxidant action", 《NEUROSCIENCE LETTERS》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018064953A1 (zh) * | 2016-10-08 | 2018-04-12 | 西北大学 | Idhp在制备预防和治疗冠状动脉粥样硬化疾病药物或保健品中的应用 |
US10993926B2 (en) | 2016-10-08 | 2021-05-04 | Northwest University | Use of IDHP in preparation of drug or health product for prevention and treatment of coronary atherosclerosis disease |
Also Published As
Publication number | Publication date |
---|---|
JP2019537561A (ja) | 2019-12-26 |
US10993926B2 (en) | 2021-05-04 |
CN106420688B (zh) | 2017-11-10 |
JP6851652B2 (ja) | 2021-03-31 |
AU2017340305B2 (en) | 2020-07-09 |
IL265753B (en) | 2022-10-01 |
CA3039287C (en) | 2021-02-16 |
CA3039287A1 (en) | 2018-04-12 |
EP3524241C0 (en) | 2023-06-07 |
IL265753B2 (en) | 2023-02-01 |
SG11201902987SA (en) | 2019-05-30 |
MY195760A (en) | 2023-02-09 |
US20200038357A1 (en) | 2020-02-06 |
IL265753A (en) | 2019-06-30 |
NZ752717A (en) | 2020-12-18 |
EP3524241A1 (en) | 2019-08-14 |
CY1126073T1 (el) | 2023-11-15 |
PL3524241T3 (pl) | 2023-07-17 |
HUE063053T2 (hu) | 2023-12-28 |
EP3524241B1 (en) | 2023-06-07 |
KR102286297B1 (ko) | 2021-08-09 |
KR20190075953A (ko) | 2019-07-01 |
WO2018064953A1 (zh) | 2018-04-12 |
RU2719391C1 (ru) | 2020-04-17 |
BR112019006957A2 (pt) | 2019-07-02 |
EP3524241A4 (en) | 2020-05-27 |
AU2017340305A1 (en) | 2019-05-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106420688B (zh) | Idhp制备预防和治疗冠状动脉粥样硬化疾病药物的应用 | |
CN102647981B (zh) | 预防和治疗脑缺血的方法 | |
CN104053439A (zh) | 1-(5,6-二氯-1h-苯并[d]咪唑-2-基)-1h-吡唑-4-羧酸的葡甲胺盐制剂 | |
CN103193789A (zh) | 一种光学活性的丁苯酞开环衍生物、制备方法及医药用途 | |
JP2022503890A (ja) | 2-(1-アシルオキシ-n-ペンチル)安息香酸と塩基性アミノ酸またはアミノグアニジンによって形成される塩と、その製造方法及び用途 | |
CN109734701A (zh) | Rock抑制剂-二氯乙酸复盐及其制备方法和用途 | |
CN116407531A (zh) | 脱水淫羊藿素在制备抑制巨噬细胞铁死亡以治疗动脉粥样硬化药物中的应用 | |
CN105193795A (zh) | 两种卤酚化合物在促血管生成作用方面的应用 | |
CN104496896B (zh) | 含磺酰脲结构的索拉非尼衍生物的制备及应用 | |
CN108938615A (zh) | 苯磺酰胺基苯甲酰胺类化合物用于治疗非酒精性脂肪性肝病的用途 | |
CN104224796B (zh) | 齐墩果烷型三萜类酯衍生物抗神经退行性药物用途 | |
CN104926754A (zh) | 一种大黄酸衍生物及其应用 | |
CN103880793B (zh) | 含呋喃亚胺类化合物及其制备方法和用途 | |
CN100577180C (zh) | 藤黄酸在制备抑制血管生成药物中的应用 | |
CN101555199A (zh) | 支链脂肪酸类化合物及其衍生物用于防治缺血再灌注损伤 | |
WO2019114501A1 (zh) | α-楝子素衍生物及其制备方法与应用 | |
CN106977464A (zh) | 具有神经保护活性的川芎嗪取代肉桂酸类衍生物(lqc-w)及其应用 | |
CN104840461A (zh) | 一类反式-1-(吲哚-3-基)-2-(喹啉-4-基)-乙烯衍生物的用途及组合物 | |
CN106117174A (zh) | 黄酮乙酸类衍生物、其药物组合物、其制备方法及用途 | |
CN117752649A (zh) | 桑根酮c在制备抗血小板聚集、抗血栓形成药物中的应用 | |
CN117736251A (zh) | 一类香豆素苷及其制备方法和其药物组合物与用途 | |
CN111939148A (zh) | Deox B 7,4在制备血管生成抑制剂中的用途 | |
CN109419801A (zh) | 左旋奥拉西坦在制备预防或治疗蛛网膜下腔出血后早期脑损伤药物中的应用 | |
CN106176712A (zh) | 匹诺塞林在制备预防和/或治疗肺动脉高压中的药物用途 | |
CN105820188A (zh) | 一种含替诺福韦双(维生素e)酯的药物制剂和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |