CN109528699A - Fragrant happy amine is preparing the application in nerve protection medicine - Google Patents
Fragrant happy amine is preparing the application in nerve protection medicine Download PDFInfo
- Publication number
- CN109528699A CN109528699A CN201811610138.8A CN201811610138A CN109528699A CN 109528699 A CN109528699 A CN 109528699A CN 201811610138 A CN201811610138 A CN 201811610138A CN 109528699 A CN109528699 A CN 109528699A
- Authority
- CN
- China
- Prior art keywords
- application
- happy amine
- amine
- fragrant
- combination
- 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 60
- 150000001412 amines Chemical class 0.000 title claims abstract description 54
- 210000005036 nerve Anatomy 0.000 title claims abstract description 19
- 230000004224 protection Effects 0.000 title claims abstract description 14
- 201000006474 Brain Ischemia Diseases 0.000 claims abstract description 20
- 206010008111 Cerebral haemorrhage Diseases 0.000 claims abstract description 18
- 229940079593 drug Drugs 0.000 claims abstract description 18
- 206010008120 Cerebral ischaemia Diseases 0.000 claims abstract description 17
- 206010008118 cerebral infarction Diseases 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 239000000463 material Substances 0.000 claims abstract description 10
- 239000002552 dosage form Substances 0.000 claims abstract description 5
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 17
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
- 229920002472 Starch Polymers 0.000 claims description 11
- 239000008107 starch Substances 0.000 claims description 11
- 235000019698 starch Nutrition 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000003205 fragrance Substances 0.000 claims description 10
- 229930006000 Sucrose Natural products 0.000 claims description 8
- 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 claims description 8
- 239000000853 adhesive Substances 0.000 claims description 7
- 230000001070 adhesive effect Effects 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 7
- -1 corrigent Substances 0.000 claims description 6
- 235000003599 food sweetener Nutrition 0.000 claims description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 6
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 6
- 235000019359 magnesium stearate Nutrition 0.000 claims description 6
- 239000005720 sucrose Substances 0.000 claims description 6
- 229960004793 sucrose Drugs 0.000 claims description 6
- 239000003765 sweetening agent Substances 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 239000011159 matrix material Substances 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 239000003755 preservative agent Substances 0.000 claims description 4
- 230000002335 preservative effect Effects 0.000 claims description 4
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 4
- 239000000375 suspending agent Substances 0.000 claims description 4
- 239000008118 PEG 6000 Substances 0.000 claims description 3
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 claims description 3
- 206010036105 Polyneuropathy Diseases 0.000 claims description 3
- 239000006185 dispersion Substances 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 230000002458 infectious effect Effects 0.000 claims description 3
- 208000000813 polyradiculoneuropathy Diseases 0.000 claims description 3
- 239000002002 slurry Substances 0.000 claims description 3
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims description 2
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 108010011485 Aspartame Proteins 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 229920002101 Chitin Polymers 0.000 claims description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- 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 claims description 2
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 claims description 2
- 241000238631 Hexapoda Species 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 claims description 2
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 claims description 2
- LXIUJOQXHQOBSX-UHFFFAOYSA-N acetic acid chloroethene Chemical compound ClC=C.ClC=C.CC(O)=O LXIUJOQXHQOBSX-UHFFFAOYSA-N 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- 239000000605 aspartame Substances 0.000 claims description 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 2
- 229960003438 aspartame Drugs 0.000 claims description 2
- 229960002233 benzalkonium bromide Drugs 0.000 claims description 2
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 229960003720 enoxolone Drugs 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- 229940044949 eucalyptus oil Drugs 0.000 claims description 2
- 239000010642 eucalyptus oil Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 229940085605 saccharin sodium Drugs 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- WNIFXKPDILJURQ-UHFFFAOYSA-N stearyl glycyrrhizinate Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=O)OCCCCCCCCCCCCCCCCCC)(C)CC5C4=CC(=O)C3C21C WNIFXKPDILJURQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 208000028389 Nerve injury Diseases 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000000835 fiber Substances 0.000 claims 1
- 235000013312 flour Nutrition 0.000 claims 1
- 235000012907 honey Nutrition 0.000 claims 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims 1
- 239000010977 jade Substances 0.000 claims 1
- 229920000609 methyl cellulose Polymers 0.000 claims 1
- 239000001923 methylcellulose Substances 0.000 claims 1
- 235000010981 methylcellulose Nutrition 0.000 claims 1
- 230000008764 nerve damage Effects 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 238000012360 testing method Methods 0.000 abstract description 32
- 206010004954 Birth trauma Diseases 0.000 abstract description 5
- 208000019743 Cranial nerve injury Diseases 0.000 abstract description 5
- 230000004112 neuroprotection Effects 0.000 abstract description 3
- 241000700159 Rattus Species 0.000 description 23
- 241000699666 Mus <mouse, genus> Species 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 210000004556 brain Anatomy 0.000 description 12
- 238000000034 method Methods 0.000 description 9
- 230000001681 protective effect Effects 0.000 description 8
- 230000006378 damage Effects 0.000 description 7
- 102000003952 Caspase 3 Human genes 0.000 description 6
- 108090000397 Caspase 3 Proteins 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000014509 gene expression Effects 0.000 description 6
- 230000000302 ischemic effect Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 5
- 238000010171 animal model Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 210000003194 forelimb Anatomy 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000010410 reperfusion Effects 0.000 description 5
- 230000028527 righting reflex Effects 0.000 description 5
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- 102000003777 Interleukin-1 beta Human genes 0.000 description 4
- 108090000193 Interleukin-1 beta Proteins 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 4
- 210000001367 artery Anatomy 0.000 description 4
- 230000002146 bilateral effect Effects 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 229940099112 cornstarch Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 230000002980 postoperative effect Effects 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- INGWEZCOABYORO-UHFFFAOYSA-N 2-(furan-2-yl)-7-methyl-1h-1,8-naphthyridin-4-one Chemical compound N=1C2=NC(C)=CC=C2C(O)=CC=1C1=CC=CO1 INGWEZCOABYORO-UHFFFAOYSA-N 0.000 description 3
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 3
- 206010013786 Dry skin Diseases 0.000 description 3
- 102000001554 Hemoglobins Human genes 0.000 description 3
- 108010054147 Hemoglobins Proteins 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 206010033799 Paralysis Diseases 0.000 description 3
- 206010063837 Reperfusion injury Diseases 0.000 description 3
- 238000005345 coagulation Methods 0.000 description 3
- 230000015271 coagulation Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000004043 dyeing Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 230000009760 functional impairment Effects 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 210000003141 lower extremity Anatomy 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000001537 neural effect Effects 0.000 description 3
- 229960000715 nimodipine Drugs 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000004299 sodium benzoate Substances 0.000 description 3
- 235000010234 sodium benzoate Nutrition 0.000 description 3
- 239000011122 softwood Substances 0.000 description 3
- 238000007619 statistical method Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 208000037187 Autoimmune Experimental Neuritis Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 239000004376 Sucralose Substances 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 230000008033 biological extinction Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 230000001338 necrotic effect Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000000926 neurological effect Effects 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 210000004761 scalp Anatomy 0.000 description 2
- 210000003625 skull Anatomy 0.000 description 2
- 235000019408 sucralose Nutrition 0.000 description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010003084 Areflexia Diseases 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 238000008157 ELISA kit Methods 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
- 206010018852 Haematoma Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101001092197 Homo sapiens RNA binding protein fox-1 homolog 3 Proteins 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 208000003250 Mixed connective tissue disease Diseases 0.000 description 1
- 206010027925 Monoparesis Diseases 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 206010037714 Quadriplegia Diseases 0.000 description 1
- 102100035530 RNA binding protein fox-1 homolog 3 Human genes 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 240000003186 Stachytarpheta cayennensis Species 0.000 description 1
- 235000009233 Stachytarpheta cayennensis Nutrition 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 150000001875 compounds Chemical group 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 210000003618 cortical neuron Anatomy 0.000 description 1
- 229920003020 cross-linked polyethylene Polymers 0.000 description 1
- 239000004703 cross-linked polyethylene Substances 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 206010061811 demyelinating polyneuropathy Diseases 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 210000000613 ear canal Anatomy 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000002566 electrocorticography Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000000256 facial nerve Anatomy 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 210000005153 frontal cortex Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000006481 glucose medium Substances 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011694 lewis rat Methods 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 210000003007 myelin sheath Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000003455 parietal bone Anatomy 0.000 description 1
- 210000003681 parotid gland Anatomy 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 210000002243 primary neuron Anatomy 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000003497 sciatic nerve Anatomy 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000013042 tunel staining Methods 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 210000002385 vertebral artery Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 210000000216 zygoma Anatomy 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Vascular Medicine (AREA)
- Neurosurgery (AREA)
- Urology & Nephrology (AREA)
- Neurology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Fragrant happy amine is preparing the application in nerve protection medicine, belongs to the technical field of nerve protection medicine, and fragrant happy amine is treating or preventing the application in Cranial nerve injury as birth trauma drug, pharmaceutically acceptable auxiliary material is added in fragrant happy amine, useful clinically pharmaceutical dosage form is made.Specially fragrant happy amine treats or prevents the application in neurotrosis drug caused by cerebral hemorrhage in preparation, or fragrant happy amine treats or prevents the application in neurotrosis drug caused by cerebral ischemia re-pouring in preparation.Test confirms that fragrant happy amine has neuroprotection, and can effectively treat or prevent neurotrosis caused by cerebral ischemia re-pouring, neurotrosis caused by cerebral hemorrhage, the various neurotrosises such as Guillain Barre.
Description
Technical field
The invention belongs to the technical fields of nerve protection medicine, are related to a kind of new application of happy amine of sweet smell, are specifically related to sweet smell
Happy amine is preparing the application in nerve protection medicine.
Background technique
Fragrant happy amine (chemical name: trans- -2- (2,5- Dimethoxyphenyl) -3- (4- hydroxy 3-methoxybenzene base)-N- (4-
Oxybenzene ethyl) acrylamide) molecular structural formula is as follows:
Fragrant happy amine is the derivative of squqmosamide, and compound structure is at Chinese patent CN1445211 (publication number)
Middle disclosure, this patent describe " new squqmosamide derivative and its systems of institute of Materia Medica,Chinese Academy of Medical Sciences invention
Method and its pharmaceutical composition and purposes ".
Cranial nerve injury as birth trauma includes losing after brain trauma, cerebrovascular sclerosis (cerebral hemorrhage, cerebral thrombosis) sequelae, encephalitis and meningitis
The apoplexy sequelas such as disease, demyelinating disease.Fragrant happy amine be used to treat cerebral retrogressive disease, such as parkinson's syndrome at present
And Alzheimer's disease, for having not been reported in terms of ischemic and cerebral hemorrhage.
Summary of the invention
The present invention provides application of the fragrant happy amine in preparation treatment or prevention neurotrosis drug, especially prepares treatment
Or the application in prevention Cranial nerve injury as birth trauma drug.
Another scheme of the invention is to provide fragrant happy amine neurotrosis medicine caused by preparation treatment or prevention cerebral hemorrhage
Application in object.
Another scheme of the invention is to provide fragrant happy amine nerve caused by preparation treatment or prevention cerebral ischemia re-pouring
Application in damage medicine.
The present invention be realize its purpose the technical solution adopted is that:
Fragrant happy amine is preparing the application in nerve protection medicine, and fragrant happy amine is in the drug for treating or preventing Cranial nerve injury as birth trauma
Application, pharmaceutically acceptable auxiliary material is added in fragrant happy amine, useful clinically pharmaceutical dosage form is made.
Fragrant happy amine treats or prevents the application in neurotrosis drug caused by cerebral hemorrhage in preparation, or fragrant happy amine is controlled in preparation
The application in neurotrosis drug caused by cerebral ischemia re-pouring is treated or prevents, or comprehensive in preparation treatment or prevention guillain-Barre
Application in simulator sickness drug.
Pharmaceutically acceptable auxiliary material is selected from filler, disintegrating agent, lubricant, suspending agent, adhesive, sweetener, flavoring
One of agent, preservative, matrix, antioxidant or any combination.
Filler is selected from one of starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose
Or any combination；Disintegrating agent is selected from starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyethylene pyrrolidines
One of ketone, low-substituted hydroxypropyl cellulose, croscarmellose sodium or any combination；Lubricant be selected from magnesium stearate,
One of lauryl sodium sulfate, talcum powder, silica or any combination；Suspending agent is selected from polyvinylpyrrolidone, micro-
One of crystalline cellulose, sucrose, agar, hydroxypropyl methyl cellulose or any combination；Adhesive is selected from starch slurry, polyethylene
One of pyrrolidones, hydroxypropyl methyl cellulose or any combination；Sweetener is selected from saccharin sodium, aspartame, sucrose, sweet tea
One of sweet element, enoxolone or any combination；Corrigent is selected from sweetener and/or various essence；Preservative is selected from Ni Bo
Golden class, benzoic acid, sodium benzoate, sorbic acid and its esters, benzalkonium bromide, acetic acid chloroethene be fixed, one of eucalyptus oil or any
Combination；Matrix includes being selected from one of PEG6000, PEG4000, insect wax or any combination.Auxiliary material listed above is only to lift
Example explanation, does not constitute any restrictions to the range of technical solution of the present invention.
Pharmaceutical dosage form is tablet or capsule or granule or dry suspensoid agent or dripping pill or dispersion or injection.
The neurotrosis is neurotrosis, neurotrosis caused by cerebral hemorrhage or Green-bar caused by cerebral ischemia re-pouring
Sharp syndrome.
Beneficial effects of the present invention:
Test confirms that fragrant happy amine has neuroprotection, and can effectively treat or prevent cerebral ischemia re-pouring
Caused neurotrosis, neurotrosis caused by cerebral hemorrhage, the various neurotrosises such as actue infectious polyradiculoneuritis.
Specific embodiment
In order to confirm the technical effect of technical solution of the present invention, according to the preparation example in specific embodiment, it is made various
Drug.And carry out pharmacodynamic experiment, i.e. experimental example in specific embodiment, but these embodiments are not also to the technology of the present invention
The range of scheme constitutes any restrictions.
One, specific embodiment
The preparation of the fragrant happy amine tablet of embodiment 1
Sweet smell happy amine 150g, cornstarch 20g, lactose 325g, the magnesium stearate 5g that crushed 200 meshes respectively are weighed, it will
Fragrant happy amine, cornstarch, lactose mix well, and use 50ml pure water as adhesive, softwood is made, after the granulation of 18 meshes,
In 60 DEG C of dryings, dry particl crosses 16 mesh sieves, and magnesium stearate is added and mixes, according to 0.5g/ piece, tabletting to obtain the final product, is made 981 altogether
Piece finished product.
The preparation of the fragrant happy amine capsule of embodiment 2
Sweet smell happy amine 75g, cornstarch 212g, dextrin 10g, the magnesium stearate 3g that crushed 200 meshes respectively are weighed, it will be fragrant
Happy amine, cornstarch mix well, and with 60 DEG C of pure water 25ml, it is paste as adhesive that dextrin is molten, and softwood is made, uses
After the granulation of 20 meshes, in 65 DEG C of dryings, dry particl crosses 18 mesh sieves, and magnesium stearate is added and mixes, according to every capsule 0.3g
It is packed into No. 1 capsule to obtain the final product, 961 finished products is made altogether.
The preparation of the fragrant happy amine granule of embodiment 3
Sweet smell happy amine 150g, cane sugar powder 7339g, edible essence 1g, the soluble starch 10g that crushed 200 meshes respectively are weighed,
Fragrant happy amine, cane sugar powder, edible essence are mixed well, with 100 DEG C of pure water 100ml, soluble starch is reconstituted into starch slurry and is made
For adhesive, softwood is made, after the granulation of 20 meshes, in 60 DEG C of dryings, dry particl crosses 18 mesh sieves, according to 7.5g/ bags, dress
Bag, is made 973 bags of finished products of finished product altogether.
The preparation of the fragrant happy amine mixture of embodiment 4
Fragrant happy amine 150g, Sucralose 100g, sodium benzoate 0.5g are weighed, hydroxypropyl methyl cellulose sodium 5g eats perfume
Smart 1g, sodium benzoate is spare with the dissolution of 10ml ethyl alcohol, and hydroxypropyl methyl cellulose sodium is spare with the dissolution of 100ml pure water, by benzene
Formic acid sodium ethoxide solution, hydroxypropyl methyl cellulose sodium solution, fragrant happy amine, 8000ml is added in Sucralose, edible essence jointly
In pure water, stirring to all supplementary materials is dissolved, and is settled to 10000ml, is stirred, according to 10ml/ branch encapsulating to poly- second
In alkene bottle, it there are 991 finished products.
The preparation of the fragrant happy amine dispersion of embodiment 5
Mixing is sufficiently stirred in the PEG6000 for weighing the fragrant happy amine of 500g and 1500g melting, after placing room temperature, moves to -20 DEG C
Refrigerator overnight is crushed at low temperature up to fragrant happy amine solid dispersions.
Two, it tests
Protective effect of the fragrant happy amine of experimental example 1 to Cranial nerve injury as birth trauma caused by cerebral ischemia and cerebral ischemia re-pouring
1. instrument and material
SJ42 type polygraph (Shanghai Medical Electric Instrument Factory)；
SXP -1B type surgical operation microscope (Shanghai medical optical instrument factory)；
Test medicine, the sample prepared according to the method for embodiment 1；Positive drug: nimodipine tablet (sub- treasured medicine company, 20mg/
Piece, lot number 1408015)；Tablet is crushed, is extracted and is filtered with ethyl alcohol, after volatilizing, add pure water to be made into aqueous solution stand-by；
Wistar rat (250~350g, male) is provided by Hebei Medical University's Experimental Animal Center, raising in (25 ±
2) DEG C purification ventilation animal house, ad lib and drinking-water.
2. method and result
The foundation of 2.1 animal models
2.1.1 permanent cerebral ischemia model
With 12% chloral hydrate anesthesia (350mg/kg, ip), lateral position is fixed on operating table rat, along right external auditory canal with
Skin about 2cm is cut perpendicular to line in the midpoint of right eye outer canthus line, then successively cuts under surgical operation microscope along temporalis middle line
Disconnected temporalis and masseter, these muscle are separated to two sides, exposure jugal bridge, and when operation pays attention to protecting facial nerve and the parotid gland.It removes
Jugal bridge, and fascia is cut off along skull, expose temporo precoila.One is bored at united front lower place about 2mm before cheekbone and squamosal bone
The cranium window of diameter 2mm, through endocranium with regard to the thin vessels of visible one more straight and few branch, as intraluminal middle cerebral artery occlusion in rats
(MCA).With 1mm to the MCA between venae cerebri inferiores in coagulation fulguration solidification tractus olfactorius.It is light with fritter musculature after blocking MCA
It spreads on cranium window, reaches anastalsis, postoperative withdrawal of currency from circulation raising.Above procedure is carried out in constant room temperature.
2.1.2 complete brain ischemia reperfusion model
With 12% water platform chloralization before rat, the exposure atlas foramen transversarium after pillow solidifies bilateral with coagulation fulguration
Vertebral artery, drilling placement Cortical ECoG pole, is fixed with dental base acrylic resin powder on skull.Then it is dynamic to make a kerf separation Bilateral Cervical in neck
Arteries and veins, with No. 1 silk suture wound.It is postoperative for 24 hours, rat it is awake when, with the not damaged artery clamp with silicone tube by bilateral carotid arteries
Folder closes, that is, causes the occlusion of 4 radicular arteries to cause global cerebral ischemia, unclamp artery clamp after 1h.Ischemic stage and to fill time phase again be 1h.With
It is asked when electroencephalogram restores after physiograph record Neurons Against Cerebral Ischemia electrograph extinction time and recovery Reperfu- sion and righting reflex restores
Time.The electroencephalogram serious inhibition person that do not disappear or do not occur rejects without exception in all ischemic stages.
The protective effect of 2.2 pairs of permanent cerebral ischemias damage
2.2.1 grouping
Permanent cerebral ischemia rat model 50 are taken, is randomly divided into 5 groups, every group 10, respectively negative control group (1ml/
Kg), positive drug control group (Nimodipine, 2mg/kg), test medicine group high, medium and low dosage group (respectively 8mg/Kg, 4mg/
Kg,2mg/Kg).After coagulation MCA mono- hour, tail vein injection administration, administered volume is 1ml/Kg, and insufficient section adds physiology salt
Water is supplied.
2.2.2 evaluation index and result
Postoperative rat for 24 hours carries out neurological deficit score when awake: a, mention rat-tail away from ground about 33cm, observe forelimb feelings
Condition, two forelimb of normal rat symmetrically stretch to ground, if left shoulder inward turning, otherwise it is 0 point that receipts person in left fore, which is chosen as 4 points,；b,
By pushing away respectively on the sliding floor of rat horizontalization, left (or right) shoulder is mobile to opposite side, checks the resistance resisted and pushed, normal rat bilateral
Resistance is obvious and symmetrical, if drop in resistance, is chosen as 1~3 point depending on fall；C, two forelimb of rat is set on a metal mesh,
The Muscle tensility of forelimb is observed, two forelimb tension of normal rat is obvious and symmetrical, if left fore tension declines, depending on decline degree
Weight is chosen as 0~3 point.Three's summation is comprehensive point.Broken end takes brain after scoring, and right side MCA is further confirmed with microscope and is burnt
Situation and brain parenchym damage are burnt, slice and TTC dyeing, necrotic area and right hemisphere weighing is carried out, calculates downright bad percentage
Rate (percentage that necrotic area accounts for right hemisphere), the results are shown in Table 1.
Protective effect of 1 test medicine of table to permanent cerebral ischemia injury rats
Note: P < 0.05 compared with the control group *.
It can be seen that test medicine, which shows to reduce brain necrosis in various dose group, goes the effect of weight, middle high dose group can be with
It is obviously improved rat behavior defect, shows that test medicine has protective effect to permanent cerebral ischemia damage.
The effect of 2.3 pairs of ischemical reperfusion injuries
2.3.1 grouping
Ischemia-Reperfusion Injury Model rat 53 are taken, 5 groups, respectively negative control group (1ml/Kg) are randomly divided into, sun
Property medicine control group (Nimodipine, 2mg/kg), test medicine group high, medium and low dosage group (respectively 8mg/Kg, 4mg/Kg, 2mg/
Kg).For l/min through rat tail vein drug administration by injection, administered volume is 1ml/Kg before ischemic stage, and insufficient section adds physiological saline
It supplies.
2.3.2 evaluation index and result
Evaluation index is that the disappear recovery time of electroencephalogram and the righting reflex after fiery time, Reperfu- sion of ischemic stage electroencephalogram restores
Time.After Reperfu- sion, broken end takes brain immediately, claims weight in wet base, (the small fourth of the difference that front and back is weighed twice that 60 DEG C drying to constant weight
1%) brain water content of each group is calculated by brain water content=(brain wet weight-brain stem weight)/brain wet weight × 100% to get dry weight, tied
Fruit is shown in Table 2.
Protective effect of 2 test medicine of table to Brain Ischemia-reperfusion Injury
Note: * compared with the control group, P < 0.05；# is compared with positive drug group, P < 0.05.
It can be seen that test medicine can significantly extend rats after cerebral ischemic reperfusion Neurons Against Cerebral Ischemia electrograph extinction time, hence it is evident that shorten
Electroencephalogram recovery time and righting reflex recovery time, and the case where be obviously improved brain edema.
Protective effect of the fragrant happy amine of experimental example 2 to neurotrosis caused by cerebral hemorrhage
1 materials and methods
1.1 experimental animal
Experimental animal is cleaning grade C57BL/6 mouse, male, and 6~8 week old, 16~20g is tested by Hebei Medical University
Animal center provides.Before experiment, ad lib water inlet.
1.2 primary drugs and reagent
Fragrant happy amine raw material (self-control, lot number 20150117)；DW-2000 stereotaxic apparatus (Chengdu Tai Meng company)；IL-1
β, TNF-α and Caspase-3ELISA kit (eBioscience company, the U.S.), NeuN rabbit anti-mouse and Caspase-3 rabbit
Anti-mouse monoclonal antibody (Abcam company, the U.S.)；Goat anti-rabbit igg secondary antibody, TUNEL kit, ELISA kit and
Hoeschst dyestuff (Invitrogen company, the U.S.)；Neuronal Medium-basal culture medium, DMEM in high glucose and FBS (beauty
Gibco company, state).
1.3 mouse brain cortical neuron originally cultures
The C57 mouse of 18d gestational age is taken, tire mouse brain frontal cortex is stripped under microscope, removes meninx and blood vessel.Eye scissors are cut
It is broken to about 1mm × 1mm × 1mm, 0.125% 37 DEG C of trypsase incubation 10min, is blown and beaten 15~20 times, 2500r/min centrifugation
10min.Supernatant is abandoned, is resuspended with complete medium containing the DMEM high glucose medium of 10% fetal calf serum, 2 μm of ol/L glutamine
Cell precipitation counts cell to 5 × 105/ml, is inoculated in the coated cell training of poly-l-lysine (Poly-L-Lysine)
It supports in plate.It is placed in 37 DEG C, cultivates in the incubator containing 5%CO2 and saturated humidity, change liquid afterwards for 24 hours to containing 2%B27,0.4 × 10-
4
Mol/L cytarabine (Ara-C) and 0.5mM glutamine NeuronalMedium-basal culture medium, it is later every
It is measured every 72h half and changes liquid, culture to 8d.Experimental group: (1) blank control group is physiological saline group；(2) experimental group is 2 tested
20 μm of ol/L hemoglobins (Hb) are added into culture solution in drug concentration group (48.5mg and 4.85mg/L)；(3) experimental comparison group
For hemoglobin (Hb), handled with 20 μm of ol/L hemoglobins (Hb).
The preparation of 1.4 mouse cerebral hemorrhage (ICH) models
C57 mouse is injected with (40mg/kg) intraperitoneal anesthesia of 10% chloraldurate, and prostrate is fixed on mouse brain stereoscopic localized
On instrument, scalp alcohol disinfecting, exposure parietal bone takes 50 μ l of arteria caudalis blood, is injected to left brain striatum with syringe pump (5 μ l/min)
(2.5mm on the right side of mouse bregma, forward 0.2mm, hemad 3.5mm)；Syringe needle stops 8~10min after injection, extracts syringe needle doctor
With bone wax closed injection hole, incision of scalp is sutured.Sham-operation group injects same amount of normal saline in the same way.
1.5 groupings are tested with administration
It is grouped into sham-operation group, ICH model group, 10mg/kg and 20mg/kg test medicine treatment group, each 6 mouse.Respectively
Group does cerebral hemorrhage operation, in 2h, 12h, for 24 hours, 48h, 72h, 96h, 120h continuous gavage give relative medicine (fragrant happy amine physiology
Salt water dissolution is prepared, and sham-operation group and ICH model group mouse are given only continuous physiological saline stomach-filling processing), 1 time a day.
1.6 cerebral hemorrhage mouse Nerve functional impairments score (NDS)
36 mouse are randomly divided into 4 groups.After the postoperative successive administration of each group, and 1d, 3d, 5d, 7d after administration is to each
Processing group mouse makees neurological functional deficit scale, and Neuroscore is considered as the success of ICH model in 2 grades or more of mouse,
It is included in experimental study object, rejects scoring in 0 grade or 4 grades or more of model mice, every group of reservation 6 is only tested after rejecting.
Include mainly walk test, mention tail reflection, balance test, sensory test, areflexia and dyskinesis.Maximum is scored at 18
Point, light-duty wound: 1~6 point；Medium-sized wound: 7~12 points；Heavy type wound: 13~18 points.
The measurement of 1.7 inflammatory factor expressions
24 mouse are separately taken to be randomly divided into 4 groups referring to modeling and administration under " 1.4-1.5 " item, ELISA method measures ICH hemotoncus
TNF-α, the content of IL-1 β and Caspase-3, take sham-operation group, ICH model group, test medicine various dose in surrounding tissue
Treatment group mouse took cephalophyma stove week to organize 0.5g at ICH the 1st, 3,5,7 day, the PBS of pre-cooling is added, makes that mass concentration is made
For 10% brain tissue homogenate, 4 DEG C, 4000r/min, it is centrifuged 15min, -70 DEG C of low temperature refrigerators is set and saves backup.ELISA detection
The expression situation of change of TNF-α, IL-1 β and Caspase-3 in tissue homogenate.
1.8 statistical analysis
For statistical analysis to all data using GraphPadPrism5 software, data are all made of χ ± s expression, metering
Apply mean t inspection comparing between data two-by-two, P < 0.05 is that there were significant differences.
2 results
The survival rate of 2.1 neure damages
Pre-stage test confirms that test medicine has no significant effect the growth of neuron, neural originally culture experiment investigation
Test medicine has protective effect to Hb induced neuronal injury, light under the microscope, TUNEL and Caspase-3 apoptosis is real
It tests in terms of average, the results are shown in Table 3.
Protective effect (200 times, N=3) of 3 test medicine of table for neurotrosis
| Group | TUNEL staining positive cells number | Caspase-3 staining positive cells number |
| Control group | 1 | 1 |
| Model group | 17# | 10# |
| Test medicine group (4.85mg/L) | 8* | 6* |
| Test medicine group (48.5mg/L) | 6* | 5* |
Note: # compared with the control group, P < 0.05；* compared with model group, P < 0.05.
As seen from the above table, for Hb induction primary neuronal cell damage, test medicine can significantly improve primary neuron
Cell viability has apparent neuroprotection.
The influence of 2.2 pairs of cerebral hemorrhage mouse Nerve functional impairments scoring
Neurological functional deficit scale (NDS) is that the important references of neurotrosis degree after assessing mouse cerebral hemorrhage refer to
Mark, the test result show that control group NDS is substantially less than model group, it was demonstrated that modeling success.Two dosage groups of test medicine are the 3rd
It, the 5th day, the 7th day NDS scoring be substantially less than model group, the results are shown in Table 4
The influence that 4 test medicine of table scores for cerebral hemorrhage mouse Nerve functional impairment
| Group | N | 1st day NDS | 3rd day NDS | 5th day NDS | 7th day NDS |
| Control group | 6 | 1.9±0.5 | 1.8±0.7 | 1.8±0.4 | 1.8±0.5 |
| Model group | 6 | 14.1±1.4# | 11.5±1.2# | 9.2±0.9# | 8.3±0.6# |
| Test medicine group (10mg/Kg) | 6 | 13.7±1.6* | 8.5±1.1* | 6.5±0.8* | 4.2±0.4* |
| Test medicine group (20mg/Kg) | 6 | 12.9±1.1* | 6.8±0.9* | 5.1±0.6* | 3.9±0.5* |
Note: # compared with the control group, P < 0.05；* compared with model group, P < 0.05.
As can be seen from the above results, test medicine can improve cerebral hemorrhage mouse Nerve function, and have certain continue
Property.
The influence of 2.3 pairs of inflammatory factor expressions
The TNF-α of Hematoma, the content of IL-1 β and Caspase-3 are referring to table 5 after each group mouse ICH.
Influence of 5 test medicine of table for inflammatory factor expression after mouse ICH
Note: # compared with the control group, P < 0.05；* compared with model group, P < 0.05.
As can be seen from the above results, test medicine has significant inflammatory factor expression after reducing ICH, and it is scorching to mitigate part
Disease reaction, neurotrosis after effective protection bleeding.
Therapeutic effect of the fragrant happy amine of experimental example 3 for Guillain Barre syndrome
Actue infectious polyradiculoneuritis (GBS) is also known as acute inflammatory demyelinating polyneuropathy, be with peripheral nerve and
The inflammatory reaction of the demyelinate and thin vessels peripheral lymphocyte and macrophage of nerve root is the autoimmunity disease of pathological characteristic
Disease.It is similar to mankind GBS in the clinical manifestation of experimental autoimmune neuritis, pathogenesis, it is the reason of generally acknowledged research GBS
Think animal model.This experiment observes the traditional chinese medicine composition of the invention by production rat experimental autoimmune nerve inflammation model
The neuritic effect of granules of rats experimental autoimmune.
1. materials and methods
1.1 animals and grouping: Lewis rat, male, 200-220g, tie up tonneau China experimental animal technology purchased from Beijing by 36
Co., Ltd.Rat is randomly divided into: Normal group, model group, treatment group (tablet prepared according to the method for embodiment 1, agent
Amount: according to 20mg/kg, treatment group), every group 12.Model group and rats in normal control group give equal amount of distilled water.
1.2 modelings and administration: the double 200 μ l antigen emulsions of hind leg subplantar injection of rat (contain 200 μ g peripheral nerve myelin sheath antigens
P0180-199 polypeptide, 1.5mgH37Ra tubercle bacillus, 100 μ l 0.1mol/L phosphate buffers and 100 μ l complete Freund assistants
Agent is mixed into water-in-oil emulsion with pin type homogenizer).Start to carry out groups of animals gastric infusion on the day of modeling, continuous 15 days.
1.3 signs scoring: 0 grade: without exception；1 grade: tail portion tension reduces；2 grades: tail paralysis, righting reflex excalation；3
Grade: righting reflex missing；4 grades: ataxic gait, posture are abnormal；5 grades: hind leg paresis；6 grades: moderate paralysis；7 grades: hind leg is serious
Paralysis；8 grades: quadriplegia；9 grades: dying；10 grades: dead.
1.4HE dyeing: putting to death rat, is immediately disconnected sciatic nerve, carries out HE dyeing, calculates the average inflammation in 5 visuals field
Property cell number.
1.5 flow cytomery INF- γ, Th17: rat is put to death, inguinal lymph nodes is taken, prepares the single core of lymph node
Cell suspension, flow cytomery INF- γ, Th17 are horizontal.
1.6ELISA detects antibody: putting to death rat, leaves and takes cardiac blood, P0180-199 polypeptide is dissolved in packet by centrifuging and taking serum
By liquid, the confining liquid containing 10% fetal calf serum is added and is incubated for, the rabbit-anti anti-rat IgG antibody of biotin labeling is added, is added afterwards peppery
The Streptavidin of root peroxidase labelling, after terminating reaction, as a result microplate reader measurement is indicated with OD value.
1.7 statistical methods: all data mean ± standard deviationIt indicates.Using SPSS statistical package, T is carried out
It examines.
2 results
The variation of 2.1 signs scoring: compared with model group, the initial disease time for the treatment of group is obviously prolonged (P < 0.01)；It controls
The scoring for the treatment of group peak period is substantially reduced (P < 0.01), is shown in Table 6.
The comparison of 6 each group sign of table scoring
Compared with model group:△△P<0.01。
The variation of 2.2INF- γ, Th17 level: compared with Normal group, the horizontal obvious liter of model group INF- γ, Th17
High (P < 0.01), compared with model group, treatment group INF- γ, Th17 level are remarkably decreased (P < 0.01).
The comparison of table 7 each group INF- γ, Th17 level
| Group | INF-γ | Th17 |
| Normal group | 4.7±1.2 | 7.1±1.3 |
| Model group | 21.3±4.1** | 19.8±3.2** |
| Treatment group | 7.9±2.1△△ | 8.6±1.9△△ |
Note: compared with Normal group: P < 0.01 * *；Compared with model group: P < 0.01 △ △.
The variation of 2.3 P0180-199 antibody: compared with Normal group, model group OD value is significantly raised (P < 0.01),
Compared with model group, treatment group's OD value is remarkably decreased (P < 0.01).
The comparison of 8 each group OD value of table
| Group | OD value |
| Normal group | 0.10±0.03 |
| Model group | 1.17±0.21** |
| Treatment group | 0.31±0.06△△ |
Note: compared with Normal group: P < 0.01 * *；Compared with model group: P < 0.01 △ △.
3 conclusions
Fragrant happy amine can reduce experimental autoimmune neuritis clinical symptoms, reduces INF- γ, Th17 and resists
The generation of P0180-199 antibody shows that fragrant happy amine has the function for the treatment of Guillain Barre syndrome.
Claims (6)
1. fragrant happy amine is preparing the application in nerve protection medicine, which is characterized in that fragrant happy amine is treating or preventing neurotrosis
Drug in application, pharmaceutically acceptable auxiliary material is added in fragrant happy amine, useful clinically pharmaceutical dosage form is made.
2. the happy amine of sweet smell according to claim 1 is preparing the application in nerve protection medicine, which is characterized in that fragrant happy amine exists
Preparation treats or prevents the application in neurotrosis drug caused by cerebral hemorrhage, or fragrant happy amine treats or prevents cerebral ischemia again in preparation
Application in neurotrosis drug caused by being perfused.
3. the happy amine of sweet smell according to claim 1 is preparing the application in nerve protection medicine, which is characterized in that pharmaceutically may be used
The auxiliary material of receiving is selected from filler, disintegrating agent, lubricant, suspending agent, adhesive, sweetener, corrigent, preservative, matrix, resists
One of oxygen agent or any combination.
4. the happy amine of sweet smell according to claim 3 is preparing the application in nerve protection medicine, which is characterized in that filler choosing
From one of starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose or any combination；Disintegrating agent
Selected from starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low-substituted hydroxypropyl fiber
One of element, croscarmellose sodium or any combination；Lubricant is selected from magnesium stearate, lauryl sodium sulfate, cunning
One of mountain flour, silica or any combination；Suspending agent is selected from polyvinylpyrrolidone, microcrystalline cellulose, sucrose, fine jade
One of rouge, hydroxypropyl methyl cellulose or any combination；Adhesive is selected from starch slurry, polyvinylpyrrolidone, hydroxypropyl
One of methylcellulose or any combination；Sweetener is in saccharin sodium, aspartame, sucrose, honey element, enoxolone
One kind or any combination；Corrigent is selected from sweetener and/or essence；Preservative is selected from parabens, benzoic acid, benzoic acid
Sodium, sorbic acid and its esters, benzalkonium bromide, acetic acid chloroethene be fixed, one of eucalyptus oil or any combination；Matrix includes being selected from
One of PEG6000, PEG4000, insect wax or any combination.
5. the happy amine of sweet smell according to claim 1 is preparing the application in nerve protection medicine, which is characterized in that pharmaceutical dosage form
For tablet or capsule or granule or dry suspensoid agent or dripping pill or dispersion or injection.
6. the happy amine of sweet smell according to claim 1 is preparing the application in nerve protection medicine, which is characterized in that the nerve
Damage is neurotrosis, neurotrosis caused by cerebral hemorrhage or actue infectious polyradiculoneuritis caused by cerebral ischemia re-pouring.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811610138.8A CN109528699B (en) | 2018-12-27 | 2018-12-27 | Application of phentermine in preparing neuroprotective drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811610138.8A CN109528699B (en) | 2018-12-27 | 2018-12-27 | Application of phentermine in preparing neuroprotective drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109528699A true CN109528699A (en) | 2019-03-29 |
| CN109528699B CN109528699B (en) | 2022-02-15 |
Family
ID=65858161
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811610138.8A Active CN109528699B (en) | 2018-12-27 | 2018-12-27 | Application of phentermine in preparing neuroprotective drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109528699B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1445211A (en) * | 2002-03-20 | 2003-10-01 | 中国医学科学院药物研究所 | New amide ramification of sweetsop as well as its preparing method, its medication composition and usage |
| EP1810965A1 (en) * | 2004-10-13 | 2007-07-25 | Eisai R&D Management Co., Ltd. | Hydrazide derivatives |
-
2018
- 2018-12-27 CN CN201811610138.8A patent/CN109528699B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1445211A (en) * | 2002-03-20 | 2003-10-01 | 中国医学科学院药物研究所 | New amide ramification of sweetsop as well as its preparing method, its medication composition and usage |
| EP1810965A1 (en) * | 2004-10-13 | 2007-07-25 | Eisai R&D Management Co., Ltd. | Hydrazide derivatives |
Non-Patent Citations (2)
| Title |
|---|
| BO MA 等: "Neuroprotective effects of compound FLZ in an ischemic model mediated by improving cerebral blood flow and enhancing Hsp27 expression", 《BRAIN RESEARCH》 * |
| 张建军 等: "新型化合物FLZ对脑卒中动物的保护作用", 《生物物理学报》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109528699B (en) | 2022-02-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2732559T3 (en) | Compositions comprising acid extracts of mastic | |
| AU2017317950B2 (en) | Sublingual pharmaceutical composition of edaravone and (+)-2-borneol | |
| EP2385835B1 (en) | Use of deuterium oxide for treating viral diseases of the eye | |
| CN109568253A (en) | Liquid preparation | |
| WO2009155777A1 (en) | The use and method of the compound of fasudil and the pharmaceutical composition thereof | |
| CN107312069A (en) | The treatment peptide of excititoxic associated injury | |
| JP2021505650A (en) | Ophthalmic drug preparations and their use | |
| CN110724203A (en) | A short peptide that promotes nuclear translocation of TFEB and linear short peptide based thereon and its application in reducing cerebral ischemia injury | |
| KR101909906B1 (en) | Composition for Treatment of Brain Stroke by Intranasal Delivery | |
| CN108143733B (en) | Anesthetic analgesic pharmaceutical composition and preparation method thereof | |
| CN102625707A (en) | New applications of HIP/PAP or its derivatives | |
| CN101744878B (en) | Water-soluble salvia miltiorrhiza extractive, preparation and application thereof | |
| KR101740163B1 (en) | Use of 3-n-butyl-1-isoindolinone in preparation of drugs for preventing and treating cerebral infarction | |
| CN109528699A (en) | Fragrant happy amine is preparing the application in nerve protection medicine | |
| WO2016131321A1 (en) | Use of nadph in preparing medicines for treatment of cardiovascular and cerebrovascular diseases | |
| CN103860565B (en) | Medicinal composition for treating diabetes hepatic fibrosis | |
| US20220110953A1 (en) | Methods and compositions for treating human papillomavirus (hpv)-induced cancers | |
| CN107296808B (en) | Application of compound epothilone B in preparation of medicine for repairing corneal nerve injury | |
| WO2016131320A1 (en) | Use of nadph in preparing medicines for treatment of heart diseases | |
| CN115010790A (en) | Nano small peptide FG and application thereof in preparation of drugs for treating and preventing fundus vascular diseases | |
| CN108295082A (en) | Application of the trifloroside in preventing cerebral ischemia re-pouring injured drug | |
| CN107281208B (en) | Pharmaceutical composition for preventing and treating cerebral apoplexy | |
| CN107441087A (en) | A kind of compound medicament composition with treatment senile dementia effect and application thereof | |
| CN106668050A (en) | Pharmaceutical composition for treating atherosclerosis and application of pharmaceutical composition | |
| JP2024512842A (en) | Use of α-asalone in the manufacture of a drug for the prevention or treatment of hemorrhagic stroke |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |