CN116370471A - 一种用于脑卒中的组合物 - Google Patents
一种用于脑卒中的组合物 Download PDFInfo
- Publication number
- CN116370471A CN116370471A CN202111585029.7A CN202111585029A CN116370471A CN 116370471 A CN116370471 A CN 116370471A CN 202111585029 A CN202111585029 A CN 202111585029A CN 116370471 A CN116370471 A CN 116370471A
- Authority
- CN
- China
- Prior art keywords
- composition
- group
- methyl
- phenyl
- borneol
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 51
- 208000006011 Stroke Diseases 0.000 title claims abstract description 17
- 230000002490 cerebral effect Effects 0.000 title claims abstract description 15
- 206010008190 Cerebrovascular accident Diseases 0.000 title claims abstract description 13
- 235000019156 vitamin B Nutrition 0.000 claims abstract description 15
- 239000011720 vitamin B Substances 0.000 claims abstract description 15
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 claims description 45
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 claims description 45
- 229940116229 borneol Drugs 0.000 claims description 44
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 claims description 43
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 claims description 43
- ZNOVTXRBGFNYRX-ABLWVSNPSA-N levomefolic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-ABLWVSNPSA-N 0.000 claims description 35
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 32
- 235000007635 levomefolic acid Nutrition 0.000 claims description 32
- 239000011578 levomefolic acid Substances 0.000 claims description 31
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 claims description 25
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 16
- 235000019152 folic acid Nutrition 0.000 claims description 16
- 239000011724 folic acid Substances 0.000 claims description 16
- 229960000304 folic acid Drugs 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 11
- FDJOLVPMNUYSCM-UVKKECPRSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2,7, Chemical compound [Co+3].N#[C-].C1([C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)[N-]\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O FDJOLVPMNUYSCM-UVKKECPRSA-L 0.000 claims description 10
- RBCOYOYDYNXAFA-UHFFFAOYSA-L (5-hydroxy-4,6-dimethylpyridin-3-yl)methyl phosphate Chemical compound CC1=NC=C(COP([O-])([O-])=O)C(C)=C1O RBCOYOYDYNXAFA-UHFFFAOYSA-L 0.000 claims description 6
- 238000001727 in vivo Methods 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- RADKZDMFGJYCBB-UHFFFAOYSA-N Pyridoxal Chemical compound CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims description 4
- 229930003270 Vitamin B Natural products 0.000 claims description 4
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 claims description 4
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 claims description 4
- NHZMQXZHNVQTQA-UHFFFAOYSA-N pyridoxamine Chemical compound CC1=NC=C(CO)C(CN)=C1O NHZMQXZHNVQTQA-UHFFFAOYSA-N 0.000 claims description 4
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- OAJLVMGLJZXSGX-NDSREFPTSA-L (2r,3s,4s,5r)-2-(6-aminopurin-9-yl)-5-methanidyloxolane-3,4-diol;cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12 Chemical compound [Co+3].O[C@H]1[C@H](O)[C@@H]([CH2-])O[C@H]1N1C2=NC=NC(N)=C2N=C1.C1([C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)[N-]\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O OAJLVMGLJZXSGX-NDSREFPTSA-L 0.000 claims description 2
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 claims description 2
- 235000000639 cyanocobalamin Nutrition 0.000 claims description 2
- 239000011666 cyanocobalamin Substances 0.000 claims description 2
- 229960002104 cyanocobalamin Drugs 0.000 claims description 2
- DQOCFCZRZOAIBN-WZHZPDAFSA-L hydroxycobalamin Chemical compound O.[Co+2].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O DQOCFCZRZOAIBN-WZHZPDAFSA-L 0.000 claims description 2
- 229960005321 mecobalamin Drugs 0.000 claims description 2
- 239000002207 metabolite Substances 0.000 claims description 2
- 235000007672 methylcobalamin Nutrition 0.000 claims description 2
- 239000011585 methylcobalamin Substances 0.000 claims description 2
- JEWJRMKHSMTXPP-BYFNXCQMSA-M methylcobalamin Chemical compound C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O JEWJRMKHSMTXPP-BYFNXCQMSA-M 0.000 claims description 2
- 229960003581 pyridoxal Drugs 0.000 claims description 2
- 235000008164 pyridoxal Nutrition 0.000 claims description 2
- 239000011674 pyridoxal Substances 0.000 claims description 2
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 claims description 2
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 claims description 2
- 229960001327 pyridoxal phosphate Drugs 0.000 claims description 2
- 235000008151 pyridoxamine Nutrition 0.000 claims description 2
- 239000011699 pyridoxamine Substances 0.000 claims description 2
- ZMJGSOSNSPKHNH-UHFFFAOYSA-N pyridoxamine 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(CN)=C1O ZMJGSOSNSPKHNH-UHFFFAOYSA-N 0.000 claims description 2
- 235000008160 pyridoxine Nutrition 0.000 claims description 2
- 239000011677 pyridoxine Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229940011671 vitamin b6 Drugs 0.000 claims description 2
- ASARMUCNOOHMLO-WLORSUFZSA-L cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2s)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O ASARMUCNOOHMLO-WLORSUFZSA-L 0.000 claims 1
- 235000002639 sodium chloride Nutrition 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 18
- 230000002195 synergetic effect Effects 0.000 abstract description 6
- 241000700159 Rattus Species 0.000 description 50
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 27
- 206010008118 cerebral infarction Diseases 0.000 description 20
- 238000002347 injection Methods 0.000 description 19
- 239000007924 injection Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 208000026106 cerebrovascular disease Diseases 0.000 description 12
- 230000006870 function Effects 0.000 description 12
- 125000000468 ketone group Chemical group 0.000 description 10
- 150000002576 ketones Chemical class 0.000 description 10
- -1 lipid peroxide Chemical class 0.000 description 9
- 210000005036 nerve Anatomy 0.000 description 9
- 201000006474 Brain Ischemia Diseases 0.000 description 8
- 206010008120 Cerebral ischaemia Diseases 0.000 description 8
- 230000000144 pharmacologic effect Effects 0.000 description 8
- 230000009471 action Effects 0.000 description 7
- 125000002604 borneol group Chemical group 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 230000001105 regulatory effect Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 206010063837 Reperfusion injury Diseases 0.000 description 6
- 238000010276 construction Methods 0.000 description 6
- 210000003414 extremity Anatomy 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 208000032382 Ischaemic stroke Diseases 0.000 description 5
- 210000005013 brain tissue Anatomy 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 229930003779 Vitamin B12 Natural products 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 210000001168 carotid artery common Anatomy 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 235000019163 vitamin B12 Nutrition 0.000 description 3
- 239000011715 vitamin B12 Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 208000007976 Ketosis Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 241000475481 Nebula Species 0.000 description 2
- 108010093894 Xanthine oxidase Proteins 0.000 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 description 2
- 239000005456 alcohol based solvent Substances 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 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 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 239000005453 ketone based solvent Substances 0.000 description 2
- 230000004140 ketosis Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000010410 reperfusion Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 239000006190 sub-lingual tablet Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 210000000707 wrist Anatomy 0.000 description 2
- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 1
- POAOYUHQDCAZBD-UHFFFAOYSA-N 2-butoxyethanol Chemical compound CCCCOCCO POAOYUHQDCAZBD-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010007247 Carbuncle Diseases 0.000 description 1
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 208000015220 Febrile disease Diseases 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 206010060840 Ischaemic cerebral infarction Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010061876 Obstruction Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 102100033220 Xanthine oxidase Human genes 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 208000002399 aphthous stomatitis Diseases 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- YYRMJZQKEFZXMX-UHFFFAOYSA-L calcium bis(dihydrogenphosphate) Chemical compound [Ca+2].OP(O)([O-])=O.OP(O)([O-])=O YYRMJZQKEFZXMX-UHFFFAOYSA-L 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 210000000269 carotid artery external Anatomy 0.000 description 1
- 210000004004 carotid artery internal Anatomy 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 231100000895 deafness Toxicity 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000004438 eyesight Effects 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 208000014617 hemorrhoid Diseases 0.000 description 1
- 208000021760 high fever Diseases 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 229940025708 injectable product Drugs 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019691 monocalcium phosphate Nutrition 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 230000007658 neurological function Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000002385 vertebral artery Anatomy 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4415—Pyridoxine, i.e. Vitamin B6
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种用于预防脑卒中的组合物,具体地涉及含有有效含量的B族维生素。本发明提供的组合物对脑卒中具有显著的协同治疗效果,属于药学领域。
Description
技术领域
本发明涉及治疗脑卒中的产品,属于药学领域。
背景技术
脑卒中是一种急性脑血管疾病,是由于脑部血管突然破裂或因血管阻塞导致血液不能流入大脑而引起脑组织损伤的一组疾病,包括缺血性和出血性卒中。缺血性卒中的发病率高于出血性卒中,占脑卒中总数的60%~70%。颈内动脉和椎动脉闭塞和狭窄可引起缺血性脑卒中,年龄多在40岁以上,男性较女性多,严重者可引起死亡。脑卒中具有发病率高、死亡率高和致残率高的特点。
B族维生素由生物活性相似但化学成分不同的化合物组成,可以以自由形式存在,普遍以辅酶的形式广泛参与到各种生理过程中。它们在动物和部分微生物中无法合成,因此必须从外界获得,一般植物体内可以合成各种维生素。生物机体对维生素的需求不高,但却必不可少。
冰片是一味常用中药,为无色透明或白色半透明的片状松脆结晶;气清香,味辛、凉;具挥发性,易升华,点燃发生浓烟,并有带光的火焰。冰片清香宣散,具有开窍醒神、清热散毒、明目退翳的功效,主治热病高热神昏、暑湿蒙蔽清窍、喉痹耳聋、口疮齿肿、疮痈疳痔、目赤肿痛、翳膜遮睛等。
3-甲基-1-苯基-2-吡唑啉-5-酮是自由基清除剂和抗化剂,易通过血脑屏障进入脑组织起作用。3-甲基-1-苯基-2-吡唑啉-5-酮通过抑制黄嘌呤氧化酶和次黄嘌呤氧化酶活性,降低羟自由基浓度,抑制脂质过氧化作用,减轻脑内花生四烯酸的代谢中间体脂质过氧化物引起的氧化性细胞损伤,防治血管内皮损伤,祈祷抗缺血及缩小梗死面积的作用。
发明内容
本发明的目的是提供一种具有治疗脑卒中的药物组合物,包括B族维生素。
本发明提供一种用于治疗脑卒中的组合物,含有有效含量的B族维生素,所述B 族维生素选自维生素B6、维生素B12或叶酸类物质,其中,维生素B6有效含量为0.5-50 ㎎,叶酸类物质有效含量为0.2-10㎎,维生素B12有效含量为0.1-2㎎。
在本发明中,所述维生素B6选自吡哆醇、吡哆醛、吡哆胺、磷酸吡哆醛、磷酸吡哆胺及上述物质的衍生物和可在体内释放/生成该类化合物的物质。
在本发明中,所述维生素B12选自甲钴胺素、5’-脱氧腺苷钴胺素、羟钴胺素、氰钴胺素或其他可在体内释放/生成钴胺素的物质。
在本发明中,所述叶酸类物质包括叶酸、甲酰四氢叶酸钙、5-甲基四氢叶酸等,上述物质的各种盐或活性代谢物和可在体内释放/生成叶酸的物质也包含在本发明的保护范围内。
在本发明中,所述组合物中还可以含有冰片或其提取物。本发明所述冰片包括天然冰片和合成冰片,优选使用天然冰片。在本发明中,冰片的有效含量为0.004-6g,优选4-15mg。
在本发明中,所述组合物中还可以含有3-甲基-1-苯基-2-吡唑啉-5-酮。在本发明中,3-甲基-1-苯基-2-吡唑啉-5-酮的有效含量为10-100mg,优选30-60mg。
作为一种优选,本发明提供的组合物由B族维生素、冰片和3-甲基-1-苯基-2-吡唑啉-5-酮组成。其中,所述B族维生素是5-甲基四氢叶酸和维生素B12中的一种或两种,所述冰片是右莰醇。
作为一种优选,本发明中的3-甲基-1-苯基-2-吡唑啉-5-酮和右莰醇的比例是 4:1-1:4。
作为一种优选,本发明提供的B组维生素是5-甲基四氢叶酸,其中5-甲基四氢叶酸有效含量优选0.8mg-1.6mg。
作为一种优选,在本发明中所述5-甲基四氢叶酸、3-甲基-1-苯基-2-吡唑啉-5-酮和右莰醇的比例优选1:36:9-2:36:9。
作为一种优选,本发明提供的B组维生素是叶酸,其中叶酸有效含量优选 0.8mg-1.6mg。在本发明中所述叶酸、3-甲基-1-苯基-2-吡唑啉-5-酮和右莰醇的比例优选1:36:9-2:36:9。
本发明还提供上述组合物在制备治疗脑卒中的制品中的用途。
优选地,本发明将上述组合物用于制备缺血性脑卒中或脑梗塞的制品中的用途。
在本发明提供的用途中,上述组合物还可以含有药学上的辅料,以制备成可供使用者便利使用的制品。所述的制品包括口服制品和注射制品。口服制品,包括片剂、胶囊、颗粒剂、口服液、膜剂或贴剂等,药学上的辅料包括但不限于赋形剂、填充剂、粘合剂、崩解剂等。赋形剂包括甘露醇、乳糖、右旋糖酐、半胱氨酸、环糊精等;填充剂包括乳糖、淀粉、蔗糖、甘露醇、山梨醇、微晶纤维素、磷酸二氢钙等;粘合剂包括羧甲基纤维素钠、羟丙甲纤维素、羟丙基纤维素、聚维酮、淀粉、乙基纤维素、甲基纤维素等;崩解剂包括羧甲基淀粉钠、羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮、淀粉等。注射制品,可以含有溶剂,所述溶剂可以选用水溶性有机溶剂、或者水溶性有机溶剂与水的混合物。常用的水溶剂有机溶剂包括醇类溶剂、醚类溶剂、酮类溶剂等。常用的醇类溶剂有乙醇、异丙醇、乙二醇、丙二醇等;常用的醚类溶剂有乙二醇单乙基醚、乙二醇单丁基醚等;常用的酮类溶剂有丙酮、N-甲基-2-吡咯烷酮。水溶剂有机溶剂优选使用丙二醇。
本发明提供的药物组合物对脑卒中具有显著的治疗效果,尤其是在B族维生素组合冰片或3-甲基-1-苯基-2-吡唑啉-5-酮或冰片和3-甲基-1-苯基-2-吡唑啉-5-酮的组合物后,可以显著增强治疗效果,不仅成分起效剂量低,毒性小,具有显著的协同作用,因而是一种治疗脑卒中的组合物。
下面结合具体实施方式对本发明做进一步说明,并非对本发明的限定,凡依照本发明内容进行的任何本领域的等同替换,均属于本发明的保护范围。
具体实施方式
实施例1
取3-甲基-1-苯基-2-吡唑啉-5-酮30mg,合成冰片120mg,加入丙二醇溶液中,搅拌完全溶解,缓缓加入含5mg叶酸的注射用水使之溶解,调节注射用水并至100ml,即得。
实施例2
取3-甲基-1-苯基-2-吡唑啉-5-酮30mg,天然冰片7.5mg,加入丙二醇溶液中,搅拌完全溶解,缓缓加入含0.8mg叶酸的注射用水使之溶解,调节注射用水并至100ml,即得。
实施例3
取3-甲基-1-苯基-2-吡唑啉-5-酮30mg,天然冰片7.5mg,加入丙二醇溶液中,搅拌完全溶解,缓缓加入含0.8mg5-甲基四氢叶酸的注射用水使之溶解,调节注射用水并至100ml,即得。
实施例4
取3-甲基-1-苯基-2-吡唑啉-5-酮30mg,天然冰片7.5mg,加入丙二醇溶液中,搅拌完全溶解,缓缓加入含1.6mg5-甲基四氢叶酸的注射用水使之溶解,调节注射用水并至100ml,即得。
实施例5
取3-甲基-1-苯基-2-吡唑啉-5-酮30mg,天然冰片7.5mg,加入丙二醇溶液中,搅拌完全溶解,缓缓加入含5mg5-甲基四氢叶酸和0.25mg维生素B12的注射用水使之溶解,调节注射用水并至100ml,即得。
实施例6
取3-甲基-1-苯基-2-吡唑啉-5-酮30mg,天然冰片15mg,加入丙二醇溶液中,搅拌完全溶解,缓缓加入含5mg5-甲基四氢叶酸和0.25mg维生素B12的注射用水使之溶解,调节注射用水并至100ml,即得。
实施例7
取3-甲基-1-苯基-2-吡唑啉-5-酮15mg,天然冰片15mg,加入丙二醇溶液中,搅拌完全溶解,缓缓加入含0.4mg5-甲基四氢叶酸和0.25mg维生素B12的注射用水使之溶解,调节注射用水并至100ml,即得。
实施例8
取3-甲基-1-苯基-2-吡唑啉-5-酮30g、天然冰片7.5g、5-甲基四氢叶酸800mg、甘露醇35g、羟丙甲纤维素4g、交联羧甲基纤维4g和硬脂酸镁0.8g混合均匀,压片,得 1000片含3-甲基-1-苯基-2-吡唑啉-5-酮、天然冰片和5-甲基四氢叶酸的舌下含片。
实施例9
取3-甲基-1-苯基-2-吡唑啉-5-酮40g、天然冰片10g、5-甲基四氢叶酸5g、250mg维生素B12、乳糖25g、羟丙甲纤维素4g、交联羧甲基纤维4g和硬脂酸镁0.8g混合均匀,压片,得1000片含3-甲基-1-苯基-2-吡唑啉-5-酮、天然冰片、5-甲基四氢叶酸和维生素B12的舌下含片。
实施例10
取3-甲基-1-苯基-2-吡唑啉-5-酮60g、天然冰片15g、5-甲基四氢叶酸1g、500mg维生素B12、甘露醇50g、羟丙甲纤维素4g、交联羧甲基纤维4g和硬脂酸镁0.8g混合均匀,压片,得1000片含3-甲基-1-苯基-2-吡唑啉-5-酮、天然冰片、5-甲基四氢叶酸和维生素B12的片剂。
实施例11组合物对脑缺血再灌注损伤大鼠的作用
一、方法
7-8周龄左右雄性SD大鼠随机分为假手术组、模型组、3-甲基-1-苯基-2-吡唑啉-5-酮组(简称酮组)(3mg/kg)、天然冰片组(0.75mg/kg)、5-甲基四氢叶酸组 (0.08mg/kg)、3-甲基-1-苯基-2-吡唑啉-5-酮+5-甲基四氢叶酸组(简称酮叶组) (3mg/kg+0.08mg/kg)、3-甲基-1-苯基-2-吡唑啉-5-酮+天然冰片组(简称酮冰组) (3mg/kg+0.75mg/kg)、3-甲基-1-苯基-2-吡唑啉-5-酮+天然冰片+5-甲基四氢叶酸组 (简称酮冰叶组)(3mg/kg+0.75mg/kg+0.08mg/kg),每组12只。脑缺血再灌注模型构建前3天与构建后2h,按上述剂量灌胃给药。
模型构建
麻醉大鼠,自颈部开口,分离除颈外动脉与颈内动脉,将线栓插入颈总动脉,前进至内动脉约16-18mm,固定线栓,缝合伤口。线栓插入2h后,取出线栓并结扎颈总动脉。假手术组仅麻醉后游离出颈总动脉。
神经功能评估
拔出线栓24h后,对各组大鼠神经功能进行评估。
参照Bederson神经功能分级标准,分为如下5级,每天观察一次。
0级(正常):无神经功能缺损症状。
1级(轻微):前肢蜷缩或屈曲,主要是持续性腕屈曲或肩内收伴肘部伸展。
2级(中度):前肢持续性蜷缩或屈曲,可见腕、肘全部屈曲、肩部内收或内旋。
3级(严重):持续性肢体蜷缩或屈曲,一侧肢体推力体抗持续性减弱,自主活动时不伴肢体划圈行为。
4级(甚重):双侧肢体持续性蜷缩或屈曲,一侧肢体推力体抗持续性减弱,自主活动时出现肢体划圈行为。
脑梗死评估
取大鼠分离出全脑组织并冷冻切块,切成5片约2mm厚切片,浸入2%氯化三苯基四氮唑溶剂中,避光孵育30min,37℃.4%多聚甲醛固定后分析。
正常脑组织染色后呈现红色,脑梗死呈现白色,将白色组织称重,以梗死组织重量占全脑重量的百分比作为梗死体积占比进行比较。
统计学分析
实验数据采用SPSS 22.0软件进行分析。
为证实本发明提供的药物组合物的科学性,说明药物组合物的三种组分配伍合理,相互结合可以发挥协同增效作用,而不是简单的药理作用叠加,引入金正均Q 值法分析。金正均Q值法又称概率相加法,根据在量效曲线区内,两种药物联用的药理作用及两种药物单用的药理作用,用如下计算公式计算:Q=EA+B/(EA+EB-EA*EB),式中分子代表“实测合并效应”,分母代表“期望合并效应”,(为满足组分及组合物药理作用关系的分析,将它们的药理作用转化为可以直观体现药理作用强弱的效应,计算公式:Ei=1-Pi/P模型组,Pi为各组分的药理指标,P模型组为模型组的药理指标),Q为两者之比:Q小于0.85时认为两种药物联用为拮抗作用;小于1.15大于0.85时,认为是相加作用;大于1.15时认为是协同作用。
结果
表1脑卒中神经功能分级比较(只)
与假手术组相比,模型组大鼠动物存活数低于假手术组,并且2级大鼠1只,3级大鼠3只,4级大鼠3只,说明脑缺血再灌注损伤模型造模成功。与模型组相比,酮组大鼠存活数升高,不仅出现1级大鼠,2级大鼠百分率也高于模型组,3级和4级百分率低于模型组,说明3-甲基-1-苯基-2-吡唑啉-5-酮能够改善脑缺血再灌注损伤大鼠的神经功能分级。天然冰片组没有1级大鼠,2级和4级大鼠的百分率低于模型组,3级大鼠的百分率高于模型组,说明天然冰片有轻微的改善脑缺血再灌注损伤大鼠的神经功能分级的作用。5-甲基四氢叶酸组2级大鼠百分率与模型组相同,3级大鼠百分率高于模型组,4级大鼠百分率低于模型组,说明5-甲基四氢叶酸有轻微改善大鼠的神经功能分级的作用。酮冰组大鼠存活数高于对照组,出现2只1级大鼠, 2级大鼠百分率高于模型组,3级和4级百分率低于模型组,说明酮冰组合物能够显著改善大鼠的神经功能分级;与酮组相比,酮冰组不近大鼠存活数增高,1级大鼠百分率升高,4级大鼠百分数降低,说明酮冰组改善大鼠神经功能分级的作用强于酮组。酮叶组出现1只1级大鼠,2级大鼠百分率高于模型组,3级和4级百分率低于模型组,说明酮叶组合物能够显著改善大鼠的神经功能分级;与酮组相比,酮叶组3级大鼠百分率升高,4级大鼠百分率降低,说明酮叶组合物改善大鼠神经功能分级的作用略强于酮组。酮冰叶组不仅大鼠存活数较高,1级和2级大鼠百分率是所有组里面最高的,3级和4级大鼠百分率是所有组里面最低的,说明酮冰叶组合物是所有改善大鼠神经功能分级的产品中,效果最强的。
表2各组大鼠脑梗死体积占比比较
与假手术组相比,**P<0.01;与模型组相比,#P<0.05,##P<0.01
经过染色,假手术组大鼠脑组织切片呈现红色,表明假手术组大鼠无任何梗死区域。模型组大鼠脑组织缺血侧组织染色几乎全部为白色,脑梗死体积占比达到43.8%。与模型组相比,天然冰片组和5-甲基四氢叶酸组无明显变化,但酮组和酮叶组大鼠脑梗死体积占比明显下降,具有显著的统计学差异。酮冰组大鼠脑梗死体积占比,不仅与模型组相比显著下降,具有极显著的统计学差异;与酮组相比,酮冰组大鼠脑梗死体积占比也进一步降低。分析酮冰组与酮组、天然冰片组的脑梗死体积占比的Q 值为1.11,表明两者是相加作用。酮冰叶组大鼠脑梗死体积占比,不仅与模型组具有极显著的统计学差异,与酮组、酮冰组或酮叶组相比,都进一步降低。分析酮冰叶组与酮叶组、天然冰片组的脑梗死体积占比的Q值为1.45,分析酮冰叶组与酮冰组、 5-甲基四氢叶酸组的脑梗死体积占比的Q值为1.16,表明无论是在3-甲基-1-苯基-2- 吡唑啉-5-酮与天然冰片的组合物中加入5-甲基四氢叶酸,还是在3-甲基-1-苯基-2- 吡唑啉-5-酮与5-甲基四氢叶酸组合物中加入天然冰片,3-甲基-1-苯基-2-吡唑啉 -5-酮+天然冰片+5-甲基四氢叶酸组合物都产生比原二联或单药更强的治疗脑梗死的协同作用,表明3-甲基-1-苯基-2-吡唑啉-5-酮+天然冰片+5-甲基四氢叶酸组合物是一种更有效的治疗脑卒中的药物。
实施例12组合物对脑缺血再灌注损伤大鼠的作用
一、方法
7-8周龄左右雄性SD大鼠随机分为假手术组、模型组、酮冰组(3-甲基-1-苯基 -2-吡唑啉-5-酮组+天然冰片,3+0.75mg/kg)组合物1组(3-甲基-1-苯基-2-吡唑啉 -5-酮组+天然冰片+5-甲基四氢叶酸,3+0.75+0.02mg/kg),组合物2组(3-甲基-1- 苯基-2-吡唑啉-5-酮组+天然冰片+5-甲基四氢叶酸,3+0.75+0.08mg/kg),组合物3 组(3-甲基-1-苯基-2-吡唑啉-5-酮组+天然冰片+5-甲基四氢叶酸,3+0.75+0.16 mg/kg),组合物4组(3-甲基-1-苯基-2-吡唑啉-5-酮组+天然冰片+5-甲基四氢叶酸, 3+0.75+1mg/kg),每组12只。脑缺血再灌注模型构建前3天与构建后2h,按上述剂量灌胃给药。
模型构建
见实施例11.
生化检测
取大鼠缺血侧组织,加入PBS混合匀浆。离心后取上清液,按试剂盒说明,检测MDA、SOD和GSH(试剂盒购自上海酶联生物技术公司)。
与假手术组相比,模型组MDA显著升高,SOD和GSH显著下降,具有极显著的统计学差异,表明模型组大鼠氧自由基损伤。酮冰组可显著降低MDA值、升高SOD活性和GSH水平,其作用效果与组合物1组相近。与酮冰组相比,组合物2组和组合物3 组,在酮冰组的基础上进一步显著降低MDA值、升高SOD活性和GSH水平,并且与酮冰组相比,具有极显著的统计学差异,表明3-甲基-1-苯基-2-吡唑啉-5-酮+天然冰片+5-甲基四氢叶酸组合物产生比原二联更强的改善氧自由基损伤的协同作用。组合物4组的效果与组合物3组相当,但GSH水平不升反降,表明3-甲基-1-苯基-2- 吡唑啉-5-酮和天然冰片组合物中加入5-甲基四氢叶酸具有剂量依赖性。
表3组合物对脑缺血再灌注损伤大鼠生化因子检测
与假手术组相比,**P<0.01;与模型组相比,#P<0.05,##P<0.01;与酮冰组相比,&P<0.05,&&P<0.01。
Claims (11)
1.一种用于治疗脑卒中的组合物,含有有效含量的B族维生素,所述B族维生素选自维生素B6、维生素B12或叶酸类物质,其中,维生素B6有效含量为0.5-50㎎,叶酸类物质有效含量为0.2-10㎎,维生素B12有效含量为0.1-2㎎。
2.根据权利要求1所述的组合物,其特征在于:所述维生素B6选自吡哆醇、吡哆醛、吡哆胺、磷酸吡哆醛、磷酸吡哆胺及上述物质的衍生物和可在体内释放/生成该类化合物的物质,所述维生素B12选自甲钴胺素、5’-脱氧腺苷钴胺素、羟钴胺素、氰钴胺素或其他可在体内释放/生成钴胺素的物质,所述叶酸类物质包括叶酸、甲酰四氢叶酸钙、5-甲基四氢叶酸、或其盐或活性代谢物和可在体内释放/生成叶酸的物质。
3.根据权利要求1所述的组合物,其特征在于:所述组合物中含有冰片或其提取物。
4.根据权利要求1所述的组合物,其特征在于:所述组合物含有3-甲基-1-苯基-2-吡唑啉-5-酮。
5.根据权利要求1所述的组合物,其特征在于:所述组合物由B族维生素、冰片和3-甲基-1-苯基-2-吡唑啉-5-酮组成。
6.根据权利要求1-5任一项所述的组合物,其特征在于,所述B族维生素是5-甲基四氢叶酸和维生素B12中的一种或两种,所述冰片是右莰醇。
7.根据权利要求6所述的组合物,其特征在于,所述3-甲基-1-苯基-2-吡唑啉-5-酮和右莰醇的比例是4:1-1:4。
8.根据权利要求7所述的组合物,其特征在于,所述5-甲基四氢叶酸有效含量为0.8-1.6mg。
9.根据权利要求8所述的组合物,其特征在于,所述5-甲基四氢叶酸、3-甲基-1-苯基-2-吡唑啉-5-酮和右莰醇的比例是1:36:9-2:36:9。
10.根据权利要求1所述的组合物在制备治疗脑卒中的制品中的用途。
11.根据权利要求10所述的用途,其特征在于,所述的制品包括口服制品和注射制品。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111585029.7A CN116370471A (zh) | 2021-12-22 | 2021-12-22 | 一种用于脑卒中的组合物 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111585029.7A CN116370471A (zh) | 2021-12-22 | 2021-12-22 | 一种用于脑卒中的组合物 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116370471A true CN116370471A (zh) | 2023-07-04 |
Family
ID=86971754
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111585029.7A Pending CN116370471A (zh) | 2021-12-22 | 2021-12-22 | 一种用于脑卒中的组合物 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116370471A (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101897706A (zh) * | 2009-05-27 | 2010-12-01 | 北京奥萨医药研究中心有限公司 | 含有叶酸和b族维生素的组合物及其用途 |
CN107158059A (zh) * | 2017-03-30 | 2017-09-15 | 神威药业集团有限公司 | 心脑清组合物在制备治疗和/或预防慢性脑缺血导致的脑白质损伤药物中的应用 |
CN110339204A (zh) * | 2018-04-04 | 2019-10-18 | 北京斯利安药业有限公司 | 一种含有叶酸的组合物及其在制备脑卒中药物中的应用 |
-
2021
- 2021-12-22 CN CN202111585029.7A patent/CN116370471A/zh active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101897706A (zh) * | 2009-05-27 | 2010-12-01 | 北京奥萨医药研究中心有限公司 | 含有叶酸和b族维生素的组合物及其用途 |
CN107158059A (zh) * | 2017-03-30 | 2017-09-15 | 神威药业集团有限公司 | 心脑清组合物在制备治疗和/或预防慢性脑缺血导致的脑白质损伤药物中的应用 |
CN110339204A (zh) * | 2018-04-04 | 2019-10-18 | 北京斯利安药业有限公司 | 一种含有叶酸的组合物及其在制备脑卒中药物中的应用 |
Non-Patent Citations (3)
Title |
---|
HAI-YIN WU ETAL.: "The synergetic effect of edaravone and borneol in the rat model of ischemic stroke", 《EUROPEAN JOURNAL OF PHARMACOLOGY》, vol. 740, 27 June 2014 (2014-06-27), pages 522 - 531, XP009510121, DOI: 10.1016/j.ejphar.2014.06.035 * |
王展等: "依达拉奉联合维生素B2、叶酸治疗进展性卒中疗效观察", 《淮海医药》, vol. 29, no. 3, 2 August 2011 (2011-08-02), pages 209 - 210 * |
王文生,王月等: "冰片增强依达拉奉对脑缺血再灌注损伤大鼠", 《吉林中医药》, vol. 41, no. 11, 2 December 2021 (2021-12-02), pages 1497 - 1501 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2009221546B2 (en) | A pharmaceutical composition and the application thereof in the preparation of medicine for the treatment of cerebrovascular diseases | |
BG63612B1 (bg) | Състав и метод за профилактика и лечение на нiv идруги инфекциозни заболявания при човека | |
RU2466734C1 (ru) | Капли плетнева для восстановления метаболизма и энергообеспечения тканей и органов | |
RU2418601C2 (ru) | Средство, обладающее гепатопротекторным, детоксицирующим и регенерирующим действием | |
NZ536360A (en) | Compositions for therapeutic use comprising a vitamin, a metal salt and insulin or a growth hormone | |
ES2590209T3 (es) | Composiciones para el tratamiento de la fatiga asociada al cáncer | |
KR20190003405A (ko) | 브라우쏘칼콘 a를 유효성분으로 포함하는 염증성 장질환 예방 또는 치료용 약학 조성물 | |
CN116370471A (zh) | 一种用于脑卒中的组合物 | |
EP3069723B1 (en) | Naringin and levocetirizine hydrochloride pharmaceutical composition and preparation thereof | |
AU760967B2 (en) | Herbal composition for the prophylaxis and treatment of AIDS | |
CA2680560C (en) | The use of ginsenoside rg1, its metabolites ginsenoside rh1 and/or ppt | |
RU2296579C1 (ru) | Средство, обладающее гепатопротекторным и желчегонным действием | |
NL8702598A (nl) | Immunoregulator die een estradiolderivaat bevat. | |
KR100198490B1 (ko) | 간장질환 치료용 의약 조성물 | |
JPH03287531A (ja) | 膵炎治療薬 | |
JPH09143085A (ja) | 甘草成分含有強肝剤 | |
JPH10306031A (ja) | 生薬製剤 | |
Abd-Alhassen et al. | In vitro and in vivo antioxidant activity of Iraqi propolis against benign prostatic hyperplasia in rats | |
CN107595868B (zh) | 去半乳糖替告皂甙在制备治疗支气管炎药物中的应用 | |
JP2004262929A (ja) | α−グルコシダーゼ阻害剤 | |
JP2001157559A (ja) | 新規食品組成物 | |
KR960014990B1 (ko) | 간기능 개선용 의약조성물 | |
CN116509839A (zh) | 6-羟基染料木素在制备抗高原缺氧药物中的应用 | |
JP2018024654A (ja) | プロポリスのミセル化抽出物を有効成分とする認知機能改善剤 | |
Abortifacient et al. | Medical Glossary |
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 |