CN1323205A - 预防或治疗大脑和老化疾病的肉毒碱和白藜芦醇的复方 - Google Patents
预防或治疗大脑和老化疾病的肉毒碱和白藜芦醇的复方 Download PDFInfo
- Publication number
- CN1323205A CN1323205A CN99811952A CN99811952A CN1323205A CN 1323205 A CN1323205 A CN 1323205A CN 99811952 A CN99811952 A CN 99811952A CN 99811952 A CN99811952 A CN 99811952A CN 1323205 A CN1323205 A CN 1323205A
- Authority
- CN
- China
- Prior art keywords
- carnitine
- resveratrol
- purposes
- alkanoyl
- vitis viniferae
- 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
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 title claims abstract description 61
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 title claims abstract description 60
- 235000021283 resveratrol Nutrition 0.000 title claims abstract description 59
- 229940016667 resveratrol Drugs 0.000 title claims abstract description 58
- 238000011282 treatment Methods 0.000 title claims abstract description 20
- 230000002265 prevention Effects 0.000 title claims abstract description 9
- 230000002490 cerebral effect Effects 0.000 title claims description 6
- 230000032683 aging Effects 0.000 title claims description 5
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 claims abstract description 55
- -1 alkanoyl L-carnitine Chemical compound 0.000 claims abstract description 13
- PDHAOJSHSJQANO-OWOJBTEDSA-N Oxyresveratrol Chemical compound OC1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 PDHAOJSHSJQANO-OWOJBTEDSA-N 0.000 claims abstract description 10
- LXOPCHVYWBGPND-VOTSOKGWSA-N 4-[(e)-2-phenylethenyl]benzene-1,2,3-triol Chemical group OC1=C(O)C(O)=CC=C1\C=C\C1=CC=CC=C1 LXOPCHVYWBGPND-VOTSOKGWSA-N 0.000 claims abstract description 9
- 230000001575 pathological effect Effects 0.000 claims abstract description 5
- 241000219095 Vitis Species 0.000 claims description 30
- 235000009392 Vitis Nutrition 0.000 claims description 27
- 239000000284 extract Substances 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 13
- 125000001589 carboacyl group Chemical group 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 6
- 206010029350 Neurotoxicity Diseases 0.000 claims description 5
- 206010044221 Toxic encephalopathy Diseases 0.000 claims description 5
- 244000068697 Vitis rotundifolia Species 0.000 claims description 5
- 235000004305 Vitis rotundifolia Nutrition 0.000 claims description 5
- 231100000228 neurotoxicity Toxicity 0.000 claims description 5
- 230000007135 neurotoxicity Effects 0.000 claims description 5
- 238000012856 packing Methods 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 3
- 229930014626 natural product Natural products 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 235000013373 food additive Nutrition 0.000 claims description 2
- 239000002778 food additive Substances 0.000 claims description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 210000002569 neuron Anatomy 0.000 claims 2
- 208000000044 Amnesia Diseases 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 231100000863 loss of memory Toxicity 0.000 claims 1
- 208000018152 Cerebral disease Diseases 0.000 abstract description 5
- RDHQFKQIGNGIED-MRVPVSSYSA-N O-acetyl-L-carnitine Chemical compound CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-MRVPVSSYSA-N 0.000 abstract 1
- UFAHZIUFPNSHSL-MRVPVSSYSA-N O-propanoyl-L-carnitine Chemical compound CCC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C UFAHZIUFPNSHSL-MRVPVSSYSA-N 0.000 abstract 1
- 230000001537 neural effect Effects 0.000 abstract 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 229940127557 pharmaceutical product Drugs 0.000 abstract 1
- 241001465754 Metazoa Species 0.000 description 16
- 238000012360 testing method Methods 0.000 description 15
- 230000000694 effects Effects 0.000 description 13
- 229960004203 carnitine Drugs 0.000 description 10
- 150000008442 polyphenolic compounds Chemical class 0.000 description 9
- 235000013824 polyphenols Nutrition 0.000 description 9
- 108050009340 Endothelin Proteins 0.000 description 8
- 102000002045 Endothelin Human genes 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 6
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 6
- 229960004316 cisplatin Drugs 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 241001597008 Nomeidae Species 0.000 description 4
- 235000014787 Vitis vinifera Nutrition 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 3
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 3
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 3
- 239000008777 Glycerylphosphorylcholine Substances 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 235000009754 Vitis X bourquina Nutrition 0.000 description 3
- 235000012333 Vitis X labruscana Nutrition 0.000 description 3
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- FOYKKGHVWRFIBD-UHFFFAOYSA-N gamma-tocopherol acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 FOYKKGHVWRFIBD-UHFFFAOYSA-N 0.000 description 3
- 229960004956 glycerylphosphorylcholine Drugs 0.000 description 3
- SUHOQUVVVLNYQR-MRVPVSSYSA-O glycerylphosphorylcholine Chemical compound C[N+](C)(C)CCO[P@](O)(=O)OC[C@H](O)CO SUHOQUVVVLNYQR-MRVPVSSYSA-O 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- IGQBPDJNUXPEMT-SNVBAGLBSA-N isovaleryl-L-carnitine Chemical compound CC(C)CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C IGQBPDJNUXPEMT-SNVBAGLBSA-N 0.000 description 3
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 3
- 230000001953 sensory effect Effects 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 208000028389 Nerve injury Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 2
- 239000004410 anthocyanin Substances 0.000 description 2
- 235000010208 anthocyanin Nutrition 0.000 description 2
- 229930002877 anthocyanin Natural products 0.000 description 2
- 150000004636 anthocyanins Chemical class 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940009098 aspartate Drugs 0.000 description 2
- 235000013734 beta-carotene Nutrition 0.000 description 2
- 239000011648 beta-carotene Substances 0.000 description 2
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 2
- 229960002747 betacarotene Drugs 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 210000003792 cranial nerve Anatomy 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000035622 drinking Effects 0.000 description 2
- 235000006694 eating habits Nutrition 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 238000011067 equilibration Methods 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000008764 nerve damage Effects 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 2
- NDVRKEKNSBMTAX-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;phosphoric acid Chemical class OP(O)(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O NDVRKEKNSBMTAX-BTVCFUMJSA-N 0.000 description 1
- XLAIWHIOIFKLEO-UHFFFAOYSA-N (E)-4-<2-(4-hydroxyphenyl)ethenyl>phenol Natural products C1=CC(O)=CC=C1C=CC1=CC=C(O)C=C1 XLAIWHIOIFKLEO-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- LUKBXSAWLPMMSZ-UPHRSURJSA-N Cis-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C/C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-UPHRSURJSA-N 0.000 description 1
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 241001289529 Fallopia multiflora Species 0.000 description 1
- 235000011201 Ginkgo Nutrition 0.000 description 1
- 244000194101 Ginkgo biloba Species 0.000 description 1
- 235000008100 Ginkgo biloba Nutrition 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
- 206010019280 Heart failures Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000021642 Muscular disease Diseases 0.000 description 1
- 201000009623 Myopathy Diseases 0.000 description 1
- 210000004460 N cell Anatomy 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 244000131316 Panax pseudoginseng Species 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- DJWYOLJPSHDSAL-UHFFFAOYSA-N Pantethine Natural products OCC(C)(C)C(O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)C(O)C(C)(C)CO DJWYOLJPSHDSAL-UHFFFAOYSA-N 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 241000205407 Polygonum Species 0.000 description 1
- 206010036631 Presenile dementia Diseases 0.000 description 1
- 240000001341 Reynoutria japonica Species 0.000 description 1
- 235000018167 Reynoutria japonica Nutrition 0.000 description 1
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 229930003451 Vitamin B1 Natural products 0.000 description 1
- 229930003471 Vitamin B2 Natural products 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 244000070384 Vitis labrusca Species 0.000 description 1
- 235000004282 Vitis labrusca Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 210000002149 gonad Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 235000002532 grape seed extract Nutrition 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000009916 joint effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 230000001483 mobilizing effect Effects 0.000 description 1
- 201000006938 muscular dystrophy Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 229960000903 pantethine Drugs 0.000 description 1
- DJWYOLJPSHDSAL-ROUUACIJSA-N pantethine Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO DJWYOLJPSHDSAL-ROUUACIJSA-N 0.000 description 1
- 235000008975 pantethine Nutrition 0.000 description 1
- 239000011581 pantethine Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000272 proprioceptive effect Effects 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000008925 spontaneous activity Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 230000009441 vascular protection Effects 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 230000001720 vestibular Effects 0.000 description 1
- 235000010374 vitamin B1 Nutrition 0.000 description 1
- 239000011691 vitamin B1 Substances 0.000 description 1
- 235000019164 vitamin B2 Nutrition 0.000 description 1
- 239000011716 vitamin B2 Substances 0.000 description 1
- 235000019158 vitamin B6 Nutrition 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/15—Vitamins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Polymers & Plastics (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Botany (AREA)
- Psychiatry (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
一种包含以混合物或分别包装形式存在的(A)L－肉毒碱或链烷酰基L－肉毒碱(例如乙酰基L－肉毒碱或丙酰基L－肉毒碱)和(B)三羟基或四羟基茋(例如白藜芦醇)的药品,用于预防和治疗由神经元或大脑病变引起的病理性疾病。
Description
本发明涉及L-肉毒碱或链烷酰基L-肉毒碱和三羟基或四羟基茋的复方组合物在预防或治疗由老化和使用神经毒性药物引起的大脑疾病中的新用途。
因此，根据组合物对其特定使用个体产生的作用是补充或预防作用、还是严格的治疗作用，所述组合物可采取食品强化剂或真正药物的形式并发挥其作用。
(A)L-肉毒碱或其中直链或支链链烷酰基包含2-8个碳原子的链烷酰基L-肉毒碱或其可药用盐和(B)三羟基或四羟基茋如白藜芦醇的复方在预防和治疗许多不同病理性疾病中的用途早已是已知的。事实上，美国专利5,747,536中描述了上述复方在预防和治疗糖尿病性神经病和动脉粥样硬化性损伤以及抑制血小板聚集中的用途。
本发明的用途决不涉及所述早就已知的用途或可从中推论得到的用途。
广义地说，本发明涉及联合应用L-肉毒碱或链烷酰基L-肉毒碱或其可药用盐和三羟基或四羟基茋来预防或治疗上述病理性疾病，其中“联合应用”这些活性组分是指共同给药，即几乎共同给出L-肉毒碱或链烷酰基L-肉毒碱或其可药用盐和三羟基-或四羟基茋，或给予包含所述活性组分混合物的组合物。
下面，为了使本说明书简洁，仅述及L-肉毒碱，可以理解，本描述也适用于上述链烷酰基L-肉毒碱或其可药用盐。同样地，下文仅述及白藜芦醇(反式-3,4’,5-三羟基茋)，但是可以理解，本描述不仅适用于上述顺式-白藜芦醇和各自的反式-和顺式-糖苷，而且适用于所有三羟基-或四羟基茋。
发现，白藜芦醇存在于葡萄，特别是葡萄(Vitis vinifera)、Vitis rotundifolia和美国葡萄(Vitis labrusca)的葡萄皮、籽、茎和葡萄叶中，并且明显地存在于由这些葡萄酿制的葡萄酒和上述天然产物的提取物和粉末中。白藜芦醇也存在于许多种蓼属植物(Polygonum genus)如虎杖(Polygonum cuspidatum)和何首乌(Polygonum multiflorum)的根中。
对于本发明来说，“白藜芦醇”是指反式-3,4’,5-三羟基茋(即白藜芦醇本身)和顺式异构体、各自的糖苷和从适宜的植物种中得到的包含白藜芦醇的提取物和粉末。
流行病学研究证明，有适量饮用葡萄酒饮食习惯的人群心血管意外事故的发生率大大低于没有饮用葡萄酒饮食习惯的人群，因此，最近很多研究人员对存在于葡萄和葡萄酒中的天然多酚开始关注。在各种多酚的研究中，已经证明，白藜芦醇是最有意义的，它能够发挥明显的抗血小板聚集作用以及明显的抗炎和血管保护作用。
另一方面，存在于葡萄酒中的白藜芦醇和多酚明显降低早老性痴呆和老年性痴呆的发生率，适量饮用葡萄酒的人群，特别是老年人群能够产生这样的作用。最近，在大量人群中进行的流行病学研究证实，先前类似的研究也已经显示出，适量饮用葡萄酒者比不饮用者死亡率低。
已知的L-肉毒碱的治疗用途包括，例如，在心血管领域，该物质用于治疗急、慢性心肌局部缺血、心绞痛、心衰和心律失常以及外周血管病。在肾病领域，给予定期血透析治疗的慢性尿毒症患者L-肉毒碱用于对抗肌无力和发生肌痉挛。其它治疗用途涉及使HDL/LDL+VLDL的比值和总的非肠道营养正常化。L-肉毒碱在治疗某些肌病和肌营养不良方面的用途也是已知的。
目前意外地发现，以下列组分：
(A)、L-肉毒碱或其中直链或支链链烷酰基包含2-8个碳原子的链烷酰基L-肉毒碱，或其可药用盐；和
(B)、三羟基或四羟基茋的组合作为特性组分的组合物在预防和/或治疗由老化和使用神经毒性药物引起的大脑疾病方面是相当有效的，这是其组分发挥有效协同作用的结果。
因此，本发明涉及利用(A)L-肉毒碱或其中直链或支链链烷酰基包含2-8个碳原子的链烷酰基L-肉毒碱，或其可药用盐，和(B)三羟基或四羟基茋来制备其中(A)和(B)混合在一起或分别包装的药品用于预防和治疗与神经或大脑疾病有关的疾病形式。活性组分(A)和(B)混合在一起或分别包装符合上述关于“联合应用”所述组分的描述。优选地，所述烷酰基包含2-8个碳原子，并且更优选地选自乙酰基、丙酰基、丁酰基、戊酰基和异戊酰基L-肉毒碱。
优选地，组分(B)为3,4’,5-三羟基茋(白藜芦醇)或3,4’,5-三羟基茋-3-β-单-D-葡糖苷或其可药用盐。白藜芦醇可以是通过合成制备的形式或者可以是从葡萄、Vitis rotundifolia、美国葡萄或从虎杖或何首乌的根中提取的形式。
组分(B)也可以存在于包含白藜芦醇的天然产物的提取物或粉末中，如存在于葡萄、Vitis rotundifolia、美国葡萄的葡萄皮、籽或茎或虎杖或何首乌的根的提取物或粉末中。
(B)与(A)的重量比在1∶1-1∶1,000范围，并且优选地在1∶1-1∶500范围。
本发明预防或治疗的由老化引起的大脑疾病特别包括脑中风、早老性和老年性痴呆以及阿尔茨海默病。
已证明本发明“联合”应用非常有效地对抗其效应的神经毒性药物的实例是顺铂。
由组分(A)和(B)产生的脑神经水平的意想不到的协同作用可由试验模型得到的结果证明，公认所述试验模型可用于揭示在脑神经系统水平的保护作用和用于预测所述联合应用对抗人类受试者脑神经异常的有效用途。
毒理学
通过联合给予高剂量的L-肉毒碱或其链烷酰基衍生物和白藜芦醇或包含其中白藜芦醇含量大约为0.1％的多酚的葡萄提取物进行的小鼠或大鼠试验证明，本发明组合物具有低毒性和良好的耐受性。口服给予大鼠高达1g/kg的L-肉毒碱或其链烷酰基衍生物与高剂量白藜芦醇(高达或超过0.5mg/kg)或葡萄提取物(高达或超过1g/kg)显示没有值得注意的毒性反应。类似地，在连续3个月的时间里，每天随饮食一起给予相当于在先前剂型中所使用剂量1/4剂量的L-肉毒碱或其链烷酰基衍生物与白藜芦醇或包含白藜芦醇的葡萄提取物的组合物显示出耐受性很好。在该治疗结束时，各种所考虑的生物学参数(体重增加、血细胞比容、血清葡萄糖、BUN等)未见异常，在所检查的主要器官(肝、心脏、肺、肾、肾上腺、性腺)中未见异常组织学现象。下面我们也报道了一些试验，这些试验的发现提供了由新的包含肉毒碱或其链烷酰基衍生物和白藜芦醇或其衍生物的组合物在脑神经系统水平产生实质性协同作用的证据。关于肉毒碱和白藜芦醇单独或联合应用对行为反应异常作用的试验
血管活性肽和神经调节剂如内皮素的一个作用是它通过减少动物活动力和前庭反应对动物行为产生的影响。
在这些试验中，我们能够观察到，可通过预先给予肉毒碱和白藜芦醇将以1pmol/小鼠的剂量注射到小鼠大脑内的内皮素(ET-1)产生的典型的减少动物自发活动力的作用限制到非常显著的程度，特别是这两种类型能够产生协同作用的组合将由给予内皮素减少的活动力几乎恢复到正常值。
每次将10只小鼠放在有光电池和活动运动计数器的容器中，观察所测值；在注射内皮素后15分钟，观察小鼠5分钟并进行计数。
观察到，单独给予内皮素时，活动力减少百分数为85.5％，在试验前3天和在注射ET-1前半小时以300mg/kg剂量腹膜内分别给予动物L-肉毒碱、乙酰基L-肉毒碱和丙酰基L-肉毒碱时，其活动力减少百分数分别为69.6％、65.5％和60.3％。
单独给予白藜芦醇(2.5mg/kg)时，活动力减少百分数为60.4％，用包含多酚并标定白藜芦醇的葡萄提取物获得的活动力减少百分数与之大致相同。然而，联合给予白藜芦醇和肉毒碱可使内皮素处理动物的活动力几乎恢复至正常值。在联合给予白藜芦醇和丙酰基L-肉毒碱的情况下，动物的运动数与对照动物几乎完全相同，因此证明了所述作用意想不到的协同加强作用。
联合使用白藜芦醇或包含白藜芦醇的天然多酚产物与乙酰基L-肉毒碱或L-肉毒碱(程度较低)也可以检测到明显的协同活性。暴露到H2O2中并用L-肉毒碱或白藜芦醇处理或用两种产物联合处理的嗜铬细胞瘤细胞(PC-12)存活试验
将包含3×105个N-细胞/ml的嗜铬细胞瘤细胞(PC-12)培养物暴露到0.1mM浓度的H2O2中30分钟。尽管单独用H2O2处理的细胞24小时后的存活率大约为45％，但是用L-肉毒碱或用白藜芦醇处理的细胞的存活率明显更高，其中用浓度为10-8M的L-肉毒碱、乙酰基L-肉毒碱和丙酰基L-肉毒碱处理的细胞，其存活率分别为55、60和62％，并且用浓度为10-4M的白藜芦醇处理的细胞，其存活率为69％。
联合使用上述浓度的乙酰基L-肉毒碱和白藜芦醇，存活率为88％，由此证明了所使用物质的协同作用。
而且，和其它情况不同，该联合应用未检测到任何细胞变性的迹象。肉毒碱、白藜芦醇及其组合对由顺铂引起的感觉神经损伤保护作用的试验
在这些试验中，顺铂用作神经毒性因子，特别是它能够引起感觉神经损伤并因此损伤本体感受性知觉。该试验用于评估肉毒碱、白藜芦醇及其组合恢复由注射顺铂损伤的小鼠外周感觉的能力。该能力通过评估动物对按照摆尾(tai1-flick)试验将其尾巴浸入热水溶液引起的热痛的反应或利用转棒(rotating bar)试验进行测定(Apfel S.C.,Lipton R.B.,Ann.Neurol.,29,87-90,1991)。
连续8天以10mg/kg的剂量皮下给予顺铂。在此期间，给小鼠注射100mg/kg的肉毒碱和2.5mg/kg白藜芦醇或这些产物的组合。
这两个试验的结果为组合物所提供的、特别是乙酰基L-肉毒碱和丙酰基L-肉毒碱与白藜芦醇或包含白藜芦醇的葡萄提取物的组合物所提供的更明显的强保护作用提供了证据。
在这些情况下，对疼痛刺激的反应恢复至正常水平(与对照相比，用组合物治疗的动物对疼痛的反应增加大约2℃)。
在转棒试验中，鉴于对照动物(每组10只动物)的平衡时间为14.6秒(顺铂治疗的动物降低至大约8秒)，注意到，肉毒碱治疗组和白藜芦醇治疗组动物的平衡时间显著增加。然而，试验组合物治疗组动物的该增加值证明是非常显著的。事实上，所观察到的用乙酰基L-肉毒碱和白藜芦醇治疗动物的该值为13.5秒，用丙酰基L-肉毒碱和白藜芦醇治疗动物的该值为14.4秒。
这些试验也证明了在肉毒碱和白藜芦醇之间存在意想不到的协同作用。
下文提到的是本发明制剂说明性而非限定性实例。
1)、L-肉毒碱 mg 500
白藜芦醇 mg 5
2)、乙酰基L-肉毒碱 mg 500
白藜芦醇 mg 5
3)、丙酰基L-肉毒碱 mg 500
白藜芦醇 mg 5
4)、异戊酰基L-肉毒碱 mg 500
白藜芦醇 mg 5
5)、L-肉毒碱 mg 500
冻干葡萄提取物(mg,0.5％白藜芦醇) mg 250
6)、乙酰基L-肉毒碱 mg 500
冻干葡萄提取物(mg,0.5％白藜芦醇) mg 250
7)、丙酰基L-肉毒碱 mg 500
冻干葡萄提取物(mg,0.5％白藜芦醇) mg 250
8)、异戊酰基L-肉毒碱 mg 500
冻干葡萄提取物(mg,0.5％白藜芦醇) mg 250
9)、L-肉毒碱 mg 500
白藜芦醇 mg 5
醋酸生育酚 mg 20
β-胡萝卜素 mg 10
10)、L-肉毒碱 mg 500
冻干葡萄提取物(mg,0.5％白藜芦醇) mg 250
醋酸生育酚 mg 20
β-胡萝卜素 mg 10
11)、L-肉毒碱 mg 500
白藜芦醇 mg 5
醋酸生育酚 mg 20
维生素C mg 100
硒 mg 40
12)、乙酰基L-肉毒碱 mg 250
白藜芦醇 mg 2.5
磷脂酰胆碱 mg 50
磷脂酰丝氨酸 mg 50
甘油基磷酰胆碱菜 mg 5013)、乙酰基L-肉毒碱 mg 250
葡萄多酚 mg 100
白藜芦醇 mg 2.5
磷脂酰胆碱 mg 50
磷脂酰丝氨酸 mg 50
甘油基磷酰胆碱 mg 50
维生素E mg 10
硒 mg 10
镁 mg 5
锌 mg 314)、乙酰基L-肉毒碱 mg 250
葡萄多酚 mg 100
白藜芦醇 mg 2.5
维生素B1 mg 1
维生素B2 mg 1
维生素B6 mg 2
泛硫乙胺 mg 5
丝氨酸 mg 10
胆碱 mg 10
精氨酸 mg 10
赖氨酸 mg 10
L-肉毒碱或链烷酰基L-肉毒碱的可药用盐是指这些活性组分与酸形成的不引起不需要的有毒作用和副作用的任何盐。这些酸是药学专业人员公知的。
适宜盐的非限定性实例如下：氯化物；溴化物；碘化物；门冬氨酸盐，酸式门冬氨酸盐；柠檬酸盐，酸式柠檬酸盐；酒石酸盐；磷酸盐，酸式磷酸盐；富马酸盐，酸式富马酸盐；甘油磷酸盐；葡萄糖磷酸盐；乳酸盐；马来酸盐，酸式马来酸盐；乳清酸盐；草酸盐，酸式草酸盐；硫酸盐，酸式硫酸盐；三氯乙酸盐；三氟乙酸盐和甲磺酸盐。
Int.J.Pharm.33,(1986),201-217中提到FDA批准的可药用盐一览表；将该公开内容引入本文供参考。
上述组合物可制备成通过口服、非肠道、直肠或透皮给药的固体、半固体、液体、半液体、粉末、颗粒或脂质体形式。
除特性组分(A)和(B)外，所述复方组合物中也可以包含一种或多种下列成分：多酚、花青苷、鞣酸、花色素甙、维生素、辅酶、无机盐、植物纤维、磷脂酰胆碱、磷脂酰丝氨酸、甘油磷酰胆碱、人参和银杏提取物、维生素和抗氧化剂。
Claims (11)
1、(A)L-肉毒碱或其中直链或支链链烷酰基包含2-8个碳原子的链烷酰基L-肉毒碱或其可药用盐和(B)三羟基或四羟基茋在制备用于预防和治疗由神经元或大脑病变引起的病理性疾病的其中(A)和(B)以混合物形式或分别包装形式存在的食品强化剂或药物中的用途。
2、权利要求1的用途，其中所述链烷酰基包含2-6个碳原子。
3、权利要求2的用途，其中所述链烷酰基选自乙酰基、丙酰基、丁酰基、戊酰基和异戊酰基。
4、权利要求1-3的用途，其中组分(B)为3,4’,5-三羟基茋(白藜芦醇)或3,4’,5-三羟基茋-3-β-单-D-葡糖苷或其可药用盐或其酯。
5、权利要求4的用途，其中白藜芦醇是从葡萄、Vitisrotundifolia或美国葡萄中提取的白藜芦醇。
6、权利要求1-5的用途，其中组分(B)为葡萄、Vitis rotundifolia或美国葡萄的葡萄皮或葡萄茎和虎杖或何首乌的根的提取物或天然产物粉末。
7、权利要求1-6的用途，其中(B)与(A)的重量比为1∶1-1∶1000。
8、权利要求7的用途，其中(B)与(A)的重量比为1∶1-1∶500。
9、权利要求1-8的用途，用于预防或治疗由老化和使用神经毒性药物引起的大脑病变。
10、权利要求9的用途，用于预防和治疗脑中风、记忆丧失、早老性和老年性痴呆以及阿尔茨海默病。
11、一种包装盒，它包含：
(A)、L-肉毒碱或其中直链或支链链烷酰基包含2-8个碳原子的链烷酰基L-肉毒碱，或其可药用盐，和
(B)、三羟基或四羟基茋，
(A)和(B)以混合物或分别包装的形式存在，所述包装盒中备有关于(A)和(B)适用于预防/治疗由神经元或大脑病变引起的病理性疾病的说明书。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITRM98A000636 | 1998-10-09 | ||
| IT1998RM000636A IT1302365B1 (it) | 1998-10-09 | 1998-10-09 | Uso di carnitine e resveratrolo per produrre una composizione per laprevenzione o il trattamento terapeutico di alterazioni cerebrali |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1323205A true CN1323205A (zh) | 2001-11-21 |
Family
ID=11406160
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99811952A Pending CN1323205A (zh) | 1998-10-09 | 1999-10-06 | 预防或治疗大脑和老化疾病的肉毒碱和白藜芦醇的复方 |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US6515020B1 (zh) |
| EP (1) | EP1117394B1 (zh) |
| JP (1) | JP4166951B2 (zh) |
| KR (1) | KR20010079981A (zh) |
| CN (1) | CN1323205A (zh) |
| AR (1) | AR020762A1 (zh) |
| AT (1) | ATE249823T1 (zh) |
| AU (1) | AU767492B2 (zh) |
| BR (1) | BR9915918A (zh) |
| CA (1) | CA2344893C (zh) |
| CZ (1) | CZ2001920A3 (zh) |
| DE (1) | DE69911441T2 (zh) |
| DK (1) | DK1117394T3 (zh) |
| EE (1) | EE200100205A (zh) |
| ES (1) | ES2207287T3 (zh) |
| HK (1) | HK1040935A1 (zh) |
| HU (1) | HU229364B1 (zh) |
| IL (1) | IL142046A0 (zh) |
| IS (1) | IS5896A (zh) |
| IT (1) | IT1302365B1 (zh) |
| NO (1) | NO20011693D0 (zh) |
| PL (1) | PL197342B1 (zh) |
| PT (1) | PT1117394E (zh) |
| SK (1) | SK3782001A3 (zh) |
| TN (1) | TNSN99186A1 (zh) |
| TR (1) | TR200100947T2 (zh) |
| WO (1) | WO2000021526A1 (zh) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002047193A (ja) * | 2000-07-31 | 2002-02-12 | Sunstar Inc | アレルギー性皮膚炎予防または治療用組成物 |
| WO2002038141A2 (en) * | 2000-11-08 | 2002-05-16 | Massachusetts Institute Of Technology | Compositions and methods for treatment of mild cognitive impairment |
| BRPI0106382B1 (pt) * | 2001-03-13 | 2017-07-11 | Universidade Do Estado Do Rio De Janeiro - Uerj | Process for obtaining decocts from vitis labrusca and vitis vinifera casts, process for obtaining the hydro-alcoholic extract, process for obtaining the hydro-alcoholic extract-ethyl acetate and pharmaceutical compositions |
| DE50111204D1 (de) * | 2001-08-18 | 2006-11-23 | Cognis Ip Man Gmbh | Wirkstoffmischungen |
| US20070218151A1 (en) * | 2002-03-12 | 2007-09-20 | Universidade Do Estado Do Rio De Janeiro | Process for obtention of decoctions of Vitis labrusca and Vitis vinifera skins |
| US7977049B2 (en) * | 2002-08-09 | 2011-07-12 | President And Fellows Of Harvard College | Methods and compositions for extending the life span and increasing the stress resistance of cells and organisms |
| KR100574392B1 (ko) * | 2003-02-07 | 2006-05-02 | 재단법인서울대학교산학협력재단 | 신경보호활성을 갖는 신규 페닐환 유도체 및 이를함유하는 약학 조성물 |
| WO2005002672A2 (en) * | 2003-07-01 | 2005-01-13 | President And Fellows Of Harvard College | Sirt1 modulators for manipulating cells/organism lifespan/stress response |
| US20060025337A1 (en) * | 2003-07-01 | 2006-02-02 | President And Fellows Of Harvard College | Sirtuin related therapeutics and diagnostics for neurodegenerative diseases |
| KR100543056B1 (ko) * | 2003-11-07 | 2006-01-20 | (주)네추럴에프앤피 | 신경세포 보호 활성이 있는 포도씨 추출물을 포함하는뇌질환 예방 및 치료용 조성물 |
| CA2548671C (en) | 2003-12-29 | 2015-02-24 | President And Fellows Of Harvard College | Compositions for treating or preventing obesity and insulin resistance disorders |
| US8017634B2 (en) | 2003-12-29 | 2011-09-13 | President And Fellows Of Harvard College | Compositions for treating obesity and insulin resistance disorders |
| ES2245609B1 (es) * | 2004-06-18 | 2007-08-16 | Universidad De Barcelona | Nuevo agente terapeutico para el tratamiento de la infertilidad y/o subfertilidad masculina en mamiferos. |
| WO2006004722A2 (en) * | 2004-06-30 | 2006-01-12 | Biomol Research Laboratories, Inc. | Compositions and methods for selectively activating human sirtuins |
| US20060121137A1 (en) * | 2004-12-07 | 2006-06-08 | Hartle Diane K | Muscadine grape pomace in the treatment of intestinal inflammation |
| US20060276393A1 (en) * | 2005-01-13 | 2006-12-07 | Sirtris Pharmaceuticals, Inc. | Novel compositions for preventing and treating neurodegenerative and blood coagulation disorders |
| WO2006138418A2 (en) * | 2005-06-14 | 2006-12-28 | President And Fellows Of Harvard College | Improvement of cognitive performance with sirtuin activators |
| EP1993522A2 (en) | 2005-10-26 | 2008-11-26 | Kao Corporation | Resveratrol and/or grape leaf extract as i.a. endurance improver, anti-aging agent, muscle strength improver |
| FR2898493B1 (fr) * | 2006-03-16 | 2008-08-08 | Af Consulting | Compositions cosmetiques, pharmaceutiques, alimentaires et veterinaires dont l'action d'activation de genes de type sirtuin permet de retarder le vieillissement des mammiferes et ses effets nefastes |
| US20120016037A1 (en) * | 2006-07-24 | 2012-01-19 | Frank Toppo | Method for prevention and treatment of Alzheimers |
| US20100047177A1 (en) * | 2007-01-26 | 2010-02-25 | Washington University | Methods and compositions for treating neuropathies |
| AT506014A1 (de) * | 2007-10-24 | 2009-05-15 | Karl Mag Dr Zehethofer | Functional drink |
| SG185692A1 (en) * | 2010-06-16 | 2013-01-30 | Sigma Tau Ind Farmaceuti | Acetyl-carnitine for use in a method for increasing neurogenesis in neural tissue |
| KR101327936B1 (ko) * | 2011-07-06 | 2013-11-13 | 한국식품연구원 | 옥시레스베라트롤 이민 유도체를 유효성분으로 함유하는 뇌신경보호 효과를 가지는 조성물 |
| CN102919943A (zh) * | 2012-10-26 | 2013-02-13 | 郑全辉 | 保健饮品-葡藤素 |
| CN103877170B (zh) * | 2012-12-19 | 2015-11-04 | 中国医学科学院药用植物研究所 | 一种虎杖的乙酸乙酯提取物及其制备方法和应用 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4346107A (en) * | 1979-02-12 | 1982-08-24 | Claudio Cavazza | Pharmaceutical composition comprising acyl-carnitine for the treatment of impaired cerebral metabolism |
| IT1276225B1 (it) * | 1995-10-17 | 1997-10-27 | Sigma Tau Ind Farmaceuti | Composizioni farmaceutiche contenenti l-carnitina e alcanoil l- carnitine in associazione con resveratrolo o suoi derivati utili per |
| IT1283967B1 (it) * | 1996-03-29 | 1998-05-07 | Sigma Tau Ind Farmaceuti | Uso di l-carnitina o derivati della l-carnitina ed antiossidanti nella prevenzione e trattamento di patologie derivanti da danni ossidativi |
| WO1998033494A1 (en) | 1997-02-04 | 1998-08-06 | Kosbab John V | Compositions and methods for prevention and treatment of vascular degenerative diseases |
| IT1291113B1 (it) | 1997-03-20 | 1998-12-29 | Sigma Tau Ind Farmaceuti | Composizione nutritiva terapeutica per soggetti affetti da diabete mellito |
| CH692837A5 (it) * | 1997-07-02 | 2002-11-29 | Lisapharma Spa | Composizione farmaceutica per uso alimentare, dietetico o medicinale adatta a migliorare l'assorbimento orale dei polifenoli e particolarmente del resveratrolo presenti nell'uva e nei suoi p |
| US5904924A (en) * | 1997-11-04 | 1999-05-18 | Oncologics, Inc. | Green nutritional powder composition |
| AU4084599A (en) | 1998-05-18 | 1999-12-06 | Oklahoma Medical Research Foundation | Resveratrol inhibition of myeloperoxidase |
-
1998
- 1998-10-09 IT IT1998RM000636A patent/IT1302365B1/it active IP Right Grant
-
1999
- 1999-10-05 TN TNTNSN99186A patent/TNSN99186A1/fr unknown
- 1999-10-06 BR BR9915918-0A patent/BR9915918A/pt not_active Application Discontinuation
- 1999-10-06 KR KR1020017004267A patent/KR20010079981A/ko not_active Application Discontinuation
- 1999-10-06 PT PT99947853T patent/PT1117394E/pt unknown
- 1999-10-06 JP JP2000575502A patent/JP4166951B2/ja not_active Expired - Fee Related
- 1999-10-06 EP EP99947853A patent/EP1117394B1/en not_active Expired - Lifetime
- 1999-10-06 DE DE69911441T patent/DE69911441T2/de not_active Expired - Lifetime
- 1999-10-06 US US09/806,454 patent/US6515020B1/en not_active Expired - Fee Related
- 1999-10-06 AT AT99947853T patent/ATE249823T1/de active
- 1999-10-06 PL PL347209A patent/PL197342B1/pl not_active IP Right Cessation
- 1999-10-06 EE EEP200100205A patent/EE200100205A/xx unknown
- 1999-10-06 AU AU61213/99A patent/AU767492B2/en not_active Ceased
- 1999-10-06 CN CN99811952A patent/CN1323205A/zh active Pending
- 1999-10-06 CA CA002344893A patent/CA2344893C/en not_active Expired - Fee Related
- 1999-10-06 DK DK99947853T patent/DK1117394T3/da active
- 1999-10-06 CZ CZ2001920A patent/CZ2001920A3/cs unknown
- 1999-10-06 IL IL14204699A patent/IL142046A0/xx unknown
- 1999-10-06 SK SK378-2001A patent/SK3782001A3/sk unknown
- 1999-10-06 ES ES99947853T patent/ES2207287T3/es not_active Expired - Lifetime
- 1999-10-06 WO PCT/IT1999/000311 patent/WO2000021526A1/en not_active Application Discontinuation
- 1999-10-06 HU HU0104021A patent/HU229364B1/hu unknown
- 1999-10-06 TR TR2001/00947T patent/TR200100947T2/xx unknown
- 1999-10-08 AR ARP990105115A patent/AR020762A1/es unknown
-
2001
- 2001-03-16 IS IS5896A patent/IS5896A/is unknown
- 2001-04-04 NO NO20011693A patent/NO20011693D0/no not_active Application Discontinuation
-
2002
- 2002-04-17 HK HK02102885.2A patent/HK1040935A1/zh unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1323205A (zh) | 预防或治疗大脑和老化疾病的肉毒碱和白藜芦醇的复方 | |
| DE69801047T2 (de) | Nährungserganzungmittel | |
| DE69904173T2 (de) | Nervenschützende zusammensetzung zur prophylaxe und behandlung von nervös- und verhaltungsänderungen durch angstartigen zuständen oder depressionen, die acetyl-l-carnitin und hypericin enthalt | |
| US20240277741A1 (en) | Agent for preventing or ameliorating alzheimer's disease | |
| US20050282772A1 (en) | New dietary supplement composition for obesity and inflammation | |
| JP2022169695A (ja) | ルテイン類またはその塩およびヒシ属植物の加工物を含有する脳機能障害の予防および／または改善用組成物 | |
| ES2229514T3 (es) | Composicion que comprende l-carnitina o una alcanoil-l-carnitina y alcanoles de cadena larga. | |
| DE60021247T2 (de) | Carnitin und inositolphosphat enthaltende zusammensetzung als diätzusatz oder arzneimittel | |
| CN111388511A (zh) | 一种改善记忆力、预防老年痴呆的组合物及其制备方法和应用 | |
| EP3461479B1 (en) | Nutraceutical and pharmaceutical compositions, and uses thereof for preserving cognitive functions | |
| Senou et al. | Antidiabetic Activity of Aqueous Extracts of Laurus nobilis, a Spice Used by Beninese Traditional Therapists | |
| CN1309393C (zh) | 一种辅助降血脂的磷脂颗粒剂 | |
| DE60103854T2 (de) | Zusammensetzung zur vorbeugung und/oder behandlung von lipidstoffwechselstörungen und allergischen formen | |
| DE202018101715U1 (de) | Mittel zur Behandlung von neurodegenerativen Erkrankungen | |
| Lubkowska et al. | Distribution of fluoride in selected structures of the central nervous system in rats exposed to NaF and AICI 3 in drinking water. | |
| ES2425045T3 (es) | Acetil-L-carnitina para la prevención de la neuropatía diabética periférica dolorosa | |
| MXPA01003569A (es) | Combinacion de carnitinas y resveratrol para prevenir o tratar enfermedades cerebrales y del envejecimiento | |
| GB2620279A (en) | Herbal composition for use in the improvement of physical and mental health recovery and maintenance, including the improvement of cognitive function or | |
| AT16233U1 (de) | Mittel zur Behandlung von neurodegenerativen Erkrankungen | |
| CZ20004623A3 (cs) | Přípravek k prevenci a/nebo léčbě nervových chorob a poruch chování vlivem stresu či deprese | |
| DE102004057758A1 (de) | Synergistische Arginin-Kombination |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1040935 Country of ref document: HK |