CN107468688A - 用于治疗帕金森病的新治疗方法 - Google Patents
用于治疗帕金森病的新治疗方法 Download PDFInfo
- Publication number
- CN107468688A CN107468688A CN201710551364.2A CN201710551364A CN107468688A CN 107468688 A CN107468688 A CN 107468688A CN 201710551364 A CN201710551364 A CN 201710551364A CN 107468688 A CN107468688 A CN 107468688A
- Authority
- CN
- China
- Prior art keywords
- baclofen
- parkinson
- acamprosate
- cnc
- composition
- 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
- 238000011282 treatment Methods 0.000 title description 49
- 239000003814 drug Substances 0.000 claims abstract description 170
- 239000000203 mixture Substances 0.000 claims abstract description 102
- 229940079593 drug Drugs 0.000 claims abstract description 84
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 229960000794 baclofen Drugs 0.000 claims description 97
- 229960004047 acamprosate Drugs 0.000 claims description 81
- AFCGFAGUEYAMAO-UHFFFAOYSA-N acamprosate Chemical compound CC(=O)NCCCS(O)(=O)=O AFCGFAGUEYAMAO-UHFFFAOYSA-N 0.000 claims description 73
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 claims description 66
- 150000003839 salts Chemical class 0.000 claims description 63
- 206010034010 Parkinsonism Diseases 0.000 claims description 62
- 239000000651 prodrug Substances 0.000 claims description 62
- 229940002612 prodrug Drugs 0.000 claims description 62
- VDHAWDNDOKGFTD-MRXNPFEDSA-N cinacalcet Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 VDHAWDNDOKGFTD-MRXNPFEDSA-N 0.000 claims description 61
- 229960005461 torasemide Drugs 0.000 claims description 60
- 229960003404 mexiletine Drugs 0.000 claims description 55
- 239000003405 delayed action preparation Substances 0.000 claims description 50
- VLPIATFUUWWMKC-SNVBAGLBSA-N (2r)-1-(2,6-dimethylphenoxy)propan-2-amine Chemical compound C[C@@H](N)COC1=C(C)C=CC=C1C VLPIATFUUWWMKC-SNVBAGLBSA-N 0.000 claims description 46
- 229960004502 levodopa Drugs 0.000 claims description 46
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 45
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 44
- NGBFQHCMQULJNZ-UHFFFAOYSA-N Torsemide Chemical compound CC(C)NC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 NGBFQHCMQULJNZ-UHFFFAOYSA-N 0.000 claims description 41
- 210000005064 dopaminergic neuron Anatomy 0.000 claims description 26
- 239000000126 substance Substances 0.000 claims description 25
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- 230000033001 locomotion Effects 0.000 claims description 18
- 239000003937 drug carrier Substances 0.000 claims description 8
- 208000006083 Hypokinesia Diseases 0.000 claims description 6
- 206010006100 Bradykinesia Diseases 0.000 claims description 5
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 3
- 239000010931 gold Substances 0.000 claims description 3
- 229910052737 gold Inorganic materials 0.000 claims description 3
- 238000004925 denaturation Methods 0.000 claims description 2
- 230000036425 denaturation Effects 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims 1
- 230000003252 repetitive effect Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 54
- 210000002569 neuron Anatomy 0.000 abstract description 27
- 238000002648 combination therapy Methods 0.000 abstract description 14
- 230000002776 aggregation Effects 0.000 abstract description 8
- 238000004220 aggregation Methods 0.000 abstract description 8
- 108090000185 alpha-Synuclein Proteins 0.000 abstract description 8
- 102000003802 alpha-Synuclein Human genes 0.000 abstract 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 230000000694 effects Effects 0.000 description 44
- 210000004027 cell Anatomy 0.000 description 36
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 33
- -1 Formate ester Chemical class 0.000 description 29
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 28
- 208000024891 symptom Diseases 0.000 description 28
- 201000010099 disease Diseases 0.000 description 26
- 231100000419 toxicity Toxicity 0.000 description 26
- 230000001988 toxicity Effects 0.000 description 26
- 230000001681 protective effect Effects 0.000 description 24
- 230000001225 therapeutic effect Effects 0.000 description 23
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 20
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 20
- 229930195712 glutamate Natural products 0.000 description 19
- 238000012360 testing method Methods 0.000 description 19
- 230000004224 protection Effects 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 239000003826 tablet Substances 0.000 description 16
- 238000009472 formulation Methods 0.000 description 15
- 238000013270 controlled release Methods 0.000 description 14
- 230000006378 damage Effects 0.000 description 13
- 239000008194 pharmaceutical composition Substances 0.000 description 13
- 239000001963 growth medium Substances 0.000 description 12
- 229960000245 rasagiline Drugs 0.000 description 12
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 description 12
- 229960003946 selegiline Drugs 0.000 description 12
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 11
- BKRGVLQUQGGVSM-KBXCAEBGSA-N Revanil Chemical compound C1=CC(C=2[C@H](N(C)C[C@H](C=2)NC(=O)N(CC)CC)C2)=C3C2=CNC3=C1 BKRGVLQUQGGVSM-KBXCAEBGSA-N 0.000 description 11
- 230000006698 induction Effects 0.000 description 11
- 230000000302 ischemic effect Effects 0.000 description 11
- 229960003587 lisuride Drugs 0.000 description 11
- DIVDFFZHCJEHGG-UHFFFAOYSA-N oxidopamine Chemical compound NCCC1=CC(O)=C(O)C=C1O DIVDFFZHCJEHGG-UHFFFAOYSA-N 0.000 description 11
- 239000000546 pharmaceutical excipient Substances 0.000 description 11
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 10
- WYDUSKDSKCASEF-LJQANCHMSA-N (1s)-1-cyclohexyl-1-phenyl-3-pyrrolidin-1-ylpropan-1-ol Chemical compound C([C@](O)(C1CCCCC1)C=1C=CC=CC=1)CN1CCCC1 WYDUSKDSKCASEF-LJQANCHMSA-N 0.000 description 10
- QXWYKJLNLSIPIN-YUMQZZPRSA-N (2s,3s)-2-azaniumyl-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoate Chemical compound [O-]C(=O)[C@@H]([NH3+])[C@@H](O)C1=CC=C(O)C(O)=C1 QXWYKJLNLSIPIN-YUMQZZPRSA-N 0.000 description 10
- OQDPVLVUJFGPGQ-UHFFFAOYSA-N 2-[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]pyrimidine Chemical compound C=1C=C2OCOC2=CC=1CN(CC1)CCN1C1=NC=CC=N1 OQDPVLVUJFGPGQ-UHFFFAOYSA-N 0.000 description 10
- 102100026882 Alpha-synuclein Human genes 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 10
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 10
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 10
- AMHPTVWBZSYFSS-BZUAXINKSA-N [(1r,3r,5r)-6,6,9-trimethyl-9-azabicyclo[3.3.1]nonan-3-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound O([C@H]1C[C@@H]2C(C)(C)CC[C@H](C1)N2C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 AMHPTVWBZSYFSS-BZUAXINKSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 10
- 229960003805 amantadine Drugs 0.000 description 10
- 229960004046 apomorphine Drugs 0.000 description 10
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 10
- VHGCDTVCOLNTBX-QGZVFWFLSA-N atomoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C VHGCDTVCOLNTBX-QGZVFWFLSA-N 0.000 description 10
- 229960002430 atomoxetine Drugs 0.000 description 10
- GIJXKZJWITVLHI-PMOLBWCYSA-N benzatropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(C=1C=CC=CC=1)C1=CC=CC=C1 GIJXKZJWITVLHI-PMOLBWCYSA-N 0.000 description 10
- 229960001081 benzatropine Drugs 0.000 description 10
- YSXKPIUOCJLQIE-UHFFFAOYSA-N biperiden Chemical compound C1C(C=C2)CC2C1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 YSXKPIUOCJLQIE-UHFFFAOYSA-N 0.000 description 10
- 229960003003 biperiden Drugs 0.000 description 10
- 229960004170 clozapine Drugs 0.000 description 10
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 10
- 229960003530 donepezil Drugs 0.000 description 10
- 229960003638 dopamine Drugs 0.000 description 10
- 229960001104 droxidopa Drugs 0.000 description 10
- 229960000219 mazaticol Drugs 0.000 description 10
- 229960001158 nortriptyline Drugs 0.000 description 10
- UQZKYYIKWZOKKD-UHFFFAOYSA-N orphenadrine hydrochloride Chemical compound [Cl-].C=1C=CC=C(C)C=1C(OCC[NH+](C)C)C1=CC=CC=C1 UQZKYYIKWZOKKD-UHFFFAOYSA-N 0.000 description 10
- 229960002296 paroxetine Drugs 0.000 description 10
- 229960004851 pergolide Drugs 0.000 description 10
- YEHCICAEULNIGD-MZMPZRCHSA-N pergolide Chemical compound C1=CC([C@H]2C[C@@H](CSC)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 YEHCICAEULNIGD-MZMPZRCHSA-N 0.000 description 10
- 229960004310 piribedil Drugs 0.000 description 10
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 10
- 229960003089 pramipexole Drugs 0.000 description 10
- 229960005253 procyclidine Drugs 0.000 description 10
- 229960004136 rivastigmine Drugs 0.000 description 10
- 229960003179 rotigotine Drugs 0.000 description 10
- KFQYTPMOWPVWEJ-INIZCTEOSA-N rotigotine Chemical compound CCCN([C@@H]1CC2=CC=CC(O)=C2CC1)CCC1=CC=CS1 KFQYTPMOWPVWEJ-INIZCTEOSA-N 0.000 description 10
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 10
- 229960004688 venlafaxine Drugs 0.000 description 10
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 9
- KORNTPPJEAJQIU-KJXAQDMKSA-N Cabaser Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)N(CCCN(C)C)C(=O)NCC)=C3C2=CNC3=C1 KORNTPPJEAJQIU-KJXAQDMKSA-N 0.000 description 9
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 9
- 238000000540 analysis of variance Methods 0.000 description 9
- 210000004556 brain Anatomy 0.000 description 9
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 9
- 229960002802 bromocriptine Drugs 0.000 description 9
- 229960004596 cabergoline Drugs 0.000 description 9
- 239000002775 capsule Substances 0.000 description 9
- 229960001653 citalopram Drugs 0.000 description 9
- 229960001284 citicoline Drugs 0.000 description 9
- FGXWKSZFVQUSTL-UHFFFAOYSA-N domperidone Chemical compound C12=CC=CC=C2NC(=O)N1CCCN(CC1)CCC1N1C2=CC=C(Cl)C=C2NC1=O FGXWKSZFVQUSTL-UHFFFAOYSA-N 0.000 description 9
- 229960001253 domperidone Drugs 0.000 description 9
- QPJBWNIQKHGLAU-IQZHVAEDSA-N ganglioside GM1 Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@H](NC(=O)CCCCCCCCCCCCCCCCC)[C@H](O)\C=C\CCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)[C@@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](CO)O1 QPJBWNIQKHGLAU-IQZHVAEDSA-N 0.000 description 9
- 230000036542 oxidative stress Effects 0.000 description 9
- YWAFNFGRBBBSPD-OCMLZEEQSA-M sodium;[[(2r,3s,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound [Na+].O[C@@H]1[C@H](O)[C@@H](COP([O-])(=O)OP([O-])(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 YWAFNFGRBBBSPD-OCMLZEEQSA-M 0.000 description 9
- QDWJJTJNXAKQKD-UHFFFAOYSA-N trihexyphenidyl hydrochloride Chemical compound Cl.C1CCCCC1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 QDWJJTJNXAKQKD-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- DHSSDEDRBUKTQY-UHFFFAOYSA-N 6-prop-2-enyl-4,5,7,8-tetrahydrothiazolo[4,5-d]azepin-2-amine Chemical compound C1CN(CC=C)CCC2=C1N=C(N)S2 DHSSDEDRBUKTQY-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 8
- 229960004640 memantine Drugs 0.000 description 8
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 8
- 229960004431 quetiapine Drugs 0.000 description 8
- 229950008418 talipexole Drugs 0.000 description 8
- 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 7
- 102000011931 Nucleoproteins Human genes 0.000 description 7
- 108010061100 Nucleoproteins Proteins 0.000 description 7
- 208000005374 Poisoning Diseases 0.000 description 7
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 7
- 238000000576 coating method Methods 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 210000001259 mesencephalon Anatomy 0.000 description 7
- 231100000572 poisoning Toxicity 0.000 description 7
- 230000000607 poisoning effect Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 6
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 240000007594 Oryza sativa Species 0.000 description 6
- 235000007164 Oryza sativa Nutrition 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 6
- 238000009825 accumulation Methods 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 230000004064 dysfunction Effects 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 210000003470 mitochondria Anatomy 0.000 description 6
- 230000016273 neuron death Effects 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 235000009566 rice Nutrition 0.000 description 6
- 230000035882 stress Effects 0.000 description 6
- 206010011224 Cough Diseases 0.000 description 5
- 208000012661 Dyskinesia Diseases 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 101000619542 Homo sapiens E3 ubiquitin-protein ligase parkin Proteins 0.000 description 5
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 206010044565 Tremor Diseases 0.000 description 5
- 210000003618 cortical neuron Anatomy 0.000 description 5
- 230000003291 dopaminomimetic effect Effects 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 239000004220 glutamic acid Substances 0.000 description 5
- 235000013922 glutamic acid Nutrition 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 238000007689 inspection Methods 0.000 description 5
- 230000003902 lesion Effects 0.000 description 5
- 239000004005 microsphere Substances 0.000 description 5
- 239000002674 ointment Substances 0.000 description 5
- 102000045222 parkin Human genes 0.000 description 5
- 230000001575 pathological effect Effects 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 229940107333 phenergan Drugs 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 description 5
- 229960001879 ropinirole Drugs 0.000 description 5
- 229930182490 saponin Natural products 0.000 description 5
- 150000007949 saponins Chemical class 0.000 description 5
- 238000011287 therapeutic dose Methods 0.000 description 5
- 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 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 4
- 102000018899 Glutamate Receptors Human genes 0.000 description 4
- 108010027915 Glutamate Receptors Proteins 0.000 description 4
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 206010021143 Hypoxia Diseases 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- 102100037499 Parkinson disease protein 7 Human genes 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 108010032428 Protein Deglycase DJ-1 Proteins 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000006399 behavior Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000001054 cortical effect Effects 0.000 description 4
- 230000007850 degeneration Effects 0.000 description 4
- 229960003914 desipramine Drugs 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229940088679 drug related substance Drugs 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- 230000007954 hypoxia Effects 0.000 description 4
- 239000007943 implant Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 229920000609 methyl cellulose Polymers 0.000 description 4
- 239000001923 methylcellulose Substances 0.000 description 4
- 235000010981 methylcellulose Nutrition 0.000 description 4
- 239000003094 microcapsule Substances 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 230000032405 negative regulation of neuron apoptotic process Effects 0.000 description 4
- 210000005036 nerve Anatomy 0.000 description 4
- 208000015122 neurodegenerative disease Diseases 0.000 description 4
- 230000004112 neuroprotection Effects 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 230000035935 pregnancy Effects 0.000 description 4
- 230000002335 preservative effect Effects 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 4
- 229940124530 sulfonamide Drugs 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 3
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical class CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 3
- 206010002653 Anosmia Diseases 0.000 description 3
- 206010012289 Dementia Diseases 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 238000011199 Dunnett post hoc test Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000001856 Ethyl cellulose Substances 0.000 description 3
- 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 3
- 102000034615 Glial cell line-derived neurotrophic factor Human genes 0.000 description 3
- 108091010837 Glial cell line-derived neurotrophic factor Proteins 0.000 description 3
- 101000979001 Homo sapiens Methionine aminopeptidase 2 Proteins 0.000 description 3
- 101000969087 Homo sapiens Microtubule-associated protein 2 Proteins 0.000 description 3
- 101000887201 Homo sapiens Polyamine-transporting ATPase 13A2 Proteins 0.000 description 3
- 101000605835 Homo sapiens Serine/threonine-protein kinase PINK1, mitochondrial Proteins 0.000 description 3
- 102100023174 Methionine aminopeptidase 2 Human genes 0.000 description 3
- 102100023055 Neurofilament medium polypeptide Human genes 0.000 description 3
- 101710109612 Neurofilament medium polypeptide Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 102100039917 Polyamine-transporting ATPase 13A2 Human genes 0.000 description 3
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 3
- 102100038376 Serine/threonine-protein kinase PINK1, mitochondrial Human genes 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 235000019558 anosmia Nutrition 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 description 3
- 229960000911 benserazide Drugs 0.000 description 3
- 230000031018 biological processes and functions Effects 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229960004205 carbidopa Drugs 0.000 description 3
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 description 3
- 230000030833 cell death Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 235000019325 ethyl cellulose Nutrition 0.000 description 3
- 229920001249 ethyl cellulose Polymers 0.000 description 3
- 230000007717 exclusion Effects 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 238000009115 maintenance therapy Methods 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 239000002105 nanoparticle Substances 0.000 description 3
- 230000004751 neurological system process Effects 0.000 description 3
- 230000006576 neuronal survival Effects 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 230000000750 progressive effect Effects 0.000 description 3
- 210000000664 rectum Anatomy 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 230000000946 synaptic effect Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 229940081615 DOPA decarboxylase inhibitor Drugs 0.000 description 2
- 206010067889 Dementia with Lewy bodies Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010017577 Gait disturbance Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 208000009829 Lewy Body Disease Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000001089 Multiple system atrophy Diseases 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 208000037273 Pathologic Processes Diseases 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 229920001800 Shellac Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 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
- 230000006978 adaptation Effects 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000037147 athletic performance Effects 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 230000037058 blood plasma level Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 235000019437 butane-1,3-diol Nutrition 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000004203 carnauba wax Substances 0.000 description 2
- 210000000078 claw Anatomy 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000000534 dopa decarboxylase inhibitor Substances 0.000 description 2
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 229960003337 entacapone Drugs 0.000 description 2
- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 229940125532 enzyme inhibitor Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000003492 excitotoxic effect Effects 0.000 description 2
- 231100000063 excitotoxicity Toxicity 0.000 description 2
- 210000003754 fetus Anatomy 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 229940014259 gelatin Drugs 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 210000001905 globus pallidus Anatomy 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 208000013403 hyperactivity Diseases 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 239000002917 insecticide Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 231100000636 lethal dose Toxicity 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- 229960002900 methylcellulose Drugs 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000000116 mitigating effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 238000011859 neuroprotective therapy Methods 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000009054 pathological process Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 239000002574 poison Substances 0.000 description 2
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920000915 polyvinyl chloride Polymers 0.000 description 2
- 239000004800 polyvinyl chloride Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 2
- JADFCQKRKICRKI-UHFFFAOYSA-N quinoline;sulfane Chemical compound S.N1=CC=CC2=CC=CC=C21 JADFCQKRKICRKI-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000011514 reflex Effects 0.000 description 2
- 230000000862 serotonergic effect Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000004208 shellac Substances 0.000 description 2
- 229940113147 shellac Drugs 0.000 description 2
- 235000013874 shellac Nutrition 0.000 description 2
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 230000007480 spreading Effects 0.000 description 2
- 238000003892 spreading Methods 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 210000003523 substantia nigra Anatomy 0.000 description 2
- 210000004281 subthalamic nucleus Anatomy 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 210000001364 upper extremity Anatomy 0.000 description 2
- 210000004291 uterus Anatomy 0.000 description 2
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- 101150000874 11 gene Proteins 0.000 description 1
- WCOXQTXVACYMLM-UHFFFAOYSA-N 2,3-bis(12-hydroxyoctadecanoyloxy)propyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC(O)CCCCCC)COC(=O)CCCCCCCCCCC(O)CCCCCC WCOXQTXVACYMLM-UHFFFAOYSA-N 0.000 description 1
- FWWOWPGPERBCNJ-UHFFFAOYSA-N 2-hydroxy-4-(2-hydroxyethoxy)-4-oxobutanoic acid Chemical compound OCCOC(=O)CC(O)C(O)=O FWWOWPGPERBCNJ-UHFFFAOYSA-N 0.000 description 1
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 1
- BYDRTKVGBRTTIT-UHFFFAOYSA-N 2-methylprop-2-en-1-ol Chemical group CC(=C)CO BYDRTKVGBRTTIT-UHFFFAOYSA-N 0.000 description 1
- SNKZJIOFVMKAOJ-UHFFFAOYSA-N 3-Aminopropanesulfonate Chemical compound NCCCS(O)(=O)=O SNKZJIOFVMKAOJ-UHFFFAOYSA-N 0.000 description 1
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 102000007471 Adenosine A2A receptor Human genes 0.000 description 1
- 108010085277 Adenosine A2A receptor Proteins 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- 239000012099 Alexa Fluor family Substances 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- QLMMOGWZCFQAPU-UHFFFAOYSA-N CGP-3466 Chemical compound C#CCN(C)CC1=CC2=CC=CC=C2OC2=CC=CC=C12 QLMMOGWZCFQAPU-UHFFFAOYSA-N 0.000 description 1
- 241000345998 Calamus manan Species 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229940099362 Catechol O methyltransferase inhibitor Drugs 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000004381 Choline salt Substances 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 102100021809 Chorionic somatomammotropin hormone 1 Human genes 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-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
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 208000014094 Dystonic disease Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000027534 Emotional disease Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 101000895818 Homo sapiens Chorionic somatomammotropin hormone 1 Proteins 0.000 description 1
- 101000956228 Homo sapiens Chorionic somatomammotropin hormone 2 Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 1
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 1
- 229940086616 Monoamine oxidase B inhibitor Drugs 0.000 description 1
- 208000002430 Multiple chemical sensitivity Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- PRPAGESBURMWTI-UHFFFAOYSA-N [C].[F] Chemical compound [C].[F] PRPAGESBURMWTI-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 229920006221 acetate fiber Polymers 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
- UGZICOVULPINFH-UHFFFAOYSA-N acetic acid;butanoic acid Chemical compound CC(O)=O.CCCC(O)=O UGZICOVULPINFH-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940065524 anticholinergics inhalants for obstructive airway diseases 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
- 239000007900 aqueous suspension Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000000386 athletic effect Effects 0.000 description 1
- 210000000467 autonomic pathway Anatomy 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 210000004227 basal ganglia Anatomy 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 229940074995 bromine Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 description 1
- 230000008809 cell oxidative stress Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000019417 choline salt Nutrition 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 210000002932 cholinergic neuron Anatomy 0.000 description 1
- 229960003315 cinacalcet Drugs 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 208000013044 corticobasal degeneration disease Diseases 0.000 description 1
- 239000002837 defoliant Substances 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- MHUWZNTUIIFHAS-CLFAGFIQSA-N dioleoyl phosphatidic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-CLFAGFIQSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000006733 dopaminergic cell loss Effects 0.000 description 1
- 230000007977 dopaminergic denervation Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 208000010118 dystonia Diseases 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000005530 etching Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 210000001362 glutamatergic neuron Anatomy 0.000 description 1
- UHUSDOQQWJGJQS-UHFFFAOYSA-N glycerol 1,2-dioctadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCCCC UHUSDOQQWJGJQS-UHFFFAOYSA-N 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 210000004565 granule cell Anatomy 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- SCMLRESZJCKCTC-KMYQRJGFSA-N gtpl8173 Chemical compound C12=CC=C(CSCC)C=C2C2=C(CNC3=O)C3=C3C4=CC(CSCC)=CC=C4N4C3=C2N1[C@]1(C)[C@@](O)(C(=O)OC)C[C@H]4O1 SCMLRESZJCKCTC-KMYQRJGFSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- PKIFBGYEEVFWTJ-UHFFFAOYSA-N hexaphene Chemical compound C1=CC=C2C=C3C4=CC5=CC6=CC=CC=C6C=C5C=C4C=CC3=CC2=C1 PKIFBGYEEVFWTJ-UHFFFAOYSA-N 0.000 description 1
- 239000000416 hydrocolloid Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000003483 hypokinetic effect Effects 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- QRWOVIRDHQJFDB-UHFFFAOYSA-N isobutyl cyanoacrylate Chemical compound CC(C)COC(=O)C(=C)C#N QRWOVIRDHQJFDB-UHFFFAOYSA-N 0.000 description 1
- 150000002545 isoxazoles Chemical class 0.000 description 1
- 229960004427 isradipine Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 238000004900 laundering Methods 0.000 description 1
- 239000011133 lead Substances 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- YKSNLCVSTHTHJA-UHFFFAOYSA-L maneb Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S YKSNLCVSTHTHJA-UHFFFAOYSA-L 0.000 description 1
- 229920000940 maneb Polymers 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- YLOWTPHXXDJBAH-UHFFFAOYSA-N methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.COC(=O)C(C)=C YLOWTPHXXDJBAH-UHFFFAOYSA-N 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 230000003990 molecular pathway Effects 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 238000002610 neuroimaging Methods 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000001129 nonadrenergic effect Effects 0.000 description 1
- 230000002536 noncholinergic effect Effects 0.000 description 1
- 201000003077 normal pressure hydrocephalus Diseases 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229950001999 omigapil Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- FIKAKWIAUPDISJ-UHFFFAOYSA-L paraquat dichloride Chemical compound [Cl-].[Cl-].C1=C[N+](C)=CC=C1C1=CC=[N+](C)C=C1 FIKAKWIAUPDISJ-UHFFFAOYSA-L 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000008823 permeabilization Effects 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical group [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 230000001144 postural effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 235000012950 rattan cane Nutrition 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 229960004181 riluzole Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960004603 tolcapone Drugs 0.000 description 1
- MIQPIUSUKVNLNT-UHFFFAOYSA-N tolcapone Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC(O)=C(O)C([N+]([O-])=O)=C1 MIQPIUSUKVNLNT-UHFFFAOYSA-N 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 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
-
- 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
- A61K31/13—Amines
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
-
- 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
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- 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
- A61K31/4164—1,3-Diazoles
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
- A61K31/42—Oxazoles
-
- 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
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
-
- 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
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic 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
- A61K31/33—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
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- 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
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
-
- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- 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
-
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
- A61K31/33—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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
-
- 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
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及用于治疗帕金森病及相关障碍的组合物和方法。更具体地,本发明涉及靶向α‑突触核蛋白聚集网络的帕金森病及相关障碍的新型组合疗法。特别地,本发明涉及这样的化合物,其单独或组合地可以有效地保护神经元细胞免于α‑突触核蛋白聚集。本发明还涉及生产用于治疗帕金森病的药物或药物组合的方法以及治疗帕金森病或相关障碍的方法。
Description
本申请为分案申请,原申请的申请日为2013年2月28日,申请号为201380011335.7(PCT/EP2013/054026),发明名称为“用于治疗帕金森病的新治疗方法”。
发明领域
本发明涉及用于治疗帕金森病及相关障碍的组合物和方法。更具体地,本发明涉及帕金森病及相关障碍的新型组合疗法。
发明背景
帕金森综合征或帕金森病症是一类进行性、多中心神经退行性疾病,其主要特征是休息时震颤、僵硬、运动徐缓和姿势不稳。帕金森病(PD)是帕金森综合征的最常见形式并且是阿尔茨海默病之后的第二最常见神经退行性疾病。在发达国家,PD的患病率被估算在总人口的大约0.3%,老年人是最危险的(据估算80以上的人群的4%受影响)。发作的平均年龄为约60岁,尽管可能发生早期发作(年轻到20岁)(1)。
PD通常被归类为运动障碍。休息性震颤是最常见且通常是最早发展的症状。运动徐缓也通常出现在具有完成任务如书写或穿衣的困难的早期阶段。多动性运动障碍已被报道为帕金森病的一些治疗的副作用。在这方面,US5,952,389专利公开了阿坎酸用于减轻左旋多巴-诱发的多动性运动障碍的用途。然而,药物的限制第二作用是不同的并且远离治疗疾病或相关症状。僵硬出现并且进展至僵硬和整个身体运动的抗性,降低运动的能力。在后期阶段,疾病进展为姿势不稳,导致受损平衡和经常跌倒。其他运动症状如步态或吞咽障碍可能升高。如果不治疗,则运动症状可能导致患者在平均十年后卧床不起(2,3)。
在疾病的后期阶段,PD导致许多非运动症状,其个体地变化极大。失能然后通过发展自主神经错乱极大恶化。说话、认知、情绪、行为和/或思想的障碍将发展,最终导致痴呆。其他常见症状包括感觉、睡眠和情绪问题。那些障碍降低受影响个体的预期寿命并且死亡率为约没有PD的人的两倍(2-4)。
PD是特发病并且其病理生理学也保持很差的理解(4)。然而,至少5%的PD病例可以归属于遗传变异。基因内的突变如SNCA(α-突触核蛋白),PRKN(parkin),LRRK2(富含亮氨酸重复激酶2),PINK1(PTEN-诱导的公认激酶1),DJ-1和ATP13A2以及十一个基因座位(PARK1-PARK11)已与家族性PD相关联(5)。DJ1被怀疑是普遍存在的氧化还原响应的细胞保护蛋白,由此确认PD中的氧化应激的关键作用,这由缺氧诱导因子(Hypoxia InducibleFactor)在针对氧化应激、线粒体功能障碍和铁稳态扰动的黑质多巴胺能细胞保护中的保护作用所证实(29)。除了遗传因素,已经提出许多环境危险因素涉及PD的发作,但都没有确凿的证据。最频繁重复的危险因素是暴露于金属、杀虫剂或除草剂如落叶剂(AgentOrange)。另一方面,抽烟和咖啡因消费看起来保护个体免于PD(1)。
PD的病理生理学由四个特征表征(4):
(i)突触核蛋白淡漠,特征在于α-突触核蛋白蛋白质异常积累到脑中的称为路易斯小体的内含物中。路易斯小体在整个脑中的分布随个体不同而变化但经常直接与临床症状的表达和程度相关。
(ii)谷氨酸盐是哺乳动物神经系统中最丰富的兴奋性神经递质。在病理学条件下,其在突触间隙中的异常积累导致谷氨酸盐受体过度活化。谷氨酸盐在突触间隙中的异常积累导致谷氨酸盐受体的过度活化,这导致病理学过程并且最后导致神经元细胞死亡。这个过程,称为兴奋性中毒,通常在急性或慢性神经障碍期间在神经元组织中观察到。变得明显的是,兴奋性中毒涉及帕金森病的发病机理。
(iii)由于黑质(中脑的一个区域)中产生多巴胺的细胞死亡所致的多巴胺能活性缺乏。这导致失去肌肉运动和音调控制,从而导致PD的运动症状。
(iv)NANC(非肾上腺素能,非胆碱能)、血清素能和胆碱能神经元的退化也发生在疾病的后期,导致PD的非运动症状。
由于没有可用的生物学试验,所以PD的诊断主要基于临床症状的观察和具有类似临床特征的其他障碍的排除(3)。对于明确诊断需要死后确认。通过神经成像的神经学检查可用用来检测多巴胺能神经元的变化以及排除其他疾病的可能性。对左旋多巴的阳性治疗响应是另一个诊断标准。一旦形成诊断,则使用阶段量表如统一的帕金森病评级量表对疾病的进展和严重度进行评级。
最广泛使用的治疗,尤其是在早期阶段,是多巴胺前体左旋多巴(L-DOPA)(6)。药物将缺乏的神经递质带入多巴胺能神经元,由此降低运动症状。然而,大多数的药物在到达血脑屏障之前被代谢,引起各种副作用,尤其是胃肠道反应(如厌食症、恶心或呕吐)、运动障碍和精神症状(7)。因此,为了防止运动障碍现象,L-DOPA通常联合卡比多巴(carbidopa)或苄丝肼(benserazide)(外周多巴脱羧酶抑制剂)并且经常还联合儿茶酚-O-甲基转移酶抑制剂如恩他卡朋(entacapone)一起给予。这些药物旨在防止在到达大脑之前的L-DOPA代谢作用,增强药物的活性(6)。尽管在改善运动症状方面较不有效,但是多巴胺激动剂如培高利特,卡麦角林,阿朴吗啡或麦角乙脲以及单胺氧化酶-B抑制剂(涉及多巴胺的代谢分解)如司来吉兰或雷沙吉兰通常在疾病的早期使用。尽管较不有效,但是它们可能在延迟使用左旋多巴并因此延迟运动障碍的发作方面有用(7)。
其他药物如抗胆碱能类和烟碱乙酰基胆碱受体激动剂可以是有用的但它们对于PD的效力有待确认(7)。目前的研究还集中在神经保护性治疗,但是都没有提供改善的退化的证据。它们瞄准细胞凋亡(omigapil,CEP-1347)、谷氨酸受体、腺苷A2A受体、钙通道(伊拉地平(isradipine))、生长因子(GDNF)、α-突触核蛋白和炎症(8)。
进行的药物研究已经显示出对基因治疗和神经移植越来越大的兴趣(8)。
WO 2009/133128,WO 2009/133141,WO 2009/133142,WO 2011/054759,WO 2009/068668,WO 2009/153291披露了对于多种神经变性疾病(在其中,PD)的潜在治疗。
至今PD仍是不可治愈的基本并且还没有发现有效的疾病修饰治疗。因此,当前的治疗旨在缓解症状和减轻疾病的缓慢进展。
发明内容
本发明涉及用于治疗帕金森综合征的新的治疗方法和组合物。本发明尤其源于药物组合的鉴别,该药物组合对具有帕金森综合征病症的对象,特别是具有帕金森病的对象提供改善的治疗效果和临床益处。
更特别地,本发明的一个目的涉及用于治疗帕金森综合征,特别是帕金森病的组合物,其包含选自以下的一种,优选至少两种的药物:阿坎酸,巴氯芬,西那卡塞特,美西律,磺胺异噁唑和托拉塞米,或其盐,前药,任何化学纯度的衍生物,或缓释制剂。
本发明的另一个目的是一种用于治疗有需要的对象的帕金森综合征,特别是帕金森病的的方法,包括向所述对象施用选自以下的至少两种药物:阿坎酸,巴氯芬,西那卡塞特,美西律,磺胺异噁唑和托拉塞米,或其盐,前药,任何化学纯度的衍生物,或缓释制剂。
用于本发明的药物组合的优选实例包括,例如,巴氯芬和阿坎酸,巴氯芬和西那卡塞特,美西律和西那卡塞特,托拉塞米和巴氯芬,或托拉塞米和磺胺异噁唑。在一个特别的实施方式中,所述组合物和方法还包括左旋多巴。
本发明中的组合物可以进一步包含一种或多种药用载体或赋形剂,并且它们可以重复地施用至对象。优选的组合物经口施用。此外,药物可以一起、单独或依次配制或施用。
本发明适用于治疗处于疾病的任何阶段的任何哺乳动物对象,特别是人对象中的帕金森综合征。本发明可以例如用于减慢疾病的发展,减少、延迟或防止震颤、运动功能减退(例如,运动徐缓,运动不能,僵硬)姿势不稳,和/或疼痛,和/或增加存活。
附图说明
图1:西那卡塞特和美西律联合治疗对于神经元皮层细胞上的谷氨酸毒性的作用。谷氨酸盐中毒通过西那卡塞特(64pM)和美西律(25.6pM)的组合被显著防止,而在那些浓度下,单独的西那卡塞特和美西律对中毒没有显著效果。*:p<0.001,显著不同于谷氨酸盐中毒;(ANOVA+Dunnett事后检验)。
图2:磺胺异噁唑和托拉塞米联合治疗对于神经元皮层细胞上的谷氨酸毒性的作用。谷氨酸盐中毒通过磺胺异噁唑(6.8nM)和托拉塞米(400nM)的组合被显著防止,而在那些浓度下,单独的磺胺异噁唑和托拉塞米对中毒没有显著效果。*:p<0.001,显著不同于谷氨酸盐中毒;(ANOVA+Dunnett事后检验)。
图3:巴氯芬和阿坎酸联合治疗对于神经元皮层细胞上的谷氨酸毒性的作用。谷氨酸盐中毒通过巴氯芬(400nM)和阿坎酸(1.6nM)的组合被显著防止,而在那些浓度下,单独的巴氯芬和阿坎酸对中毒没有显著效果。*:p<0.001,显著不同于谷氨酸盐中毒;(ANOVA+Dunnett事后检验)。
图4:巴氯芬和阿坎酸组合对于缺血性损伤的保护作用。虽然当巴氯芬(80nM)或阿坎酸(0.32nM)单独使用时没有获得显著保护作用,但在相同浓度下对于两种药物的组合观察到显著的保护作用(*:p<0.0001)。
图5:西那卡塞特和美西律组合对于缺血性损伤的保护作用。虽然当西那卡塞特(64pM)或美西律(25.6pM)单独使用时没有观察到显著保护作用,但在相同浓度下对于两种药物的组合观察到显著的保护作用(*:p<0.0001)。
图6:托拉塞米和磺胺异噁唑组合对于缺血性损伤的保护作用。磺胺异噁唑(1.36nM)和托拉塞米(80nM)的组合诱导显著的保护作用(*:p<0.0001),比单独使用托拉塞米获得的保护作用高110%,而当单独使用磺胺异噁唑时没有获得保护作用。
图7:巴氯芬和阿坎酸联合治疗对于多巴胺能神经元细胞上的6OHDA损伤的作用。保护作用关联地随混合物浓度增加。观察到显著保护作用,其中TH神经元存活在剂量1(分别为16nM和64pM)下增加34%,在剂量2(80nM和144pM)下增加46%,以及在剂量3(400nM和1600pM)下增加51%(***:p<0.0001;*:p<0.001:显著不同于6OHDA中毒的细胞(ANOVA+Dunnett检验))。
图8:巴氯芬和托拉塞米联合治疗对于多巴胺能神经元细胞上的6OHDA损伤的作用。观察到显著的保护作用,其中TH神经元存活在低剂量1(分别为80nM和16nM)下增加50%,在中间剂量2(240nM和48nM)下增加62%以及在高剂量3(720nM和144nM)下增加58%(***:p<0.0001:显著不同于6OHDA中毒的细胞(ANOVA+Dunnett检验))。
图9:西那卡塞特和美西律联合治疗对于多巴胺能神经元细胞上的6OHDA损伤的作用。所有测试的浓度对于6OHDA提供显著的保护作用。事实上,观察到显著的保护作用,其中TH神经元存活在剂量1(分别为64pM和5pM)下增加36%,在剂量2(64pM和26pM)下增加38%以及在剂量3(1600pM和64pM)下增加48%(***:p<0.0001;*:p<0.001:显著不同于6OHDA中度的细胞(ANOVA+Dunnett检验))。
图10:起始时间试验,巴氯芬和阿坎酸联合治疗对于左侧黑质致密部中的6OHDA立体定向病变的作用。左爪:没有显著变化。右爪:作为左侧黑质中的神经元死亡的结果,6OHDA注射强烈地延迟起始时间。巴氯芬-阿坎酸治疗有力地保护免于6OHDA诱导的运动不能并且这来自最弱剂量1(分别地,巴氯芬-阿坎酸剂量1:0.6mg/kg/bid和0.04mg/kg/bid;剂量2:1.5mg/kg/bid和0.1mg/kg/bid;剂量3:3.75mg/kg/bid和0.25mg/kg/bid;***:p<0.0001;**:p<0.001;*:p<0.05:显著不同于6OHDA中毒的细胞(ANOVA+Dunnett检验))。
图11:反应时间试验,巴氯芬和阿坎酸联合治疗对于左侧黑质致密部中的6OHDA立体定向病变的作用。左爪:没有显著变化。右爪:作为左侧黑质中的神经元死亡的结果,6OHDA注射强烈地延迟反应时间。巴氯芬-阿坎酸治疗有力地保护免于6OHDA诱导的运动不能并且这来自最弱剂量1、剂量2和3,几乎完全减轻6OHDA诱导的运动不能(巴氯芬-阿坎酸剂量1:0.6mg/kg/bid和0.04mg/kg/bid;剂量2:1.5mg/kg/bid和0.1mg/kg/bid;剂量3:3.75mg/kg/bid和0.25mg/kg/bid;***:p<0.0001;**:p<0.001;*:p<0.05:显著不同于6OHDA中毒的细胞(ANOVA+Dunnett检验))。
具体实施方式
本发明的目的是提供用于治疗帕金森综合征,更具体是帕金森病的新的治疗方式。更特别地,本发明公开了药物和药物组合的新用途及方法,其允许有效校正这样的疾病并且可以用于任何哺乳动物对象。
帕金森综合征定义一类进行性神经退行性疾病,其特征在于休息性震颤和/或运动徐缓,相关于僵硬、姿势不稳、丧失姿势反射(postural reflexes)、弯曲姿势和/或冻结现象(当脚短暂地“粘接”至地面时)。帕金森综合征病症的实例包括帕金森病、进行性核上麻痹(progressive supranuclear palsy)、多系统萎缩症(multiple system atrophy)、皮质基底节变性(cortical-basal ganglionic degeneration)、弥漫性Lewy体疾病(diffuseLewy body disease)、帕金森-痴呆(Parkinson-dementia)、X连锁肌张力障碍(X-linkeddystonia)-帕金森综合征和二次帕金森综合征(由于环境病因,例如毒素、药物、脑炎后、脑肿瘤、头部创伤、正常压力脑积水所致)。
帕金森病是帕金森综合征的最常见形式。帕金森病(“PD”)是这样的神经退行性疾病,其导致运动和非运动表现并且特征在于黑质纹状体系统中的多巴胺能神经元的广泛变性。PD的运动表现可归因于黑质内的多巴胺能神经元的退化。它们包括震颤,运动功能减退(例如,运动徐缓,运动不能,僵硬)姿势不稳,步态异常和吞咽障碍。非运动症状包括自主神经和神经精神障碍如嗅觉丧失,或睡眠异常。本发明上下文中,术语PD包括上述疾病表现的任一种。
如本文使用的,“治疗”包括由帕金森综合征,优选帕金森病的病因触发的症状或其症状的治疗、防止、预防、延缓和减少。术语治疗还表示震颤的延缓或延迟发作,疼痛减少,运动徐缓、运动不能、僵硬、姿势不稳、步态异常、嗅觉丧失和/或睡眠异常的降低或减少,和/或存户增加。术语治疗尤其包括控制疾病进展及相关的运动和非运动症状。术语治疗特别包括:在治疗对象中,i)针对由α-突触核蛋白引起的毒性的保护,或所述毒性的减少或延缓,和/或ii)针对由异常谷氨酸积累、氧化性应激、线粒体功能障碍或神经炎症所致的毒性的多巴胺能神经元的保护,或所述毒性的减少或延缓。
在本发明的上下文中,特异性药物或化合物的名称意指不仅包括具体指明的分子,而且包括任何化学纯度的其任何药用盐、水合物、衍生物、异构体、外消旋物、轭合物、前药或衍生物。
术语“组合或联合治疗/疗法”表示这样的治疗,其中至少两种以上药物共同施用至对象以引起生物学作用。在根据本发明的联合治疗中,至少两种药物可以一起或单独地、在同时或依次地施用。而且,至少两种药物可以通过不同途径和方案施用。因此,尽管他们可以一起配制,但是组合的药物也可以单独配制。
若干生物学过程如氧化性应激、线粒体功能障碍和神经炎症伴随聚集的α-突触核蛋白的积累,这导致多巴胺能神经元的退化。在另一方面,谷氨酸在突触间隙中的异常积累导致谷氨酸受体的过度活化,这导致病理过程并且最终导致神经元细胞死亡。称为兴奋性中毒的这个过程现在被识别为设计帕金森病发展的重要病因。
本发明的发明人能够建立在α-突触核蛋白聚集下潜在的网络,其是帕金森病中受影响的主要功能网络。本发明的发明人已鉴别了在α-突触核蛋白聚集网络内的由若干靶蛋白质构成的功能分子。这样的蛋白质与帕金森病和帕金森综合征的起源和控制功能性地相关,并且代表对于治疗并且特别是联合治疗的有价值的靶标。
因此,本发明涉及特定药物,单独或优先组合地,调节治疗帕金森综合征,特别是帕金森病的上述路径的用途。
在一个特别的实施方式中,本发明更具体地设计使用药物组合的组合物和方法,该药物组合物抑制在α-突触核蛋白聚集网络中涉及的至少两种不同蛋白质的活性。本发明的治疗方式有效保护神经元细胞,特别是有效保护中脑并且更特别地黑质中的多巴胺能神经元。
更特别地,本发明涉及用于治疗帕金森综合征,特别是帕金森病(PD)的组合物,其包含选自以下中的至少两种药物:阿坎酸,巴氯芬,西那卡塞特,美西律,磺胺异噁唑和托拉塞米,或其盐或前药或任何纯度的衍生物或缓释制剂。
事实上,本发明的发明人已令人惊讶地发现,这些化合物对于谷氨酸毒性表现出保护活性,谷氨酸毒性是一种已知的帕金森病和帕金森综合征中神经元死亡的原因。本发明的化合物和组合治疗还对于缺血性应激表现出保护活性,其与帕金森病共享共同的生理特征(尤其是线粒体功能障碍和氧化性应激)。更特别地,本发明的化合物对于氧化性应激在体内外特别有效,其是对于多巴胺能神经元的α-突触核蛋白毒性的一个组分。
本发明还涉及一种用于治疗帕金森综合征,特别是帕金森病(PD)的方法,包括向需要其的对象施用选自以下的至少两种化合物:阿坎酸,巴氯芬,西那卡塞特,美西律,磺胺异噁唑和托拉塞米,或其盐或前药或任何纯度的衍生物或缓释制剂。
如本文使用的,术语"前药"是指本发明化合物的任何功能性衍生物(或前体),其在施用至生物系统时,作为例如自发性化学反应、酶催化的化学反应、和/或代谢化学反应的结果而产生所述化合物。前药通常是无活性或比所得药物更低活性的,并且可以用来例如改善药物的物理化学性质、将药物靶向特定组织、改善药物的药动学和药效学性质和/或减少不期望的副作用。顺从前药设计的一些常见官能团包括但不限于羧基、羟基、胺基、磷酸/膦酸基和羰基。经由这些基团改性产生的前药通常包括但不限于酯类、碳酸酯类、氨基甲酸酯类、酰胺类和磷酸酯类。用于选择合适前药的具体计数指南是通用常识(29-33)。此外,前药的制备可以通过本领域计数人员已知的常规方法进行。可以用来合成其他前药的方法描述于大量关于该主题的综述(9;14-20)。例如,阿巴氯芬placarbil列于ChemID+高级数据库(网址:chem.sis.nlm.nih.gov/chemidplus/)并且阿巴氯芬placarbil是一种熟知的巴氯芬的前药(21-22)。巴氯芬的前药的具体实例提供于Hanafi等,2011(26),特别是巴氯芬酯和巴氯芬酯氨基甲酸酯,其对于CNS靶向是特别关注的。因此,这样的前药特别适合于本发明的组合物。如前面体积的阿巴氯芬placarbil是一种熟知的前药并因此可以使用代替本命佛组合物的巴氯芬。巴氯芬的其他前药发现于以下专利申请:WO2010102071,US2009197958,WO2009096985,WO2009061934,WO2008086492,US2009216037,WO2005066122,US2011021571,WO2003077902和WO2010120370。
阿坎酸的有用前药,如阿坎酸的泛解酸酯新戊基磺酰基酯、新戊基磺酰基酯前药或掩蔽羧酸酯新戊基磺酰基酯前药尤其列于WO2009033069,WO2009033061,WO2009033054WO2009052191,WO2009033079,US 2009/0099253,US 2009/0069419,US2009/0082464,US 2009/0082440和US 2009/0076147。
可以使用如上所述的前药代替本文中公开的本发明的化合物。
术语化合物的“衍生物”包括与所述化合物功能和结构相关的任何分子,如这样的化合物的酸、酰胺、酯、醚、乙酰化变体、羟基化变体或烷基化(C1-C6)变体。术语衍生物还包括失去如上所列的一个或多个取代基的结构相关化合物。例如,高牛磺酸是阿坎酸的脱乙酰化衍生物。化合物的优选衍生物是与所述化合物具有显著相似度的分子,如通过已知的方法确定的。连同其与亲本分子的相似性指数的类似化合物可以发现于大量数据库如PubChem(http://pubchem.ncbi.nlm.nih.gov/search/)或药物库(http://www.drugbank.ca/)。在一个更优选的实施方式中,衍生物具有的与亲本药物的Tanimoto相似性指数应大于0.4,优选大于0.5,更优选地大于0.6,甚至更优选地大于0.7。Tanimoto相似性指数广泛用于测量两个分子之间的结构相似度。Tanimoto相似性指数可以通过软件如可在线(http://www.ebi.ac.uk/thornton-srv/software/SMSD/)获得的小分子子探测器(Small Molecule Subgraph Detector)计算(23-24)。优选的衍生物应是结构和功能与亲本化合物相关的,即,它们还应保留亲本药物的至少部分活性,更优选地它们应对多巴胺能神经元具有保护活性以免于6OHDA-诱导的应激和/或谷氨酸毒性和/或缺血性应激(如在实验部分例示的)。
术语衍生物还包括药物的代谢物,例如,由在施用至有机体后所述药物的(生物化学)改性或加工产生的分子,通常通过专化酶系统,并且其展示或保留药物的生物学活性。代谢物已被公开作为负责亲本药物的许多治疗作用。在一个具体实施方式中,如本文使用的,“代谢物”是指保留亲本药物的至少一部分活性的改性或加工药物,优选对多巴胺能神经元具有保护活性以免于6OHDA-诱导的应激和/或谷氨酸毒性和/或缺血性应激。代谢物的实例包括由于药物的肝代谢产生的托拉塞米的羟基化形式(27)。
术语“盐”是指本发明的化合物的药用和相关无毒的、无机或有机酸加成盐。药物盐形成包括使酸性、碱性或两性药物分子与相反离子成对以产生药物的盐形式。各种各样的化学物质可以在中和反应中使用。本发明的药用盐因此包括通过使充当碱的主要化合物与无机或有机酸反应以形成盐而获得的那些,例如,乙酸、硝酸、酒石酸、氢氯酸、硫酸、磷酸、甲磺酸、樟脑磺酸、草酸、马来酸、琥珀酸或柠檬酸的盐。本发明的药用盐还包括其中主要化合物充当酸并且与适当碱反应以形成例如钠盐、钾盐、钙盐、镁盐、铵盐或胆碱盐的那些。尽管指定活性成分的大多数盐是生物等效物,但是一些可能尤其具有增加的溶解性或生物利用度性质。盐选择现在在药物开发工艺中是常见的标准操作,如由H.Stahl和C.GWermuth在其手册中教导的(25)。
在一个优选实施方式中,化合物的名称意思是指化合物本身,及其任何药用盐、水合物、异构体、外消旋物。
下表I提供了用于本发明的化合物以及这些化合物的盐、衍生物、代谢物和/或前药的CAS编号的非限制性实例。
表1
在一个特别的实施方式中,使用所述化合物的缓释制剂。
本发明的发明人已发现,阿坎酸,巴氯芬,西那卡塞特,美西律,磺胺异噁唑和托拉塞米在校正α-突触核蛋白聚集分子途径方面特别有效。
如实施例中公开的,本发明的分子对帕金森综合征,特别是帕金森病中涉及的生物学过程具有强大的、出乎意料的作用,并且代表病理学的新的治疗方法。特别地,本发明的组合物对谷氨酸毒性提供出乎意料的作用。此外,本发明的药物和药物组合在6OHDA-诱导的氧化性应激以及缺血性应激下增加多巴胺能神经元存活率,并且对PD的运动和非运动表现诱导保护作用。因此,本发明的治疗方法对于保护神经元细胞,特别是保护中脑并且更特别地黑质中的多巴胺能神经元是有效的,如体内显示的。
在一个特别的实施方式中,本发明涉及用于治疗帕金森综合征,特别是帕金森病的组合物和方法,使用选自以下的化合物:阿坎酸,巴氯芬,西那卡塞特,美西律,磺胺异噁唑和托拉塞米。
调节α-突触核蛋白聚集网络中涉及的至少两种不同蛋白质的活性的药物组合构成本发明的特别有利的实施方式。事实上,本发明的发明人已观察到,上述药物,当以组合施用时,协同地起作用而有效地保护多巴胺能神经元。特别地,本发明的组合物对谷氨酸毒性、缺血诱导的细胞死亡和氧化性应激具有出乎意料的作用。这样的对帕金森综合征,特别是帕金森病涉及的生物学过程的强大且出乎意料的作用使得这些病理学的新联合治疗方法特别被关注。
因此,本发明还涉及用于治疗帕金森综合征,特别是帕金森病的组合物和方法,使用选自以下的至少两种药物:阿坎酸,巴氯芬,西那卡塞特,美西律,磺胺异噁唑和托拉塞米。
本发明的组合物和方法通过它们作用于疾病的运动以及非运动症状而导致PD的改善。本发明的治疗方法对于氧化性应激、线粒体功能障碍、兴奋性中度损伤、神经炎症或细胞凋亡提供特别是多巴胺能神经元的有效神经元保护。更特别地,它们对于聚集的α-突触核蛋白的毒性提供黑质神经元的保护以减少多巴胺能细胞损失的速率或程度并由此影响疾病进展的过程。
在这一方面,本发明的一个目的涉及用于治疗帕金森综合征,特别是PD的组合物,包含选自由以下各项组成的组中的化合物:阿坎酸,巴氯芬,西那卡塞特,美西律,磺胺异噁唑和托拉塞米,或其盐或前药或任何纯度的衍生物或缓释制剂。在一个优选实施方式中,组合物包含托拉塞米或美西律,或其盐或前药或任何纯度的衍生物或缓释制剂。
本发明涉及用于治疗帕金森综合征,特别是PD的组合物,包含选自以下的至少两种化合物:阿坎酸,巴氯芬,西那卡塞特,美西律,磺胺异噁唑和托拉塞米,或其盐,前药,任何化学纯度的衍生物,或缓释制剂。
本发明涉及用于治疗帕金森综合征,特别是PD的组合物,包含选自以下的至少一种化合物:阿坎酸,西那卡塞特,和托拉塞米,或其盐,前药,任何化学纯度的衍生物,或缓释制剂;以及选自以下的至少一种化合物:巴氯芬,美西律,或磺胺异噁唑,或其盐,前药,任何化学纯度的衍生物,或缓释制剂。
更特别地,本发明涉及用于同时、相继或单独使用的包含以下药物组合中的至少一种的组合物:
-巴氯芬和阿坎酸,
-巴氯芬和西那卡塞特,
-西那卡塞特和阿坎酸,
-美西律和西那卡塞特,
-托拉塞米和巴氯芬,或
-托拉塞米和磺胺异噁唑,
或其盐或前药或任何纯度的衍生物或缓释制剂,其用于治疗帕金森综合征,特别是帕金森病。
本发明还涉及用于治疗对象的帕金森综合征,特别是帕金森病的方法,其使用上述药物或组合物中的任一种。
本发明的一种特别优选的组合物或方法使用巴氯芬和阿坎酸,或其盐,前药,任何化学纯度的衍生物,或缓释制剂。
本发明的另一种优选的组合物或方法使用巴氯芬和托拉塞米,或其盐,前药,任何化学纯度的衍生物,或缓释制剂。
在另一个特别的实施方式中,本发明的组合物或方法使用阿坎酸和西那卡塞特,或其盐或前药或任何纯度的衍生物或缓释制剂,其中阿坎酸的日剂量等于或低于10mg。
本发明还涉及巴氯芬,或其盐,前药,任何化学纯度的衍生物,或缓释制剂,以与阿坎酸,或其盐,前药,任何化学纯度的衍生物,或缓释制剂的组合施用,用于治疗帕金森综合征,特别是帕金森病,通过组合、单独或相继施用至对象。
因此本发明的优选药物组合物包含2,3,4或5种不同药物,更优选地2,3或4种不同药物,用于组合治疗有需要的对象的帕金森综合征,特别是帕金森病。在一个优选实施方式中,本发明的药物以组合用于联合、单独或相继施用,以便提供最有效的作用。
本发明的发明人进一步发现,选自由以下组成的组中的至少一种药物组合与不同于之前的选自药物阿坎酸,巴氯芬,西那卡塞特,美西律,磺胺异噁唑和托拉塞米的药物的组合:
-巴氯芬和阿坎酸,
-巴氯芬和西那卡塞特,
-美西律和西那卡塞特,
-西那卡塞特和阿坎酸,
-托拉塞米和巴氯芬,或
-托拉塞米和磺胺异噁唑,
并且其增强二元组合的治疗作用并且导致用于治疗帕金森综合征,特别是PD的甚至更有效的组合物。
因此,本发明还涉及用于治疗帕金森综合征,特别是PD的组合物,包含西那卡塞特和阿坎酸,其与选自药物巴氯芬,美西律,磺胺异噁唑和托拉塞米或其盐,前药,衍生物或缓释制剂的药物组合,用于联合、单独或相继地施用。
本发明还涉及用于治疗帕金森综合征,特别是PD的组合物,包含巴氯芬和阿坎酸,其与选自西那卡塞特,美西律,磺胺异噁唑和托拉塞米或其盐,前药,衍生物或缓释制剂的药物组合,用于联合、单独或相继地施用。
本发明还涉及用于治疗帕金森综合征,特别是PD的组合物,包含巴氯芬和西那卡塞特,其与选自阿坎酸,美西律,磺胺异噁唑和托拉塞米或其盐,前药,衍生物或缓释制剂的药物组合,用于联合、单独或相继地施用。
在一个实施方式中,本发明还涉及用于治疗帕金森综合征,特别是PD的组合物,包含美西律和西那卡塞特,其与选自阿坎酸,巴氯芬,磺胺异噁唑和托拉塞米或其盐,前药,衍生物或缓释制剂组合,用于联合、单独或相继地施用。
在另一个实施方式中,本发明涉及用于治疗帕金森综合征,特别是PD的组合物,包含托拉塞米和巴氯芬,其与选自阿坎酸,磺胺异噁唑,西那卡塞特和美西律或其盐,前药,衍生物或缓释制剂组合,用于联合、单独或相继地施用。
本发明还涉及用于治疗帕金森综合征,特别是PD的组合物,包含托拉塞米和磺胺异噁唑,其与选自阿坎酸,巴氯芬,美西律和西那卡塞特或其盐,前药,衍生物或缓释制剂组合,用于联合、单独或相继地施用。
在更特别的实施方式中,本发明涉及用于治疗帕金森综合征,特别是PD的组合物,包含以下药物组合中的至少一种:
-巴氯芬和西那卡塞特和美西律,
-西那卡塞特和阿坎酸和美西律,
-巴氯芬和阿坎酸和西那卡塞特,
-巴氯芬和阿坎酸和托拉塞米,
-巴氯芬和阿坎酸和美西律,或
-托拉塞米和巴氯芬和西那卡塞特,
或其盐,前药,衍生物或缓释制剂,用于联合、单独或相继地施用。
本发明的另一个目的在于如上所述的组合物在制备用于治疗帕金森综合征,特别是PD的药物中的用途。
如之前指出的,在本发明的联合治疗中,所述化合物或药物可以一起配制,或单独配制,并且一起、单独或相继地施用。
本发明的另一个目的是治疗帕金森综合征,特别是PD的方法,所述方法包括向有需要的对象同时、单独或相继地施用有效量的上述组合物。
在这方面,本发明的一个特别目的是一种治疗帕金森综合征,特别是PD的方法,所述方法包括向有需要的对象同时、单独或相继地施用有效量的上述药物组合。
在一个优选实施方式中,本发明涉及一种治疗有需要的对象的帕金森综合征,特别是PD的方法,包括向所述对象同时、单独或相继地施用有效量的选自由以下各项组成的组中至少一种化合物的组合物:阿坎酸,巴氯芬,西那卡塞特,美西律,磺胺异噁唑和托拉塞米。
在一个更优选的实施方式中,本发明涉及一种治疗有需要的对象的帕金森综合征,特别是PD的方法,包括向所述对象同时、单独或相继地施用有效量的选自由以下各项组成的组中至少两种化合物的组合:阿坎酸,巴氯芬,西那卡塞特,美西律,磺胺异噁唑和托拉塞米。
在甚至更优选的实施方式中,本发明所涉及一种治疗有需要的对象的帕金森综合征,特别是PD的方法,包括向所述对象同时、单独或相继地施用有效量的以下药物组合的至少一种的组合,或其盐,前药衍生物或缓释制剂:
-巴氯芬和阿坎酸,
-巴氯芬和西那卡塞特,
-西那卡塞特和阿坎酸,
-美西律和西那卡塞特,
-托拉塞米和巴氯芬,或
-托拉塞米和磺胺异噁唑。
在另一个优选的实施方式中,本发明涉及一种治疗有需要的对象的帕金森综合征,特别是PD的方法,包括向所述对象同时、单独或相继地施用有效量的以下药物组合的至少一种的组合,或其盐,前药衍生物或缓释制剂:
-巴氯芬和西那卡塞特和美西律,
-西那卡塞特和阿坎酸和美西律,
-巴氯芬和阿坎酸和西那卡塞特,
-巴氯芬和阿坎酸和托拉塞米,
-巴氯芬和阿坎酸和美西律,或
-托拉塞米和巴氯芬和西那卡塞特。
本发明的组合物典型地包含一种或多种药用载体或赋形剂。对于用于本发明,所述药物或化合物通常与药用赋形剂或载体混合。
在这方面,本发明的另一个目的是制备药物组合物的方法,所述方法包括在适当赋形剂或载体这种混合上述化合物或化合物组合。
尽管在体内外非常有效,但是取决于对象或具体病症,上述方法、组合物或组合治疗可以进一步联合或结合或组合另外的药物或治疗使用。
联合根据本发明的药物或药物组合施用的另外的治疗可以包括减轻帕金森病的症状的一种或多种药物、可以用于帕金森病的姑息治疗的一种或多种药物或当前在用于治疗帕金森病的临床试验范围中评价的一种或多种药物。
因此,本发明的组合物可以组合多巴胺能药物如多巴胺前体(优选左旋多巴,甲左多巴),多巴胺受体激动剂(优选他利克索,吡贝地尔,罗替戈汀,溴隐亭,培高利特,卡麦角林,麦角乙脲,普拉克索,罗平尼咯或阿朴吗啡)或多巴胺代谢酶的抑制剂(优选司来吉兰,雷沙吉兰)。
本发明的组合物还可以组合用于PD的其他已知治疗、用于PD的辅助治疗、或PD的非运动症状的治疗,或优选神经节苷脂GM1,胞磷胆碱,屈昔多巴马扎替可,普鲁米近,喹硫平,普环啶,邻甲苯海拉明,多潘立酮,苯扎托品,三己芬迪,比哌立登,氯氮平,地昔帕明,西酞普兰,去甲替林,帕罗西汀,阿托西汀,文拉法辛,金刚胺,多奈哌齐,利凡斯的明或美金刚。
本发明的方法、组合物和组合与上述治疗的这样的使用将允许降低关注药物的治疗剂量并因此将减少、延迟后避免与这些药物相关的已知副作用,例如峰值剂量运动障碍,其在用左旋多巴治疗的患者中观察到。
在这方面,本发明的另一个目的涉及用于治疗帕金森综合征,特别是PD的组合物,包含上述的组合物,组合有选自由以下各项组成的组中的至少一种化合物:左旋多巴,他利克索,吡贝地尔,罗替戈汀,溴隐亭,培高利特,卡麦角林,麦角乙脲,普拉克索,罗平尼咯,阿朴吗啡,司来吉兰,雷沙吉兰,神经节苷脂GM1,胞磷胆碱,屈昔多巴马扎替可,普鲁米近,喹硫平,普环啶,邻甲苯海拉明,多潘立酮,苯扎托品,三己芬迪,比哌立登,氯氮平,地昔帕明,西酞普兰,去甲替林,帕罗西汀,阿托西汀,文拉法辛,金刚胺,多奈哌齐,利凡斯的明和美金刚,或其盐或前药或任何纯度的衍生物或缓释制剂。
因此,本发明的特别实施方式涉及用于治疗帕金森综合征,特别是PD的组合物,包含选自由以下各项组成的组中的至少一种化合物:阿坎酸,巴氯芬,西那卡塞特,美西律,磺胺异噁唑和托拉塞米或其盐,前药,任何化学纯度的衍生物,或缓释制剂,其组合有选自由以下各项组成的组中的至少一种化合物:左旋多巴,他利克索,吡贝地尔,罗替戈汀,溴隐亭,培高利特,卡麦角林,麦角乙脲,普拉克索,罗平尼咯,阿朴吗啡,司来吉兰,雷沙吉兰,神经节苷脂GM1,胞磷胆碱,屈昔多巴马扎替可,普鲁米近,喹硫平,普环啶,邻甲苯海拉明,多潘立酮,苯扎托品,三己芬迪,比哌立登,氯氮平,地昔帕明,西酞普兰,去甲替林,帕罗西汀,阿托西汀,文拉法辛,金刚胺,多奈哌齐,利凡斯的明和美金刚,或其盐或前药或任何纯度的衍生物或缓释制剂。
本发明的一个优选实施方式涉及用于治疗帕金森综合征,特别是PD的组合物,包含以下药物组合的至少一种:
-巴氯芬和左旋多巴,
-托拉塞米和左旋多巴,
-磺胺异噁唑和左旋多巴,
-美西律和左旋多巴,或
-西那卡塞特和左旋多巴,
或其盐或前药或任何纯度的衍生物或缓释制剂,用于联合、单独或相继地施用。
本发明还涉及包含以下药物组合的至少一种的组合物本身:
-巴氯芬和左旋多巴,
-托拉塞米和左旋多巴,
-磺胺异噁唑和左旋多巴,
-美西律和左旋多巴,或
-西那卡塞特和左旋多巴,
或其盐或前药或任何纯度的衍生物或缓释制剂,用于联合、单独或相继地施用。
在一个实施方式中,本发明涉及治疗有需要的对象的帕金森综合征,特别是PD的方法,包括向所述对象同时、单独或相继地施用有效量的选自由以下各项组成的组中的至少两种化合物的组合:左旋多巴,他利克索,吡贝地尔,罗替戈汀,溴隐亭,培高利特,卡麦角林,麦角乙脲,普拉克索,罗平尼咯,阿朴吗啡,司来吉兰,雷沙吉兰,神经节苷脂GM1,胞磷胆碱,屈昔多巴马扎替可,普鲁米近,喹硫平,普环啶,邻甲苯海拉明,多潘立酮,苯扎托品,三己芬迪,比哌立登,氯氮平,地昔帕明,西酞普兰,去甲替林,帕罗西汀,阿托西汀,文拉法辛,金刚胺,多奈哌齐,利凡斯的明和美金刚,或其盐或前药或任何纯度的衍生物或缓释制剂。
在另一个实施方式中,本发明涉及治疗有需要的对象的帕金森综合征,特别是PD的方法,包括向所述对象同时、单独或相继地施用有效量的巴氯芬和阿坎酸或其盐,前药,衍生物或缓释制剂,其组合有选自由以下各项组成的组中的至少一种化合物:左旋多巴,他利克索,吡贝地尔,罗替戈汀,溴隐亭,培高利特,卡麦角林,麦角乙脲,普拉克索,罗平尼咯,阿朴吗啡,司来吉兰,雷沙吉兰,神经节苷脂GM1,胞磷胆碱,屈昔多巴马扎替可,普鲁米近,喹硫平,普环啶,邻甲苯海拉明,多潘立酮,苯扎托品,三己芬迪,比哌立登,氯氮平,地昔帕明,西酞普兰,去甲替林,帕罗西汀,阿托西汀,文拉法辛,金刚胺,多奈哌齐,利凡斯的明和美金刚,或其盐或前药或任何纯度的衍生物或缓释制剂。
在另一个实施方式中,本发明涉及治疗有需要的对象的帕金森综合征,特别是PD的方法,包括向所述对象同时、单独或相继地施用有效量的美西律和西那卡塞特或其盐,前药,衍生物或缓释制剂,其组合有选自由以下各项组成的组中的至少一种化合物:左旋多巴,他利克索,吡贝地尔,罗替戈汀,溴隐亭,培高利特,卡麦角林,麦角乙脲,普拉克索,罗平尼咯,阿朴吗啡,司来吉兰,雷沙吉兰,神经节苷脂GM1,胞磷胆碱,屈昔多巴马扎替可,普鲁米近,喹硫平,普环啶,邻甲苯海拉明,多潘立酮,苯扎托品,三己芬迪,比哌立登,氯氮平,地昔帕明,西酞普兰,去甲替林,帕罗西汀,阿托西汀,文拉法辛,金刚胺,多奈哌齐,利凡斯的明和美金刚,或其盐或前药或任何纯度的衍生物或缓释制剂。
在另一个实施方式中,本发明涉及治疗有需要的对象的帕金森综合征,特别是PD的方法,包括向所述对象同时、单独或相继地施用有效量的托拉塞米和巴氯芬或其盐,前药,衍生物或缓释制剂,其组合有选自由以下各项组成的组中的至少一种化合物:左旋多巴他利克索,吡贝地尔,罗替戈汀,溴隐亭,培高利特,卡麦角林,麦角乙脲,普拉克索,罗平尼咯,阿朴吗啡,司来吉兰,雷沙吉兰,神经节苷脂GM1,胞磷胆碱,屈昔多巴马扎替可,普鲁米近,喹硫平,普环啶,邻甲苯海拉明,多潘立酮,苯扎托品,三己芬迪,比哌立登,氯氮平,地昔帕明,西酞普兰,去甲替林,帕罗西汀,阿托西汀,文拉法辛,金刚胺,多奈哌齐,利凡斯的明和美金刚,或其盐或前药或任何纯度的衍生物或缓释制剂。
在另一个实施方式中,本发明涉及治疗有需要的对象的帕金森综合征,特别是PD的方法,包括向所述对象同时、单独或相继地施用有效量的磺胺异噁唑和托拉塞米或其盐,前药,衍生物或缓释制剂,其组合有选自由以下各项组成的组中的至少一种化合物:左旋多巴,他利克索,吡贝地尔,罗替戈汀,溴隐亭,培高利特,卡麦角林,麦角乙脲,普拉克索,罗平尼咯,阿朴吗啡,司来吉兰,雷沙吉兰,神经节苷脂GM1,胞磷胆碱,屈昔多巴马扎替可,普鲁米近,喹硫平,普环啶,邻甲苯海拉明,多潘立酮,苯扎托品,三己芬迪,比哌立登,氯氮平,地昔帕明,西酞普兰,去甲替林,帕罗西汀,阿托西汀,文拉法辛,金刚胺,多奈哌齐,利凡斯的明和美金刚,或其盐或前药或任何纯度的衍生物或缓释制剂。
在另一个实施方式中,本发明涉及治疗有需要的对象的帕金森综合征,特别是PD的方法,包括向所述对象同时、单独或相继地施用有效量的西那卡塞特和阿坎酸或其盐,前药,衍生物或缓释制剂,其组合有选自由以下各项组成的组中的至少一种化合物:左旋多巴,他利克索,吡贝地尔,罗替戈汀,溴隐亭,培高利特,卡麦角林,麦角乙脲,普拉克索,罗平尼咯,阿朴吗啡,司来吉兰,雷沙吉兰,神经节苷脂GM1,胞磷胆碱,屈昔多巴马扎替可,普鲁米近,喹硫平,普环啶,邻甲苯海拉明,多潘立酮,苯扎托品,三己芬迪,比哌立登,氯氮平,地昔帕明,西酞普兰,去甲替林,帕罗西汀,阿托西汀,文拉法辛,金刚胺,多奈哌齐,利凡斯的明和美金刚,或其盐或前药或任何纯度的衍生物或缓释制剂。
在另一个实施方式中,本发明涉及治疗有需要的对象的帕金森综合征,特别是PD的方法,包括向所述对象同时、单独或相继地施用有效量的巴氯芬和西那卡塞特或其盐,前药,衍生物或缓释制剂,其组合有选自由以下各项组成的组中的至少一种化合物:左旋多巴,他利克索,吡贝地尔,罗替戈汀,溴隐亭,培高利特,卡麦角林,麦角乙脲,普拉克索,罗平尼咯,阿朴吗啡,司来吉兰,雷沙吉兰,神经节苷脂GM1,胞磷胆碱,屈昔多巴马扎替可,普鲁米近,喹硫平,普环啶,邻甲苯海拉明,多潘立酮,苯扎托品,三己芬迪,比哌立登,氯氮平,地昔帕明,西酞普兰,去甲替林,帕罗西汀,阿托西汀,文拉法辛,金刚胺,多奈哌齐,利凡斯的明和美金刚,或其盐或前药或任何纯度的衍生物或缓释制剂。
在一个优选实施方式中,本发明的组合物,用于治疗帕金森综合征,特别是PD,包含以下药物组合的至少一种,或其盐,前药,衍生物或缓释制剂,所述组合每一个中的药物用于联合、单独或相继地施用:
-巴氯芬和阿坎酸和左旋多巴,
-美西律和西那卡塞特和左旋多巴,
-托拉塞米和巴氯芬和左旋多巴,
-巴氯芬和西那卡塞特和左旋多巴,
-西那卡塞特和阿坎酸和左旋多巴,或
-磺胺异噁唑和托拉塞米和左旋多巴。
本发明还涉及组合物本身,其包含以下药物组合的至少一种,或其盐,前药,衍生物或缓释制剂,所述组合的每一个中的药物用于联合、单独或相继地施用:
-巴氯芬和阿坎酸和左旋多巴,
-美西律和西那卡塞特和左旋多巴,
-托拉塞米和巴氯芬和左旋多巴,
-巴氯芬和西那卡塞特和左旋多巴,
-西那卡塞特和阿坎酸和左旋多巴,或
-磺胺异噁唑和托拉塞米和左旋多巴。
在另一个优选实施方式中,本发明涉及本发明的组合物,用于治疗帕金森综合征,特别是PD,包含以下药物组合的至少一种,或其盐,前药,衍生物或缓释制剂,所述组合的每一个中的药物用于联合、单独或相继地施用:
-巴氯芬,西那卡塞特,美西律和左旋多巴,
-西那卡塞特,阿坎酸,美西律和左旋多巴,
-巴氯芬,阿坎酸,西那卡塞特和左旋多巴,
-巴氯芬,阿坎酸,托拉塞米和左旋多巴,
-巴氯芬,阿坎酸,美西律,和左旋多巴,或
-托拉塞米,巴氯芬,西那卡塞特和左旋多巴。
在一个特别的实施方式中,当本发明的组合物或组合治疗包含多巴胺前体时,它们可以进一步组合选自以下的至少一种化合物:外周多巴脱羧酶抑制剂,儿茶酚-O-甲基转移酶抑制剂或单胺氧化酶抑制剂。更特别地,当本方面的组合物或组合治疗包含多巴胺前体时,它们可以进一步组合选自以下的至少一种化合物:卡比多巴,苄丝肼,托卡朋,恩他卡朋,司来吉兰或雷沙吉兰。
本发明的另一目的在于如上所述的组合物在制备用于治疗帕金森综合征,特别是PD的药物中的用途。
在另一个实施方式中,本发明的组合物或组合治疗可以联合用于帕金森病的手术治疗如深脑刺激使用。更特别地,手术治疗是底丘脑核或苍白球内的深部脑刺激。
在这方面,本发明涉及一种组合物,其包含选自由以下各项组成的组中的至少一种化合物:阿坎酸,巴氯芬,西那卡塞特,美西律,磺胺异噁唑和托拉塞米,或其盐,前药,任何化学纯度的衍生物,或缓释制剂,其组合底丘脑核或苍白球内的深部脑刺激用于治疗帕金森综合征,特别是PD。
PD运动症状可以在纹状体的多巴胺能去神经支配和黑质多巴胺能神经元损失已广泛发生时后期形成。因此,在运动症状出现之前和预防中的PD的治疗是必需的以便改变疾病的进展和进程。
在这方面,在一个优选实施方式中,任何上述方法、组合物或组合治疗可以用于防止、预防或延迟由帕金森病因触发的症状或其症状。
利用成像技术(单个光子发射计算技术,正电子成像术)来评估纹状体多巴胺转运体的变化,非运动症状,最特别是嗅觉丧失的早期检测的组合可以是合适的方法以鉴别在出现运动症状之前处于风险PD患者,从而允许神经保护性治疗的早期开始。
一些PD情形可以归属于基因内的突变如SNCA(α-突触核蛋白),PRKN(parkin),LRRK2(富含亮氨酸重复激酶2),PINK1(PTEN-诱导的公认激酶1),DJ-1和ATP13A2以及十一个基因座位(PARK1-PARK11)。在这方面,在一个特别实施方式中,本发明涉及上述方法、组合物或组合治疗的用途,用于治疗具有在以下基因的至少一个的突变的对象中的PD:SNCA,PRKN,LRRK2,PINK1,DJ-1,ATP13A2和PARK1至PARK11。
高浓度暴露或慢性暴露于金属如锰、铜或铅,或化学品如杀虫剂(例如百草枯,鱼藤酮和代森锰),有可能引起帕金森综合征,特别是PD。在这方面,在一个特别实施方式中,本发明涉及上述方法、组合物或组合治疗用于治疗对象的帕金森综合征,特别是PD的用途,所述对象暴露于、怀疑已暴露于或处于暴露于已知是发展PD或相关障碍的危险因素的化学品或金属。
在一个优选实施方式中,上述方法、组合物或组合治疗可以用于处于发展帕金森病或与帕金森病相关症状的风险的对象。
根据本发明的治疗可以提供在家庭、医生办公室、临床、医院门诊部或医院,以使医生能够密切地观察治疗效果并且进行需要的任何调整。
治疗的持续时间取决于治疗的疾病的阶段、患者的年龄和状况、以及患者如何响应于治疗。组合的每个组分的施用剂量、频率和模式可以独立地控制。例如,一种药物可以经口地施用而第二药物可以肌肉内地施用。联合治疗可以在包括休息期的打开和关闭周期中给予以使患者身体具有从任何还没有预见的副作用中恢复的机会。药物也可以一起配制以使一次施用递送所有药物。
组合的每个药物的施用可以是任何合适的方式,其导致与其他组分组合能够减轻患者病症或有效地治疗疾病或障碍的药物的浓度。
虽然组合的药物可能作为纯化学物质施用,但是优选作为药物组合物呈现,在本上下文中也称为药物制剂。可能的组合物包括适用于经口、直肠、局部(包括透皮,颊下和舌下),或肠胃外(包括皮下,肌肉内,静脉内和皮内)施用的那些。
更常见地,这些药物制剂对患者以“患者包装”开处方,该患者包装包含大量用药单位或用于在单个包装中的不同治疗期期间施用的计量单位剂量,通常为泡罩包装。患者包装相对于传统处方具有优势,其中药剂师将患者的药物供应从整体供应划分,因为患者总是访问患者包装中容纳的包装说明书,通常在传统处方中缺失。包括包装说明书已被证实改善患者与医师指示的顺应性。因此,本发明进一步包括一种药物制剂,如本文之前描述的,其组合有适用于所述制剂的包装材料。在这样的患者包装中,用于组合治疗的制剂的所需用途可以通过说明书、设施、规定、适应和/或其他工具推断以有助于使用最适合治疗的制剂。这样的措施使得患者包装特别适合于并且适应于用本发明的组合的治疗。
药物可以以任何适当的量包含在任何合适的载体物质中。药物可以以多至组合物的总重量的99%重量的量提供。组合物可以以剂型提供,所述剂型适用于经口、胃肠外(例如,静脉内,肌肉内)、直肠、皮肤、经鼻、阴道、吸入、皮肤(贴剂)或眼部施用途径。因此,组合物可以为例如片剂、胶囊、丸剂、粉剂、颗粒剂、混悬剂、乳剂、溶液、凝胶剂包括水凝胶、糊剂、软膏、霜剂、药膏、浸润剂(drenches)、等张递送装置、栓剂、灌肠剂、注射剂、植入物、喷雾剂或气溶胶的形式。
药物组合物可以根据常规制药学实践配制(参见,例如,Remington:The Scienceand Practice of Pharmacy(20th ed.),ed.A.R.Gennaro,Lippincott Williams&Wilkins,2000和Encyclopedia ofPharmaceutical Technology,eds.J.Swarbrick andJ.C.Boylan,1988-1999,Marcel Dekker,NewYork)。
根据本发明的药物组合物可以配制成在施用后立即或以在使用之后任何预定时间或时间期基本上释放活性药物。
受控释放制剂包括(i)在延长的时间期内在身体内产生基本上恒定的药物浓度的制剂;(ii)在预定延迟时间后,在延长的时间期内在身体内产生基本上恒定的药物浓度的制剂;(iii)在与活性药物物质的血浆水平波动相关的不期望副作用的伴随最小化下,通过维持身体中相对恒定的有效药物水平,在预定时间期期间持续药物作用的制剂;(iv)通过例如在患病组织或器官附近或之中空间放置受控释放组合物定位药物作用的制剂;和(v)通过使用载体或化学衍生物来将药物递送至特定靶标细胞型而靶向药物的制剂。
以受控释放制剂的形式施用药物在这样的情况下是特别优选的,其中所述药物具有(i)窄的治疗指数(即,导致有害副作用或毒性反应的血浆浓度和导致治疗作用的血浆浓度之间的差异小;一般地,治疗指数TI被定义为半致死量(LD50)与半有效剂量(ED50)的比率);(ii)在胃肠道中的窄吸收窗;或(iii)极端的生物学半衰期使得需要一天期间的频繁用药以便将血浆水平维持在治疗水平。
可以进行大量策略的任一个以获得受控释放,其中释放速率胜过所述药物的代谢速率。受控释放可以通过适当选择各种制剂参数和成分而获得,包括例如各种类型的受控释放组合物和包衣。因此,所述药物与适当赋形剂配制成药物组合物,其在施用后,以受控方式释放所述药物(单个或多个单位片剂或胶囊组合物,油溶液,混悬剂,乳剂,微胶囊,微球体,纳米粒子,贴剂和脂质体)。
用于经口使用的固体剂型
用于经口使用的制剂包括含有与无毒药用赋形剂混合的本发明的组合物的片剂。这些赋形剂可以是例如惰性稀释剂或填料(例如,蔗糖,微晶纤维素,淀粉,包括马铃薯淀粉,碳酸钙,氯化钠,磷酸钙,硫酸钙,或磷酸钠);粒化和崩解剂(例如,纤维素衍生物,包括微晶纤维素,淀粉,包括马铃薯淀粉,交联羧甲基纤维素钠,海藻酸盐或藻酸);粘合剂(例如,阿拉伯树胶,褐藻酸,褐藻酸钠,明胶,淀粉,预凝胶化淀粉,微晶纤维素,羧甲基纤维素钠,甲基纤维素,羟丙甲纤维素,乙基纤维素,聚乙烯吡咯烷酮,或聚乙二醇);和润滑剂、助流剂,以及抗粘剂(例如,硬脂酸,硅酸盐或滑石)。其他药用赋形剂可以是着色剂、调味剂、增塑剂、保湿剂、缓冲剂等。
片剂可以是未包衣的或者他们可以通过已知的技术包衣,任选地用于延迟胃肠道中的崩解和吸收并由此在更长时期内提供持续作用。包衣可以适于以预定模式释放活性药物物质(例如,为了实现受控释放制剂)或者它可以适于直到通过胃后才释放活性药物物质(肠溶衣)。包衣可以是糖包衣、薄膜包衣(例如基于羟丙甲纤维素,甲基纤维素,甲基羟乙基纤维素,羟丙基纤维素,羧甲基纤维素,丙烯酸酯共聚物,聚乙二醇和/或聚乙烯吡咯烷酮),或肠溶衣(例如,基于甲基丙烯酸共聚物,邻苯二甲酸乙酸纤维素,邻苯二甲酸羟丙甲纤维素,琥珀酸乙酸羟丙基甲基纤维素,聚乙酸乙烯邻苯二甲酸酯,虫胶和/或乙基纤维素)。可以采用时间延迟材料如例如单硬脂酸甘油酯或二硬脂酸甘油酯。
固体片剂组合物可以包括适于保护组合物免于不希望的化学变化(例如,在活性药物物质释放之前的化学降解)的包衣。包衣可以以在药剂百科全书中描述的类似方式施加到固体剂型上。
药物可以在片剂中混合在一起,或者可以分隔开。例如,第一药物容纳在片剂的内侧,而第二药物在外侧上,以使第二药物的大部分在第一药物释放之前释放。
用于经口使用的制剂也可以作为咀嚼片或作为其中活性成分与惰性固体稀释剂(例如,马铃薯淀粉,微晶纤维素,碳酸钙,磷酸钙或高岭土)混合的硬明胶胶囊,或作为其中活性成分与水活油介质,例如液体石蜡或橄榄油混合的软明胶胶囊呈现。粉剂和颗粒剂可以一常规方式在片剂和胶囊下使用上述成分制备。
用于经口使用的受控释放组合物例如可以构建成通过控制活性药物物质的溶解和/或扩散而释放活性药物。
溶解或扩散受控释放可以通过适当包衣药物的片剂、胶囊、丸子或颗粒制剂,或通过将药物整合到适当基质中而实现。受控释放包衣可以包括一种或多种上述包衣物质,和/或例如,虫胶,蜂蜡,糖蜡(glycowax),蓖麻蜡,巴西棕榈蜡,硬脂醇,单硬脂酸甘油酯,二硬脂酸甘油酯、.硬脂酸棕榈酸甘油酯,乙基纤维素,丙烯酸树脂,dl-聚乳酸,丁酸乙酸纤维素,聚氯乙烯,乙烯吡咯烷酮,聚乙烯,聚甲基丙烯酸酯,甲基丙烯酸甲酯,2-羟基甲基丙烯酸酯,甲基丙烯酸酯水凝胶,1,3丁二醇,甲基丙烯酸乙二醇酯,和/或聚乙二醇。在受控释放基质制剂中,基质材料也可以包括例如水合甲基纤维素,巴西棕榈蜡和硬脂醇,聚羧乙烯934,硅酮,三硬脂酸甘油酯,甲基丙烯酸甲酯-甲基丙烯酸甲酯,聚氯乙烯,聚乙烯,和/或卤代氟碳。
含有所要求保护的组合的一种或多种药物的受控释放组合物也可以为胃漂浮片(buoyant tablet)或胶囊的形式(即在经口施用后,漂浮在胃内容物顶部一段时间的片剂或胶囊)。药物的胃漂浮片剂制剂可以通过对药物与赋形剂以及20-75%w/w的水状胶体如羟乙基纤维素、羟丙基纤维素或羟丙甲基纤维素的混合物粒化而制备。获得的颗粒然后可以压缩成片剂。在接触胃液后,该片剂在其表面周围形成基本上水不可渗透凝聚屏障。此凝聚屏障参与维持密度小于1,由此允许片剂在胃液中保持漂浮。
用于经口施用的液体
适用于通过加入水制备含水混悬剂的粉剂、可分散粉剂或颗粒剂是用于经口施用的方便剂型。作为混悬剂的制剂提供与分散剂或润湿剂、悬浮剂以及一种或多种防腐剂混合的活性成分。合适的悬浮剂例如是羧甲基纤维素钠、甲基纤维素、海藻酸钠等。
胃肠外组合物
药物组合物也可以通过注射、关注或植入(静脉内,肌肉内,皮下等)以含有常规的无毒药用载体和助剂的剂型、制剂,或经由合适的递送装置或植入物胃肠外施用。这样的组合物的配方和制剂对于药物制剂领域的技术人员是熟知的。
用于肠胃外使用的组合物可以以单位剂型(例如在单个剂量安剖瓶中)或在容纳多个剂量的小瓶中提供,并且其中可以添加合适的防腐剂(参见下文)。组合物可以为溶液、混悬剂、乳液、关注装置和用于植入的递送装置的形式,或者可以作为待用水活另一合适媒介物在使用前重建的干粉末呈现。除了活性药物,组合物可以包括适合肠胃外可接受的载体和/或赋形剂。活性药物可以整合到微球体、微胶囊、纳米粒子、脂质体等中用于受控释放。组合物可以包括悬浮剂、增溶剂、稳定剂、pH调节剂和/或分散剂。
根据本发明的药物组合物可以为适用于无菌注射的形式。为了制备这样的组合物,将合适的活性药物溶解或悬浮在肠胃外可接受的液体媒介物中。在可以采用的可接受的液体媒介物和溶剂中,可以是水、通过加入适当量的盐酸、氢氧化钠或合适的缓冲剂调节至合适pH的水、1,3-丁二醇、林格溶液、等张氯化钠溶液。含水制剂也可以含有一种或多种防腐剂(例如对羟基苯甲酸甲酯、乙酯或正丙酯)。在其中药物之一仅很少或微溶于水的情况下,可以加入溶解增强或增溶剂,或则溶剂可以包括10-60%w/w的丙二醇等。
受控释放的胃肠外组合物可以为水性悬浮液、微球体、微胶囊、磁性微球体、油性溶液、油性悬浮液或乳液的形式。可替换地,活性药物可以整合到生物相容性载体、脂质体、纳米粒子、植入物或关注装置中。用于之额比微球体和/或微胶囊的材料例如是生物可降解/生物蚀解聚合物如聚催乳激素、聚-(氰基丙烯酸异丁酯)、聚(2-羟乙基-L-谷氨酰胺)。当配制受控释放的胃肠外制剂是可以使用的生物相容性载体是糖类(例如右旋糖)、蛋白质(例如白蛋白)、脂蛋白或抗体。用于植入物的材料可以是非生物降解的(例如聚二甲基硅氧烷)或生物降解的(例如聚(己内酯),聚(乙醇酸)或聚(原酸酯))。
替代路径
尽管较不优选和较不方便,但是可以考虑其他施用路径,并且因此其他制剂。在这方面,对于直肠施用,组合物的合适剂型包括栓剂(乳剂或混悬剂类型),和直肠明胶胶囊(溶液或混悬剂)。在典型的栓剂制剂中,活性药物与适当药用栓剂基质如可可油、酯化的脂肪酸、甘油化明胶和各种水溶性或分散性基质如聚乙二醇组合。可以整合各种添加剂、增强剂或表面活性剂。
药物组合物也可以以含有常规无毒的药用载体和赋形剂包括微球体和脂质体的剂型或制剂局部施用到皮肤上,用于经皮吸收。制剂包括霜剂、软膏、洗剂、擦剂、凝胶剂、水凝胶、溶液、混悬剂、贴剂、喷雾剂、糊剂、药膏和其他种类的透皮药物递送系统。药用载体或赋形剂可以包括乳化剂、抗氧化剂、缓冲剂、防腐剂、保湿剂、渗透增强剂、螯合剂、胶凝剂、软膏基质、香料和皮肤保护剂。
防腐剂、保湿剂、渗透增强剂可以是对羟基苯甲酸酯类,如对羟基苯甲酸甲酯或丙酯,以及杀藻胺、甘油、丙二醇、尿素等。
上述用于局部施用到皮肤上的药物组合物也可以联合局部施用懂啊或靠近要治疗的身体部分使用。上述组合物可以适用于直接施用或借助于特殊药物递送装置如绷带或替代药膏、垫、海绵、条或其他形式的合适柔性材料施用。
治疗的剂量和持续时间
应理解,所述组合的药物可以在相同或不同药物制剂中同时施用或相继地施用。如果是相继施用,施用第二(或另外的)活性成分的延迟不应为使得失去活性成分的组合的有效作用的益处。对于根据本说明书的组合的最低要求是所述组合应意图为具有活性成分的组合的有效作用的益处的联合使用。组合的意图使用可以通过设施、假设、适应和/或其他手段推断以有助于利用根据本发明的组合。
在本发明的组合中的药物的治疗有效量包括,例如,对于减少帕金森病症状、终止或减慢疾病的进展(一旦其已是临床明显的)、或防止或减少形成该疾病的风险是有效的量。
尽管本发明的活性药物可以以分开的剂量施用,例如每天两次或三次,但是优选组合中的每个药物的单个日剂量,其中最优选在单个药物组合物中的所有药物的单个日剂量(单位剂型)。
施用可以是每天一次至多次,持续若干天至若干年,或者可以甚至持续患者是一生。慢性或至少周期性重复的长期施用在大多数情况下被指明。
术语“单位剂型”是指适合作为用于人对象的单一剂量的物理上离散的单位(如胶囊,片剂,或装载注射器筒),每个单位含有预定量的活性材料或多种材料(被计算产生期望的治疗效果)连同所需的药物载体。
在优选单位剂量组合物中的每个药物的量取决于多种因素,包括施用方法、患者的体重和年龄、考虑到要治疗个人的总体健康状况的潜在副作用的风险。另外,关于特定患者的宏观信息(基因型对治疗剂的药动学、药效学或效力分布的作用)会影响所使用的剂量。
除了当响应于特别受损情况外,在可能需要更高剂量的情况下,所述组合中的每个药物的优选剂量通常在不高于对于长期维持治疗规定的或证实在3期临床研究中是安全的剂量范围内。
本发明的一个显著优点是,每个化合物可以在联合治疗中以低剂量施用,同时以组合对患者产生实质性的临床益处。联合治疗实际上可以在其中化合物单个地具有低效果或没有效果的剂量下是有效的。因此,本发明的特别优点在于施用每个化合物的亚最佳剂量的能力,即低于通常规定的治疗剂量的剂量,优选为治疗剂量的1/2,更优选地1/3,1/4,1/5,或甚至更优选地为治疗剂量的1/10。在特别的实例中,使用的剂量低至治疗剂量的1/20,1/30,1/50,1/100,或甚至更低。
这样的子治疗剂量下,所述化合物将不会表现出副作用,同时根据本发明的组合在治疗帕金森病方面是完全有效的。
优选的剂量对应于对于长期维持治疗通常规定的那些的1%直至50%的量。
最优选的剂量可以对应于对于长期维持治疗通常规定的那些的1%直至10%的量。
用于本发明的药物的剂量(相当于活性分子的量)的具体实例在以下提供:
-阿坎酸:1000mg以下/天,优选小于500mg/天,优选小于400mg/天,更优选地小于200mg/天,更优选地小于50mg/天,甚至更优选地为约1至50mg/天,或甚至小于10mg/天,这样的剂量特别适用于经口施用。
-巴氯芬:150mg以下/天,优选小于100mg/天,更优选地小于50mg/天,更优选地小于30mg/天,甚至更优选地为0.01mg至30mg/天,这样的剂量特别适用于经口施用。
-西那卡塞特:150mg以下/天,优选小于100mg/天,优选小于50mg/天,更优选地小于36mg/天,并且甚至更优选地为0.01至25mg/天,这样的剂量特别适用于经口施用,
-美西律:120mg以下/天,优选小于60mg/天,更优选地小于30mg/天,更优选地小于15mg/天,甚至更优选地为6至15mg/天,这样的剂量特别适用于经口施用,
-托拉塞米:4mg以下/天,优选小于2mg/天,更优选地小于1mg/天,更优选地小于0.5mg/天,并且甚至更优选地为0.05至0.5mg/天,这样的剂量特别适用于经口施用,
-磺胺异噁唑800mg以下/天,优选小于400mg,更优选地小于200mg/天,更优选地小于100mg/天,甚至更优选地小于20mg/天,这样的剂量特别适用于经口施用,
-左旋多巴1,5g以下/天,优选小于750mg/天,更优选地小于375mg/天,甚至更优选地小于100mg/天,这样的剂量特别适用于经口施用。
应理解,实际施用的药物或药物组合的量将由医师决定,依据相关情况,包括要治疗的病症或多种病症,要施用的精确组合物,个体患者的年龄、重量和反应,患者症状的严重度,以及所选的施用途径。因此,上述剂量范围意在提供本文教导的指导和支持,但不意图限制本发明的范围。
给出以下实施例用于举例说明的目的而绝不用于限制的目的。
实施例
所有动物程序依照美国国立卫生研究院(NIH)对于实验室动物的护理和使用指南进行,并且由国家动物实验委员会批准。
A-神经元细胞上的谷氨酸毒性的防止
谷氨酸毒性涉及帕金森病的致病机理。在这组实验中,测试候选化合物防止或减少神经元细胞上的谷氨酸毒性的毒性作用。药物首先单个地测试,介质测定它们的组合作用。
神经元细胞制备
本发明的药物组合的效力在原代皮层神经元细胞上进行评估。
大鼠皮层神经元如由Singer等所述进行培养(30)。简而言之,将15天孕期的怀孕雌性大鼠通过颈脱位法(Rats Wistar)杀死并且从子宫取出胎仔。取下皮层并置于含有2%的青霉素10.000U/ml和链霉素10mg/ml以及1%的牛血清白蛋白(BSA)的Leibovitz的冰冷介质(L15)中。在37℃皮质通过胰蛋白酶(0.05%)分离。通过加入Dulbecco改性伊戈尔培养基(DMEM)(含有II级DNA酶1和10%的胎牛血清(FCS))停止反应。然后细胞通过3次系列通过10ml移液管机械地分离并在+4℃以515x g离心10min。抛弃上清并且细胞团粒再悬浮在确定培养基(由补充有B27(2%),L-谷氨酰胺(0.2mM),2%的PS溶液和10ng/ml的BDNF的Neurobasal组成)中。使用台盼蓝排斥试验在Neubauer细胞仪中计数存活的细胞。将细胞以30000个细胞/孔的密度接种到96孔板中(孔用聚-L-赖氨酸(10μg/ml)预先涂覆)并且在加湿的空气(95%)/CO2(5%)气氛中在+37℃培养。
谷氨酸毒性测定
化合物的神经保护作用通过量化神经突网络(神经丝蛋白免疫染色(NF))进行评估,其分别揭示谷氨酸能神经元。
在神经元培养12天后,候选组合的药物溶解在培养基(+0.1%DMSO)中。然后候选组合在谷氨酸损伤之前用神经元预先温育1小时。在温育后一小时,在候选组合存在下,在20min加入谷氨酸至终浓度为40μM,以避免进一步的药物稀释。在温育结束时,用具有候选组合但没有谷氨酸的培养基改变培养基。培养物在谷氨酸损伤后24小时固定。MK801(地卓西平氢马来酸盐,77086-22-7-20μM)用作阳性对照。
在用皂角苷(Sigma)渗透后,细胞用含有10%羊血清的PBS封闭2h,然后细胞用针对神经丝蛋白抗体(NF,Sigma)的小鼠单克隆一次抗体温育。这种抗体用Alexa Fluor 488羊抗-小鼠IgG揭示。
细胞的核通过荧光标记物(Hoechst溶液,SIGMA)标记,并且神经突网络量化。使用六个孔/条件来评估3个不同培养物中的神经元存活率。
结果
所有测试的药物组合对于皮层神经元细胞的谷氨酸毒性提供保护作用。结果示于下表2。
如图1至图3所例示的,本发明的组合在上述实验条件下强大地保护神经元免于谷氨酸毒性。值得注意的是,使用单独使用的药物不具有显著或更低的保护作用的药物浓度观察到有效保护。
事实上,如图1所例示的,美西律-西那卡塞特组合有效地保护神经元细胞免于谷氨酸毒性,而通过单个的药物不提供保护。巴氯芬-阿坎酸(图3)组合对于皮层神经元细胞的谷氨酸毒性提供保护作用。巴氯芬和阿坎酸的组合诱导相比于单独阿坎酸更多200%的提高并且相比于单独是用的巴氯芬更多47%。
表2
B-对于缺血/缺氧诱导的神经元细胞死亡的保护作用。
大鼠神经元皮层细胞制备
细胞如之前地制备。
氧和葡萄糖缺乏测定(缺血的体外模型)
化合物的神经保护作用通过使用MAP2抗体量化神经突网络(神经丝蛋白免疫组化染色(NF))进行评估。利鲁唑(一种神经保护药物)(5μM)用作阳性对照。
在神经元培养10天后,候选药物溶解在培养基(+0.1%DMSO)中然后在氧和葡萄糖缺乏之前用神经元预温育1小时。在候选药物温育后一小时,移出培养基并且加入没有葡萄糖的新鲜培养基。这种培养基由没有葡萄糖的DMEM(lnvitrogen)构成,其补充有2%B27,0.2mM L-谷氨酰胺,1%PS溶液,10ng/ml的BDNF。在37℃,将细胞转移到具有95%N2和5%CO2的厌氧温育器中。
在2小时后,25mM的D-葡萄糖加入到培养基中并在37℃将细胞转移到具有95%空气/5%CO2的典型温育器中。在氧葡萄糖再灌注24小时后,细胞通过乙醇/乙酸的冷溶液在5分钟期间固定。
在用皂角苷(Sigma)渗透化后,细胞用含有10%羊血清的PBS封闭2小时,然后细胞用针对MAP2(MAP2,Sigma)的小鼠单克隆一次抗体温育。这些抗体用Alexa Fluor 488羊抗-小鼠IgG(Molecular probe)揭示。
细胞的核通过荧光标记物(Hoechst溶液,SIGMA)标记。使用6个孔/条件来评估在3个不同培养中的神经元存活率。
使用6个孔/条件来评估在3个不同培养中的神经元存活率。对于每个条件,拍摄2x10图片/孔并使用InCell Analyzer TM 1000(GE Healthcare)在20x放大倍数下进行分析。
结果
如下表3所示,所有要求保护的药物组合对于皮层神经元细胞的缺血/缺氧诱导的细胞死亡提供保护作用。
表3
药物组合 | 对于缺血/缺氧的保护作用 |
巴氯芬和托拉塞米 | + |
巴氯芬-阿坎酸-托拉塞米 | + |
美西律和西那卡塞特 | + |
磺胺异噁唑和托拉塞米 | + |
巴氯芬和阿坎酸 | + |
阿坎酸和西那卡塞特 | + |
巴氯芬和西那卡塞特 | + |
图4至图6进一步显示本发明的组合治疗强大地保护神经元免于氧和葡萄糖缺乏。如图4至图6所示,使用单独的药物不具有显著保护作用的药物浓度观察到有效保护。例如,观察到巴氯芬(80nM)/阿坎酸(0.32nM)组合或西那卡塞特(64pM)/美西律(25.6pM)组合或托拉塞米(80nM)/磺胺异噁唑(1.36nM)在缺血中的显著保护作用,而当在相同浓度下单独使用巴氯芬,阿坎酸,西那卡塞特,美西律,托拉塞米和磺胺异噁唑时没有获得显著的保护作用。
因此,这些结果证实所述组合治疗对氧化性应激和线粒体功能障碍或细胞凋亡(其缺血病症以及帕金森病潜在的)的有效且协同作用。
C-药物对于多巴胺能神经元上的6OHDA损伤的神经保护作用
6-羟基多巴胺(6-OHDA)是神经毒性药物,其通过在细胞中产生反应性氧物种而选择性地破坏多巴胺能神经元。6OHDA毒性在体内外通常用来研究帕金森综合征。
中脑多巴胺能神经元的培养
大鼠多巴胺能神经元如由Schinelli等所描述的进行培养(31)。15天孕期的怀孕雌性大鼠通过颈脱位法杀死(Rats Wistar;Janvier)并从子宫取出胎仔。取出胚胎中脑并置于含有2%的青霉素-链霉素(PS;PanBiotech)和1%的牛血清白蛋白(BSA;PanBiotech)的Leibovitz(L15;PanBiotech)的冰冷介质中。仅中脑曲的腹侧部分被用于细胞制剂,因为这是在多巴胺能神经元中富集的发育大脑的区域。中脑通过在37℃胰蛋白酶(胰蛋白酶EDTA 1X;PanBiotech)消化20min而分离。通过加入含有II级DNA酶I(0.1mg/ml;PanBiotech)和10%胎牛血清(FCS;Invitrogen)的Dulbecco改性伊戈尔培养基(DMEM;PanBiotech)停止反应。然后细胞通过3次经过10ml移液管机械地分离并且在L15介质中的BSA(3.5%)的层上在+4°c以180x g离心10min。抛弃上清并且将团粒细胞再悬浮在由以下构成的确定培养基中:补充有B27(2%;Invitrogen),L-谷氨酰胺(2mM;PanBiotech)和2%的PS溶液的Neurobasal(Invitrogen)和10ng/ml脑源性神经营养因子(BDNF,PanBiotech)和1ng/ml的胶质细胞源性神经营养因子(GDNF,PanBiotech)。使用台盼蓝排斥试验,在Neubauer细胞仪中计数存活细胞。将细胞以40000个细胞/孔的密度接种在96孔板(预先涂覆聚-L-赖氨酸(Greiner))中并在37℃在加湿空气(95%)/CO2(5%)气氛中培养。每2天用新鲜培养基改变一半的培养基。5%至6%的神经元细胞群是多巴胺能神经元。
6-OHDA和试验化合物暴露
在培养的第6天,移去培养基并加入新鲜培养基,其中有或没有以下浓度的6OHDA:在对照培养基中稀释的48小时期间,20μM。试验化合物在48小时期间的6-OHDA施加之前预先温育1h。
终点评价:TH阳性神经元的总数量的量度
在用6OHDA中毒48小时之后,细胞通过在室温在PBS,pH=7.3中的4%多聚甲醛(Sigma)的溶液固定。细胞在PBS中再清洗两次,然后渗透并且非特异性部位在室温用0.1%皂角苷(Sigma)和1%FCS的PBS的溶液封闭15min。接着,在室温,细胞用在小树中产生的单克隆抗-酪氨酸羟化酶抗体(TH,Sigma)温育2h,该抗体以在含有1%FCS,0.1%皂角苷的PBS中的1/1000稀释。这些抗体在室温用Alexa Fluor 488羊抗-小鼠IgG(Molecular Probes)揭示1h,其以在含有1%FCS,0.1%皂角苷的PBS中的1/800稀释。
对于每种条件,利用InCell AnalyzerTM 1000(GE Healthcare)在10x放大倍数下获取2x 10图片(代表~80%的总孔面积)/孔。TH阳性神经元数量的分析使用Developer软件(GEHealthcare)进行。
数据以对照条件(没有中毒,没有6OHDA=100%)的百分比表示以便表示6OHDA损伤。所有值表示为3个培养物(n=6孔/条件/培养物)的平均值+/-SEM(s.e.mean)。统计分析包括ANOVA,接着Dunnett和PLSD Fisher检验,当使用Statview软件版本5.0允许时。
结果
在多巴胺能神经元上的48h 6-OHDA损伤后,在TH神经元中对本发明的组合观察到神经保护作用。
在所有实验(对照,图7-9)中,用中脑神经元的48h 6-OHDA(20μM)温育产生多巴胺能神经元的显著中毒(约-33%的TH神经元)。
BDNF用作阳性对照。在1,85nM的一小时BDNF预处理先出保护多巴胺能神经元免于这种6-OHDA损伤。
如下表4所示,所有要求保护的药物组合给出对于在多巴胺能神经元细胞中的6OHDA损伤的保护作用。
如图7至图9所示,巴氯芬-阿坎酸,巴氯芬-托拉塞米,美西律-西那卡塞特以剂量依赖方式成功地保护多巴胺能神经元免于6-OHDA中毒。
表4
D-对体内多巴胺能神经元损失和对运动症状的作用
动物管理和手术程序
在至少5天的适应期后,使用Wistar大鼠(5周)。在氯胺酮(50mg/kg)和甲苯噻嗪(10mg/kg)下进行手术。在左侧黑质致密部,以1μl/min的流速,动物接受单侧注射的溶解在6μl的0.9%无菌NaCl(含有0.1%抗坏血酸(以保护6-OHDA免于氧化))中的12μg的6-OHDA(sigma Aldrich)。根据由De Groot(1959)的大鼠脑立体定位阿特拉斯(stereotaxicatlas)(32),注射部位的脑立体定位坐标为:中间+2.2mm,侧向2.0mm,背腹侧+3mm,其中门牙杆在耳间平面上方的+5.0mm。
药物治疗
治疗剂(或媒介物)的第一次施用在脑立体定位注射6-OHDA(对于病变组)或媒介物前一天进行并且所有都在行为试验前15天内进行。在研究期间并且对于每只动物,基于相应组的动物的平均体重,确定P.O.施用的体积。体重每周确定两次并且施用的体积将因此相应地调整。
媒介物和化合物在上午和下午通过P.O.途径每天施用两次;两次施用间隔八小时(+/-30min),约9:30AM和约17:30PM。
在行为试验的当天,对每只动物,在行为试验之前,对L-DOPA治疗组约1h而对药物组合约2h(+/-15min)施用药物。
行为测试
每个试验在手术之前(2天或3天前)进行以确定基础水平值。行为功能的评价使用两个不同试验在手术注射6-OHDA后15天进行。
起始时间试验:动物由受训技师保持在平面前侧。两个前肢中仅一个保持为自由活动。开始朝向平面的运动所需的时间被记录,使用180秒作为断开点(33)。
踏步试验:大鼠由实验人员保持并且仅两个前肢中的一个保持为在平面上自由活动。另一只手固定没有被监测的前肢,其中一只爪接触台面。然后动物通过实验人员向后或向前慢慢移动(5秒,9m)。对右爪计数调整步子的数量(33)。
结果
体内测定用本发明的药物组合进行。测试的发明的药物组合在起始时间试验或踏步试验中都诱导显著的改善(表5)。
表5
如图10和图11中所例示的,本发明的药物组合物强大地保护大鼠免于6OHDA脑立体定位病变。值得注意的是,用巴氯芬-阿坎酸组合的治疗以剂量依赖方式导致踏步试验中的运动不能几乎全部减轻。
参考文献
1.de Lau,L.M.and M.M.Breteler,Epidemiology ofParkinson'sdisease.Lancet Neurol,2006.5(6):525-35.
2.Samii,A.,J.G.Nutt,andB.R.Ransom,Parkinson's disease.Lancet,2004.363(9423):p.1783-93.
3.Savitt,J.M.,V.L.Dawson,and T.M.Dawson,Diagnosis and treatmentofParkinson disease:molecules to medicine.JClin Invest,2006.116(7):1744-54.
4.Schapira,A.H.and P.Jenner,Etiology and pathogenesis ofParkinson'sdisease.Mov Disord,2011.26(6):1049-55.
5.Gao,H.M.and J.S.Hong,Gene-environment interactions:key tounraveling the mystery of Parkinson's disease.ProgNeurobiol,2011.94(1):1-19.
6.Abbott,A.,levodopa:the storyso far.Nature,2010.466(7310):S6-7.
7.Rascol O.,Lozano A.,Stern M.,Poewe W.,Milestones in Parkinson'sdisease therapeutics.MovDisord,2011.26(6):1072-82.
8.Obeso J.A.,Rodriguez-Oroz M.C.,Goetz C.G.,Marin C.,Kordower J.H.,Rodriguez M.,Hirsch E.C.,Farrer M.,Schapira A.H.,Halliday G.,Missing piecesin the Parkinson's disease puzzle.NatMed,2010.16(6):653-61.
9.Ettmayer,P.,Amidon,G.L.,Clement,B.&Testa,B.Lessons learned frommarketed and investigationalprodrugs.J.Med.Chem.47,2393–2404(2004).
10.Beaumont,K.,Webster,R.,Gardner,I.&Dack,K.Design ofester prodrugsto enhance oral absorption ofpoorly permeable compounds:challenges to thediscovery scientist.Curr.Drug Metab.4,461–485(2003).
11.Heimbach T,Oh DM,Li LY,Rodríguez-Hornedo N,Garcia G,FleisherD.Enzyme-mediated precipitationofparent drugs fromtheirphosphateprodrugs.Int.J.Pharm.261,81–92(2003).
12.Yang,C.Y.,Dantzig,A.H.&Pidgeon,C.Intestinal peptide transportsystems and oral drug availability.Pharm.Res.16,1331–1343(1999).
13.Steffansen B.,Nielsen C.U.,Brodin B.,Eriksson A.H.,Andersen R.,Frokjaer S.,Intestinal solute carriers:an overview oftrends and strategiesfor improving oral drug absorption.Eur.J.Pharm.Sci.21,3–16(2004).
14.Stella,Borchardt R,Hageman M,Oliyai R,Maag H,Tilley J,Prodrugs:Challenges and Rewards.Vol.Vol.1–2.2007,NewYork:AAPS Press and Springer.
15.Wermuth,CG.The Practice of Medicinal Chemistry.(Hardbound,2003).Part VI,Chap 33:Designing prodrugs and bioprecursors.
16.Pezron,I.,Mitra A.K.,Duvvuri S.,Tirucherai G.S.,Prodrug strategiesin nasal drug delivery.Expert Opin.Ther.Pat.,Vol.12,No.3,331-340(2002).
17.Stella,V.J.Prodrugs as therapeutics.Expert Opin.Ther.Pat.14,277–280(2004).
18.Stella,V.J.&Nti-Addae,K.W.Prodrug strategies to overcome poorwater solubility.Adv.Drug Deliv.Rev.59,677–694(2007).
19.Higuchi,T.;Stella,V.eds.Prodrugs As Novel Drug DeliverySystems.ACS Symposium Series.American Chemical Society:Washington,DC(1975).31.
20.Roche,E.B.Design of Biopharmaceutical Properties through Prodrugsand Analogs.American Pharmaceutical Association:Washington,DC(1977).
21.Lal R.,Sukbuntherng J.,Tai E.H.,Upadhyay S.,Yao F.,Warren M.S.,LuoW.,Bu L.,Nguyen S.,Zamora J.,Peng G.,Dias T.,Bao Y.,Ludwikow M.,Phan T.,Scheuerman R.A.,Yan H.,Gao M.,Wu Q.Q.,Annamalai T.,Raillard S.P.,Koller K.,Gallop M.A.,Cundy K.C.,Arbaclofen placarbil,a novel R-baclofen prodrug:improved absorption,distribution,metabolism,and elimination propertiescompared with R-baclofen.J Pharmacol Exp Ther,2009.330(3):911-21.
22.Feng Xu,Ge Peng,Thu Phan,Usha Dilip,Jian Lu Chen,Tania Chernov-Rogan,Xuexiang Zhang,Kent Grindstaff,Thamil Annamalai,Kerry Koller,MarkA.Gallop,David J.Wustrow,Discovery of a novel potent GABAB receptor agonist;Bioorg Med Chem Lett.2011 Nov 1;21(21):6582-5.
23.Andrew R.Leach,Valerie J.Gillet.An Introduction toChemoinformatics.Springer 2007.
24.S.Asad Rahman,M.Bashton,G.L.Holliday,R.Schrader and J.M.Thornton:Small Molecule Subgraph Detector(SMSD)Toolkit,Journal ofCheminformatics 2009,1:12.
25.Stahl H.,Wermuth C.G.(Eds.)Handbook ofPharmaceutical Salts:Properties,Selection,and Use.Wiley-VCH;2 edition(March 29,2011).
26.Hanafi R,Mosad S,Abouzid K,Niess R,Spahn-Langguth H Baclofen esterand carbamate prodrug candidates:a simultaneous chromatographic assay,resolution optimized with DryLab..J Pharm BiomedAnal.2011 Nov 1;56(3):569-76.
27.Neugebauer G,Besenfelder E,vonE.Pharmacokinetics andmetabolism of torasemide in man.Arzneimittelforschung.1988 Jan;38(1A):164-6.
28.Kahle PJ,Waak J,Gasser T.DJ-1 and prevention of oxidative stressin Parkinson's disease and other age-related disorders.Free Radic BiolMed.2009 Nov 15;47(10):1354-61.
29.Lee DW,Rajagopalan S,Siddiq A,Gwiazda R,Yang L,Beal MF,Ratan RR,Andersen JK.Inhibition of prolyl hydroxylase protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity:model for thepotential involvement ofthe hypoxia-inducible factor pathway in Parkinsondisease.J Biol Chem.2009 Oct 16;284(42):29065-76.
30.Singer CA,Figueroa-Masot XA,Batchelor RH,and Dorsa DMMitogen-activated protein kinase pathway mediates estrogen neuroprotection afterglutamate toxicity in primary cortical neurons.J.Neuroscience,1999.19(7):2455–2463.
31.Schinelli S,Zuddas A,Kopin IJ,Barker JL,di Porzio U.1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine metabolism and 1-methyl-4-phenylpyridiniumuptake in dissociated cell cultures from the embryonic mesencephalon.JNeurochem.1988 Jun;50(6):1900-7.
32.Jouve L,Salin P,Melon C,Kerkerian-Le Goff L.Deep brain stimulationof the center median-parafascicular complex of the thalamus has efficientanti-parkinsonian action associated with widespread cellular responses in thebasal ganglia network in a rat model of Parkinson's disease.J Neurosci.2010Jul 21;30(29):9919-28.
33.Olsson M,Nikkhah G,Bentlage C,A.Forelimb akinesia in therat Parkinson model:differential effects of dopamine agonists and nigraltransplants as assessed by a new stepping test.J Neurosci.1995 May;15(5 Pt2):3863-75.
Claims (15)
1. 组合物在制备用于治疗帕金森综合征的药物中的用途,所述组合物包含选自以下中的至少两种化合物:阿坎酸, 巴氯芬, 西那卡塞特, 美西律, 磺胺异噁唑和托拉塞米,或其盐, 前药, 任何化学纯度的衍生物或缓释制剂。
2. 托拉塞米, 或其盐, 前药, 任何化学纯度的衍生物或缓释制剂在制备用于治疗帕金森综合征的药物中的用途。
3. 西那卡塞特, 或其盐, 前药, 任何化学纯度的衍生物或缓释制剂在制备用于治疗帕金森综合征的药物中的用途。
4.根据权利要求1、2或3的用途,其中所述组合物包含以下药物组合中的至少一种:
-巴氯芬和阿坎酸,
-巴氯芬和西那卡塞特,
-美西律和西那卡塞特,
-托拉塞米和巴氯芬,
-托拉塞米和磺胺异噁唑,
-巴氯芬和西那卡塞特和美西律,
-西那卡塞特和阿坎酸和美西律,
-巴氯芬和阿坎酸和西那卡塞特,
-巴氯芬和阿坎酸和托拉塞米,
-巴氯芬和阿坎酸和美西律,或
-托拉塞米和巴氯芬和西那卡塞特。
5.根据权利要求1-4中任一项的用途,用于治疗帕金森病。
6. 根据权利要求5的用途,其中所述组合物进一步包含左旋多巴, 或其盐, 前药, 任何纯度的衍生物或缓释制剂。
7.根据前述权利要求中任一项的用途,其中所述组合物进一步包含药用载体或赋形剂。
8.根据前述权利要求中任一项的用途,其中所述组合物一起、单独或顺序地配制或施用。
9.根据前述权利要求中任一项的用途,其中所述组合物重复施用至对象。
10.根据前述权利要求中任一项的用途,其中所述组合物经口施用。
11. 根据权利要求1至10中任一项的用途,其中当存在时,阿坎酸以小于50 mg/天, 更优选地小于10 mg/天的剂量施用。
12. 根据权利要求1至11中任一项的用途,其中当存在时,巴氯芬以小于30 mg/天的剂量施用。
13.根据权利要求1至12中任一项的用途,用于保护黑质纹状体系统的多巴胺能神经元免于变性。
14.根据权利要求1至12中任一项的用途,用于治疗运动徐缓或运动不能。
15.前述权利要求中任一项的用途,用于有需要和处于帕金森综合征风险的对象中的预防性治疗。
Applications Claiming Priority (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EPPCT/EP2012/053568 | 2012-03-01 | ||
PCT/EP2012/053568 WO2012117075A2 (en) | 2011-03-01 | 2012-03-01 | Treatment of cerebral ischemia |
EPPCT/EP2012/053570 | 2012-03-01 | ||
EPPCT/EP2012/053565 | 2012-03-01 | ||
PCT/EP2012/053570 WO2012117076A2 (en) | 2011-03-01 | 2012-03-01 | Baclofen and acamprosate based therapy of neurogical disorders |
PCT/EP2012/053565 WO2012117073A2 (en) | 2011-03-01 | 2012-03-01 | New compositions for treating neurological disorders |
US201261696992P | 2012-09-05 | 2012-09-05 | |
EP12306063.4 | 2012-09-05 | ||
US61/696992 | 2012-09-05 | ||
EP12306063.4A EP2705842A1 (en) | 2012-09-05 | 2012-09-05 | Therapeutic approaches for treating parkinson's disease |
CN201380011335.7A CN104487062B (zh) | 2012-03-01 | 2013-02-28 | 用于治疗帕金森病的治疗方法 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201380011335.7A Division CN104487062B (zh) | 2012-03-01 | 2013-02-28 | 用于治疗帕金森病的治疗方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN107468688A true CN107468688A (zh) | 2017-12-15 |
Family
ID=46963636
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710551364.2A Pending CN107468688A (zh) | 2012-03-01 | 2013-02-28 | 用于治疗帕金森病的新治疗方法 |
CN201380011335.7A Expired - Fee Related CN104487062B (zh) | 2012-03-01 | 2013-02-28 | 用于治疗帕金森病的治疗方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201380011335.7A Expired - Fee Related CN104487062B (zh) | 2012-03-01 | 2013-02-28 | 用于治疗帕金森病的治疗方法 |
Country Status (25)
Country | Link |
---|---|
US (2) | US10004744B2 (zh) |
EP (5) | EP2705842A1 (zh) |
JP (3) | JP6184986B2 (zh) |
KR (1) | KR102014875B1 (zh) |
CN (2) | CN107468688A (zh) |
AU (3) | AU2013224960B2 (zh) |
CA (2) | CA2864012C (zh) |
CY (1) | CY1119420T1 (zh) |
DK (1) | DK2819663T3 (zh) |
EA (1) | EA032660B1 (zh) |
ES (2) | ES2644934T3 (zh) |
HK (2) | HK1203417A1 (zh) |
HR (1) | HRP20171469T1 (zh) |
HU (1) | HUE034615T2 (zh) |
IL (2) | IL234101B (zh) |
LT (1) | LT2819663T (zh) |
MX (1) | MX356865B (zh) |
NZ (1) | NZ700374A (zh) |
PL (1) | PL2819663T3 (zh) |
PT (1) | PT2819663T (zh) |
RS (1) | RS56405B1 (zh) |
SG (2) | SG10201607365PA (zh) |
SI (1) | SI2819663T1 (zh) |
WO (2) | WO2013127918A1 (zh) |
ZA (1) | ZA201406916B (zh) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9241933B2 (en) | 2011-03-01 | 2016-01-26 | Pharnext | Compositions for treating amyotrophic lateral sclerosis |
US10010515B2 (en) | 2011-03-01 | 2018-07-03 | Pharnext | Therapeutic approaches for treating Parkinson's disease |
US9248111B2 (en) | 2011-03-01 | 2016-02-02 | Pharnext | Therapeutic approaches for treating parkinson's disease |
US9867837B2 (en) | 2011-03-01 | 2018-01-16 | Pharnext | Compositions for treating neurological disorders |
EP2705841A1 (en) * | 2012-09-05 | 2014-03-12 | Pharnext | Combinations of nootropic agents for treating cognitive dysfunctions |
UA114811C2 (uk) * | 2013-02-28 | 2017-08-10 | Фарнекст | Застосування акампросату та баклофену для лікування аміотрофічного бічного склерозу |
JP6476174B2 (ja) | 2013-06-19 | 2019-02-27 | ソム イノヴェーション バイオテック、ソシエダッド リミターダ | 運動過剰障害の予防および/または治療における使用のための治療剤 |
US10111879B2 (en) * | 2013-06-27 | 2018-10-30 | Cedars-Sinai Medical Center | Adrenoceptors antagonists for the prevention and treatment of neurodegenerative conditions |
WO2015063140A1 (en) * | 2013-10-30 | 2015-05-07 | Pharnext | Compositions, methods and uses for the treatment of diabetes and related conditions by controlling blood glucose level |
EA201691602A1 (ru) | 2014-02-11 | 2017-03-31 | Фарнекст | Комбинация баклофена, акампросата и среднецепочечных триглицеридов для лечения неврологических расстройств |
US10300155B2 (en) | 2015-12-31 | 2019-05-28 | Washington University | Alpha-synuclein ligands |
AU2018258970B2 (en) | 2017-04-24 | 2021-07-15 | Pharnext | Idalopirdine-based combinatorial therapies of Alzheimer's disease |
US20220096451A1 (en) * | 2019-02-07 | 2022-03-31 | Alsatech, Inc. | Polyvalent derivatives of emoxypine |
CN111803473A (zh) * | 2019-04-10 | 2020-10-23 | 云南帕精生物科技有限公司 | 去甲替林应用于治疗帕金森病 |
EP4125840A1 (en) * | 2020-03-27 | 2023-02-08 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of synucleinopathies |
EP4281056A1 (en) * | 2021-01-20 | 2023-11-29 | Alto Neuroscience, Inc. | Combination drug strategy for the treatment of psychiatric and neurological disorders in which anhedonia or motivation- related dysfunction exists |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1682704A (zh) * | 2004-04-14 | 2005-10-19 | 中南大学 | 左旋多巴纳米制剂及其制备方法 |
WO2010085352A2 (en) * | 2009-01-22 | 2010-07-29 | Neurotherapeutics Pharma, Inc. | Bumetanide, furosemide, piretanide, azosemide, and torsemide analogs, compositions and methods of use |
CN103596562A (zh) * | 2011-03-01 | 2014-02-19 | 法耐斯特公司 | 基于巴氯芬和阿坎酸的神经性障碍疗法 |
Family Cites Families (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2044853C (en) * | 1990-07-19 | 2004-11-09 | Susan A. Greenfield | Method for treating parkinson's disease employing an atp-sensitive potassium channel blocker |
US6391922B1 (en) * | 1998-01-13 | 2002-05-21 | Synchroneuron, Llc | Treatment of posttraumatic stress disorder, obsessive-compulsive disorder and related neuropsychiatric disorders |
US5952389A (en) | 1998-01-13 | 1999-09-14 | Synchroneuron | Methods of treating tardive dyskinesia and other movement disorders |
US20030013692A1 (en) * | 2001-01-19 | 2003-01-16 | Gullans Steven R. | Methods of treating neurological disorders |
US6927036B2 (en) | 2002-02-19 | 2005-08-09 | Xero Port, Inc. | Methods for synthesis of prodrugs from 1-acyl-alkyl derivatives and compositions thereof |
KR101140559B1 (ko) | 2003-08-20 | 2012-07-05 | 제노포트 인코포레이티드 | 아실옥시알킬 카르바메이트 프로드러그, 합성 및 사용 방법 |
DE10338174A1 (de) * | 2003-08-20 | 2005-03-24 | Lts Lohmann Therapie-Systeme Ag | Transdermale Arzneimittelzubereitungen mit Wirkstoffkombinationen zur Behandlung der Parkinson-Krankheit |
US20050090554A1 (en) * | 2003-09-12 | 2005-04-28 | John Devane | Treatment of gastroparesis and nonulcer dyspepsia with GABAB agonists |
CA2551859C (en) | 2003-12-30 | 2011-10-04 | Xenoport, Inc. | Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof |
US20070149526A1 (en) * | 2005-10-17 | 2007-06-28 | Neurotherapeutics Pharma, L.L.C. | Diuretic and diuretic-like compound analogs |
AU2006318447A1 (en) * | 2005-11-21 | 2007-05-31 | The Board Of Trustees Of The University Of Alabama For And On Behalf Of The University Of Alabama | Methods of using small molecule compounds for neuroprotection |
JP5309014B2 (ja) * | 2006-03-23 | 2013-10-09 | アムジエン・インコーポレーテツド | シナカルセットの多形体の製造および使用のための方法および組成物 |
CA2606658A1 (en) * | 2006-10-13 | 2008-04-13 | Mike Tyers | Compositions and methods for treating neurological disorders or damage |
US20080206332A1 (en) | 2007-01-11 | 2008-08-28 | Kidney David J | Sustained release oral dosage forms of a prodrug of r-baclofen and methods of treatment |
CA2675638C (en) * | 2007-01-16 | 2015-11-24 | Ipintl, Llc | Composition comprising serotonin for treating metabolic syndrome |
WO2009033061A1 (en) | 2007-09-07 | 2009-03-12 | Xenoport, Inc. | Masked carboxylate neopentyl sulfonyl ester cyclization release prodrugs of acamprosate, compositions thereof, and methods of use |
WO2009033079A1 (en) | 2007-09-07 | 2009-03-12 | Xenoport, Inc. | Externally masked neopentyl sulfonyl ester cyclization release prodrugs of acamprosate, compositions thereof, and methods of use |
TW200932734A (en) | 2007-10-15 | 2009-08-01 | Xenoport Inc | Internally masked neopentyl sulfonyl ester cyclization release prodrugs of acamprosate, compositions thereof, and methods of use |
WO2009061934A1 (en) | 2007-11-06 | 2009-05-14 | Xenoport, Inc. | Use of prodrugs of gaba b agonists for treating neuropathic and musculoskeletal pain |
EP2065038A1 (en) | 2007-11-30 | 2009-06-03 | Pharnext | New therapeutic approaches for treating Charcot-Marie-Tooth disease |
US20100137442A2 (en) | 2008-02-01 | 2010-06-03 | Xenoport, Inc. | Sustained Release Particulate Oral Dosage Forms of (R)-Baclofen and Methods of Treatment |
WO2009096985A1 (en) | 2008-02-01 | 2009-08-06 | Xenoport, Inc. | Sustained release particulate oral dosage forms of (r)-baclofen prodrugs and methods of treatment |
WO2009113128A1 (ja) * | 2008-03-13 | 2009-09-17 | 独立行政法人情報通信研究機構 | 複数マッハツェンダー干渉計を有する光変調器の特性評価方法 |
MX2010011881A (es) * | 2008-04-29 | 2011-07-01 | Pharnext | Nuevos enfoques terapeuticos para tratar la enfermedad de alzheimer y trastornos relacionados mediante una modulacion de la angiogenesis. |
EA019571B1 (ru) * | 2008-04-29 | 2014-04-30 | Фарнекст | Применение сульфизоксазола для лечения болезни альцгеймера |
NZ589304A (en) | 2008-04-29 | 2012-03-30 | Pharnext | Combination compositions for treating alzheimer disease and related disorders with zonisamide and acamprosate |
EP2135607A1 (en) | 2008-06-18 | 2009-12-23 | Pharnext | Combination of pilocarpin and methimazol for treating Charcot-MarieTooth disease and related disorders |
CN102341099A (zh) | 2009-03-03 | 2012-02-01 | 什诺波特有限公司 | R-巴氯芬前药的持续释放口服剂型 |
WO2010120370A2 (en) | 2009-04-17 | 2010-10-21 | Xenoport, Inc. | Gamma-amino-butyric acid derivatives as gabab receptor ligands |
JP2011231094A (ja) * | 2009-11-02 | 2011-11-17 | Neurotherapeutics Pharma Inc | ブメタニド、フロセミド、ピレタニド、アゾセミド、およびトルセミドのアナログ、組成物および使用方法 |
EP2322163A1 (en) * | 2009-11-03 | 2011-05-18 | Pharnext | New therapeutics approaches for treating alzheimer disease |
EP3056197A1 (en) * | 2010-11-19 | 2016-08-17 | Curemark, Llc | Preparation and use of combination enzyme and gastrointestinal modulator delivery systems |
WO2012076555A1 (en) * | 2010-12-06 | 2012-06-14 | Fondazione Santa Lucia | Autophagy enhancing compounds, peptides and peptidomimetic compounds for use in the treatment of neuronal diseases |
UA115968C2 (uk) * | 2011-03-01 | 2018-01-25 | Фарнекст | Нові композиції для лікування неврологічних захворювань |
-
2012
- 2012-09-05 EP EP12306063.4A patent/EP2705842A1/en not_active Withdrawn
-
2013
- 2013-02-28 KR KR1020147027724A patent/KR102014875B1/ko active IP Right Grant
- 2013-02-28 CN CN201710551364.2A patent/CN107468688A/zh active Pending
- 2013-02-28 RS RS20170988A patent/RS56405B1/sr unknown
- 2013-02-28 CA CA2864012A patent/CA2864012C/en not_active Expired - Fee Related
- 2013-02-28 DK DK13706549.6T patent/DK2819663T3/en active
- 2013-02-28 NZ NZ700374A patent/NZ700374A/en not_active IP Right Cessation
- 2013-02-28 SG SG10201607365PA patent/SG10201607365PA/en unknown
- 2013-02-28 WO PCT/EP2013/054026 patent/WO2013127918A1/en active Application Filing
- 2013-02-28 JP JP2014559214A patent/JP6184986B2/ja not_active Expired - Fee Related
- 2013-02-28 EP EP17179482.9A patent/EP3254682A1/en not_active Withdrawn
- 2013-02-28 CA CA3081500A patent/CA3081500A1/en not_active Abandoned
- 2013-02-28 AU AU2013224960A patent/AU2013224960B2/en not_active Ceased
- 2013-02-28 MX MX2014010214A patent/MX356865B/es active IP Right Grant
- 2013-02-28 HU HUE13706549A patent/HUE034615T2/en unknown
- 2013-02-28 EA EA201400969A patent/EA032660B1/ru not_active IP Right Cessation
- 2013-02-28 CN CN201380011335.7A patent/CN104487062B/zh not_active Expired - Fee Related
- 2013-02-28 LT LTEP13706549.6T patent/LT2819663T/lt unknown
- 2013-02-28 ES ES13706549.6T patent/ES2644934T3/es active Active
- 2013-02-28 SG SG11201405292PA patent/SG11201405292PA/en unknown
- 2013-02-28 EP EP13706549.6A patent/EP2819663B1/en active Active
- 2013-02-28 PT PT137065496T patent/PT2819663T/pt unknown
- 2013-02-28 SI SI201330796T patent/SI2819663T1/en unknown
- 2013-02-28 PL PL13706549T patent/PL2819663T3/pl unknown
- 2013-09-04 US US14/425,926 patent/US10004744B2/en not_active Expired - Fee Related
- 2013-09-04 EP EP18175031.6A patent/EP3388062A1/en not_active Withdrawn
- 2013-09-04 ES ES13759492.5T patent/ES2690061T3/es active Active
- 2013-09-04 EP EP13759492.5A patent/EP2892518B1/en not_active Not-in-force
- 2013-09-04 WO PCT/EP2013/068312 patent/WO2014037416A2/en active Application Filing
-
2014
- 2014-08-13 IL IL234101A patent/IL234101B/en active IP Right Grant
- 2014-09-22 ZA ZA2014/06916A patent/ZA201406916B/en unknown
-
2015
- 2015-05-04 HK HK15104229.8A patent/HK1203417A1/zh not_active IP Right Cessation
-
2017
- 2017-07-26 JP JP2017144105A patent/JP6381751B2/ja not_active Expired - Fee Related
- 2017-10-02 HR HRP20171469TT patent/HRP20171469T1/hr unknown
- 2017-10-04 CY CY20171101033T patent/CY1119420T1/el unknown
-
2018
- 2018-02-28 AU AU2018201436A patent/AU2018201436B2/en not_active Ceased
- 2018-05-04 HK HK18105771.4A patent/HK1246192A1/zh unknown
- 2018-05-21 US US15/985,202 patent/US20180263989A1/en not_active Abandoned
- 2018-07-31 JP JP2018143229A patent/JP6727259B2/ja not_active Expired - Fee Related
-
2019
- 2019-04-10 AU AU2019202509A patent/AU2019202509A1/en not_active Abandoned
- 2019-09-22 IL IL26951119A patent/IL269511A/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1682704A (zh) * | 2004-04-14 | 2005-10-19 | 中南大学 | 左旋多巴纳米制剂及其制备方法 |
WO2010085352A2 (en) * | 2009-01-22 | 2010-07-29 | Neurotherapeutics Pharma, Inc. | Bumetanide, furosemide, piretanide, azosemide, and torsemide analogs, compositions and methods of use |
CN103596562A (zh) * | 2011-03-01 | 2014-02-19 | 法耐斯特公司 | 基于巴氯芬和阿坎酸的神经性障碍疗法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104487062B (zh) | 用于治疗帕金森病的治疗方法 | |
CN107106521A (zh) | 用于治疗帕金森病的新治疗方法 | |
KR102014883B1 (ko) | 근위축성 측삭 경화증 치료용 신규 조성물 | |
US10010515B2 (en) | Therapeutic approaches for treating Parkinson's disease |
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 | ||
AD01 | Patent right deemed abandoned |
Effective date of abandoning: 20211231 |
|
AD01 | Patent right deemed abandoned |