CN1251520A - 钠通道阻滞剂在制备用于防止与青光眼有关的视神经变性的药物中的应用 - Google Patents
钠通道阻滞剂在制备用于防止与青光眼有关的视神经变性的药物中的应用 Download PDFInfo
- Publication number
- CN1251520A CN1251520A CN98803734A CN98803734A CN1251520A CN 1251520 A CN1251520 A CN 1251520A CN 98803734 A CN98803734 A CN 98803734A CN 98803734 A CN98803734 A CN 98803734A CN 1251520 A CN1251520 A CN 1251520A
- Authority
- CN
- China
- Prior art keywords
- sodium channel
- compositions
- glaucoma
- inactivation
- cell
- 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
- 208000010412 Glaucoma Diseases 0.000 title claims abstract description 23
- 210000001328 optic nerve Anatomy 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 title description 10
- 206010056677 Nerve degeneration Diseases 0.000 title description 2
- 239000003195 sodium channel blocking agent Substances 0.000 title description 2
- 229940125794 sodium channel blocker Drugs 0.000 title 1
- 210000004027 cell Anatomy 0.000 claims abstract description 56
- 239000011734 sodium Substances 0.000 claims abstract description 44
- 108010052164 Sodium Channels Proteins 0.000 claims abstract description 28
- 102000018674 Sodium Channels Human genes 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000000203 mixture Substances 0.000 claims abstract description 24
- 241000124008 Mammalia Species 0.000 claims abstract description 16
- 230000000903 blocking effect Effects 0.000 claims abstract description 11
- 230000002779 inactivation Effects 0.000 claims description 32
- 230000002207 retinal effect Effects 0.000 claims description 29
- 230000000694 effects Effects 0.000 claims description 11
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 8
- 230000034994 death Effects 0.000 claims description 7
- 230000000574 ganglionic effect Effects 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- 210000002569 neuron Anatomy 0.000 claims description 6
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 5
- HTDFEXRUDGWNHA-UHFFFAOYSA-N lifarizine Chemical compound CC=1NC(C=2C=CC(C)=CC=2)=NC=1CN(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 HTDFEXRUDGWNHA-UHFFFAOYSA-N 0.000 claims description 5
- 229950003413 lifarizine Drugs 0.000 claims description 5
- 229960004181 riluzole Drugs 0.000 claims description 5
- 206010021143 Hypoxia Diseases 0.000 claims description 4
- 239000003416 antiarrhythmic agent Substances 0.000 claims description 4
- OZFSWVOEXHGDES-INIZCTEOSA-N lubeluzole Chemical compound C([C@@H](O)CN1CCC(CC1)N(C)C=1SC2=CC=CC=C2N=1)OC1=CC=C(F)C(F)=C1 OZFSWVOEXHGDES-INIZCTEOSA-N 0.000 claims description 4
- 229950009851 lubeluzole Drugs 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 239000002997 ophthalmic solution Substances 0.000 claims description 3
- 229940054534 ophthalmic solution Drugs 0.000 claims description 3
- 206010002660 Anoxia Diseases 0.000 claims description 2
- 241000976983 Anoxia Species 0.000 claims description 2
- 230000007953 anoxia Effects 0.000 claims description 2
- 210000001525 retina Anatomy 0.000 claims description 2
- XBHOUXSGHYZCNH-UHFFFAOYSA-N 2-phenyl-1,3-benzothiazole Chemical compound C1=CC=CC=C1C1=NC2=CC=CC=C2S1 XBHOUXSGHYZCNH-UHFFFAOYSA-N 0.000 claims 3
- 230000000324 neuroprotective effect Effects 0.000 claims 1
- 108091006146 Channels Proteins 0.000 abstract description 10
- 210000003994 retinal ganglion cell Anatomy 0.000 abstract description 9
- 230000028161 membrane depolarization Effects 0.000 abstract description 5
- 231100000518 lethal Toxicity 0.000 abstract description 4
- 230000001665 lethal effect Effects 0.000 abstract description 4
- 230000001575 pathological effect Effects 0.000 abstract description 4
- 230000030833 cell death Effects 0.000 abstract description 3
- 230000000415 inactivating effect Effects 0.000 abstract 4
- 230000004941 influx Effects 0.000 abstract 1
- 239000011575 calcium Substances 0.000 description 17
- 230000004410 intraocular pressure Effects 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 11
- 229940126121 sodium channel inhibitor Drugs 0.000 description 10
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- -1 RS6685 Chemical compound 0.000 description 7
- 229910001424 calcium ion Inorganic materials 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 208000037273 Pathologic Processes Diseases 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000009054 pathological process Effects 0.000 description 6
- 229910001415 sodium ion Inorganic materials 0.000 description 5
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 4
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 229930195712 glutamate Natural products 0.000 description 4
- 201000006366 primary open angle glaucoma Diseases 0.000 description 4
- 230000000007 visual effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002421 anti-septic effect Effects 0.000 description 3
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 3
- 210000001742 aqueous humor Anatomy 0.000 description 3
- 239000002876 beta blocker Substances 0.000 description 3
- 229940097320 beta blocking agent Drugs 0.000 description 3
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000002999 depolarising effect Effects 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 230000003547 miosis Effects 0.000 description 3
- 229960002036 phenytoin Drugs 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 2
- 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 description 2
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 2
- 241000490499 Cardamine Species 0.000 description 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 2
- 206010061323 Optic neuropathy Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 2
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000000150 Sympathomimetic Substances 0.000 description 2
- 230000036982 action potential Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 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
- 210000005056 cell body Anatomy 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 210000002592 gangliocyte Anatomy 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 231100000567 intoxicating Toxicity 0.000 description 2
- 230000002673 intoxicating effect Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 2
- 229960001848 lamotrigine Drugs 0.000 description 2
- 229960004194 lidocaine Drugs 0.000 description 2
- 229960003404 mexiletine Drugs 0.000 description 2
- VZAUGYDMVQSQAO-VOTNWUEESA-M neo-gilurytmal Chemical compound OC(=O)[C@H](O)[C@@H](O)C([O-])=O.CN([C@H]12)C3=CC=CC=C3[C@]11C[C@@H]3[N@@+](CCC)([C@@H]([C@H]4CC)O)[C@H]2C[C@@H]4[C@@H]3[C@H]1O VZAUGYDMVQSQAO-VOTNWUEESA-M 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 208000020911 optic nerve disease Diseases 0.000 description 2
- GVEAYVLWDAFXET-XGHATYIMSA-N pancuronium Chemical compound C[N+]1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 GVEAYVLWDAFXET-XGHATYIMSA-N 0.000 description 2
- 229960005457 pancuronium Drugs 0.000 description 2
- 229960001416 pilocarpine Drugs 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000001975 sympathomimetic effect Effects 0.000 description 2
- 229960004605 timolol Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- QSAWQNUELGIYBC-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-dicarboxylic acid Chemical compound OC(=O)[C@@H]1CCCC[C@H]1C(O)=O QSAWQNUELGIYBC-PHDIDXHHSA-N 0.000 description 1
- YJXQTIXFPYPQFT-SDQBBNPISA-N (2z)-n-(2-chloro-6-methylphenyl)-2-(3-methyl-4-oxo-1,3-thiazolidin-2-ylidene)acetamide Chemical compound CN1C(=O)CS\C1=C/C(=O)NC1=C(C)C=CC=C1Cl YJXQTIXFPYPQFT-SDQBBNPISA-N 0.000 description 1
- CTCZKABHVPGYMK-CTEVNEASSA-N (4ar,5as,13as,15as,15br)-6-methyl-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2h-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinoline-6-ium-14-one Chemical compound O([C@H]1CC(=O)N(C=2C3=CC=CC=2)[C@H]2[C@H]1[C@H]1C4)CC=C1C[N+]1(C)[C@@H]4C23CC1 CTCZKABHVPGYMK-CTEVNEASSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- JCIIKRHCWVHVFF-UHFFFAOYSA-N 1,2,4-thiadiazol-5-amine;hydrochloride Chemical compound Cl.NC1=NC=NS1 JCIIKRHCWVHVFF-UHFFFAOYSA-N 0.000 description 1
- LDKBTTCUTLPCOC-UHFFFAOYSA-N 1,2-diphenylpiperazine Chemical compound C1NCCN(C=2C=CC=CC=2)C1C1=CC=CC=C1 LDKBTTCUTLPCOC-UHFFFAOYSA-N 0.000 description 1
- CJDRUOGAGYHKKD-RQBLFBSQSA-N 1pon08459r Chemical compound CN([C@H]1[C@@]2(C[C@@]3([H])[C@@H]([C@@H](O)N42)CC)[H])C2=CC=CC=C2[C@]11C[C@@]4([H])[C@H]3[C@H]1O CJDRUOGAGYHKKD-RQBLFBSQSA-N 0.000 description 1
- RMXBPZNRJHINPL-UHFFFAOYSA-N 2-(2-phenylphenyl)acetamide Chemical compound NC(=O)CC1=CC=CC=C1C1=CC=CC=C1 RMXBPZNRJHINPL-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- GMAAOECEUNSKCO-UHFFFAOYSA-N 2-N-(2,6-dichlorophenyl)-4,5-dihydroimidazole-1,2-diamine Chemical compound NN1C(=NCC1)NC1=C(C=CC=C1Cl)Cl GMAAOECEUNSKCO-UHFFFAOYSA-N 0.000 description 1
- JLXLGSBBWQVJNN-UHFFFAOYSA-N 2-[[2-(diethylamino)acetyl]amino]-n-(2,6-dimethylphenyl)acetamide Chemical compound CCN(CC)CC(=O)NCC(=O)NC1=C(C)C=CC=C1C JLXLGSBBWQVJNN-UHFFFAOYSA-N 0.000 description 1
- WKJFILILEWPMQF-UHFFFAOYSA-N 5-(2,3,5-trichlorophenyl)pyrimidine-2,4-diamine Chemical compound NC1=NC(N)=NC=C1C1=CC(Cl)=CC(Cl)=C1Cl WKJFILILEWPMQF-UHFFFAOYSA-N 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- DJBNUMBKLMJRSA-UHFFFAOYSA-N Flecainide Chemical compound FC(F)(F)COC1=CC=C(OCC(F)(F)F)C(C(=O)NCC2NCCCC2)=C1 DJBNUMBKLMJRSA-UHFFFAOYSA-N 0.000 description 1
- XWLUWCNOOVRFPX-UHFFFAOYSA-N Fosphenytoin Chemical compound O=C1N(COP(O)(=O)O)C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 XWLUWCNOOVRFPX-UHFFFAOYSA-N 0.000 description 1
- 208000003098 Ganglion Cysts Diseases 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- CJDRUOGAGYHKKD-UHFFFAOYSA-N Iso-ajmalin Natural products CN1C2=CC=CC=C2C2(C(C34)O)C1C1CC3C(CC)C(O)N1C4C2 CJDRUOGAGYHKKD-UHFFFAOYSA-N 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
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- UQOFGTXDASPNLL-XHNCKOQMSA-N Muscarine Chemical class C[C@@H]1O[C@H](C[N+](C)(C)C)C[C@H]1O UQOFGTXDASPNLL-XHNCKOQMSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- QMGVPVSNSZLJIA-UHFFFAOYSA-N Nux Vomica Natural products C1C2C3C4N(C=5C6=CC=CC=5)C(=O)CC3OCC=C2CN2C1C46CC2 QMGVPVSNSZLJIA-UHFFFAOYSA-N 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- 208000030768 Optic nerve injury Diseases 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- PYEBKOFMWAMBFV-UHFFFAOYSA-O QX-314 Chemical compound CC[N+](CC)(CC)CC(=O)NC1=C(C)C=CC=C1C PYEBKOFMWAMBFV-UHFFFAOYSA-O 0.000 description 1
- 244000061121 Rauvolfia serpentina Species 0.000 description 1
- 241000167686 Reichardia Species 0.000 description 1
- PDOCBJADCWMDGL-UHFFFAOYSA-N Sipatrigine Chemical compound C1CN(C)CCN1C1=NC=C(C=2C(=C(Cl)C=C(Cl)C=2)Cl)C(N)=N1 PDOCBJADCWMDGL-UHFFFAOYSA-N 0.000 description 1
- 208000005400 Synovial Cyst Diseases 0.000 description 1
- QYUXPWDVDMSTKR-UHFFFAOYSA-O [2-(2,6-dimethylanilino)-2-oxoethyl]-trimethylammonium Chemical compound CC1=CC=CC(C)=C1NC(=O)C[N+](C)(C)C QYUXPWDVDMSTKR-UHFFFAOYSA-O 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 229960000571 acetazolamide Drugs 0.000 description 1
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229960004332 ajmaline Drugs 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000001384 anti-glaucoma Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 229960004957 aprindine Drugs 0.000 description 1
- NZLBHDRPUJLHCE-UHFFFAOYSA-N aprindine Chemical compound C1C2=CC=CC=C2CC1N(CCCN(CC)CC)C1=CC=CC=C1 NZLBHDRPUJLHCE-UHFFFAOYSA-N 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960001716 benzalkonium Drugs 0.000 description 1
- 229960005274 benzocaine Drugs 0.000 description 1
- CYDRXTMLKJDRQH-UHFFFAOYSA-N benzododecinium Chemical compound CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 CYDRXTMLKJDRQH-UHFFFAOYSA-N 0.000 description 1
- 229960004324 betaxolol Drugs 0.000 description 1
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 1
- 230000007321 biological mechanism Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 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
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 1
- 229960004484 carbachol Drugs 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 229920003090 carboxymethyl hydroxyethyl cellulose Polymers 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000000080 chela (arthropods) Anatomy 0.000 description 1
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 230000002498 deadly effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- OCUJLLGVOUDECM-UHFFFAOYSA-N dipivefrin Chemical compound CNCC(O)C1=CC=C(OC(=O)C(C)(C)C)C(OC(=O)C(C)(C)C)=C1 OCUJLLGVOUDECM-UHFFFAOYSA-N 0.000 description 1
- UVTNFZQICZKOEM-UHFFFAOYSA-N disopyramide Chemical compound C=1C=CC=NC=1C(C(N)=O)(CCN(C(C)C)C(C)C)C1=CC=CC=C1 UVTNFZQICZKOEM-UHFFFAOYSA-N 0.000 description 1
- 229960001066 disopyramide Drugs 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- PJWPNDMDCLXCOM-UHFFFAOYSA-N encainide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=CC=C1CCC1N(C)CCCC1 PJWPNDMDCLXCOM-UHFFFAOYSA-N 0.000 description 1
- 229960001142 encainide Drugs 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229960000449 flecainide Drugs 0.000 description 1
- 229960000693 fosphenytoin Drugs 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229910001410 inorganic ion Inorganic materials 0.000 description 1
- 229960000831 levobunolol Drugs 0.000 description 1
- IXHBTMCLRNMKHZ-LBPRGKRZSA-N levobunolol Chemical compound O=C1CCCC2=C1C=CC=C2OC[C@@H](O)CNC(C)(C)C IXHBTMCLRNMKHZ-LBPRGKRZSA-N 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960004083 methazolamide Drugs 0.000 description 1
- FLOSMHQXBMRNHR-DAXSKMNVSA-N methazolamide Chemical compound CC(=O)\N=C1/SC(S(N)(=O)=O)=NN1C FLOSMHQXBMRNHR-DAXSKMNVSA-N 0.000 description 1
- UHDKXFCUGVGVDP-UHFFFAOYSA-N n-ethyl-2-hydroxybenzamide Chemical compound CCNC(=O)C1=CC=CC=C1O UHDKXFCUGVGVDP-UHFFFAOYSA-N 0.000 description 1
- 210000004273 ophthalmic nerve Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 238000012402 patch clamp technique Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229940096826 phenylmercuric acetate Drugs 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- REQCZEXYDRLIBE-UHFFFAOYSA-N procainamide Chemical compound CCN(CC)CCNC(=O)C1=CC=C(N)C=C1 REQCZEXYDRLIBE-UHFFFAOYSA-N 0.000 description 1
- 229960000244 procainamide Drugs 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- JWHAUXFOSRPERK-UHFFFAOYSA-N propafenone Chemical compound CCCNCC(O)COC1=CC=CC=C1C(=O)CCC1=CC=CC=C1 JWHAUXFOSRPERK-UHFFFAOYSA-N 0.000 description 1
- 229960000203 propafenone Drugs 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 229950010950 ralitoline Drugs 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002336 repolarization Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960002372 tetracaine Drugs 0.000 description 1
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Ophthalmology & Optometry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
改变与青光眼有关的视网膜神经节细胞可能的病理过程的方法和组合物。此病理过程包括膜的去极化、毫摩尔量的钠经非失活性钠通道内流、由于Na+逆向交换而致细胞内Ca2+致死性增加。此方法包括,通过施予能够选择性地阻滞视网膜神经节细胞中有关非失活性Na+通道的组合物,来限制视网膜神经节细胞中Na+/Ca2+的交换并且防止Ca2+在视网膜神经节细胞中蓄积到致死水平。由此产生了通过将能够阻滞视神经非失活性钠离子通道的化合物施予哺乳动物的视神经,从而防止与青光眼有关的视网膜神经节细胞死亡的方法。或者,本发明涉及通过将能阻滞视网膜神经节细胞非失活性钠离子通道的化合物施予人视网膜神经节细胞,以防止人视网膜神经节细胞死亡的方法。
Description
发明背景
本发明的技术领域
本发明涉及通过将能够阻滞哺乳动物视网膜神经节细胞假设的非失活性钠离子通道的化合物施予所述细胞,来防止与青光眼有关的视网膜神经节细胞死亡的方法。
现有技术简述
青光眼是与眼内压升高(对于眼睛的正常功能,眼内压太高)有关的视神经病,并且会导致视觉功能的不可逆丧失(参见,例如Dreyer等人的“患青光眼的人和猴玻璃体内谷氨酸盐水平升高”,《眼科学文献》(Arch.0phthal-mology)114:299-305,1996)。在医学科学内,据估计,40岁以上的人群中约有2%患有青光眼,因此青光眼是一个严重的健康问题。据信,还没有引起不可逆损伤的眼高压,即眼内压升高状态,代表青光眼的最早期。在现有技术中,已经设计和开发了多种用于治疗或改善青光眼和青光眼之前的眼内压升高状态的治疗剂。
原发性开角型青光眼(POAG)与眼内压(IOP)升高有关。据信,IOP的升高导致视神经功能损失,而视神经功能损失最终导致失明。因此,在POAG的治疗中,降低IOP是决定性因素。然而,在许多个体中,降低IOP不足以或不能有效地防止与POAG有关的视觉功能损失。
据认为,位于大鼠视神经内的一新类型钠通道是引起缺氧或低氧之后大鼠视神经损伤的原因。然而,在青光眼中,导致视神经功能损失的病理过程尚未知道。
目前治疗青光眼的药物包括缩瞳剂(例如,毛果芸香碱、卡巴胆碱和乙酰胆碱酯酶抑制剂),拟交感神经药(例如,肾上腺素和双特戊酰肾上腺素),β-阻滞剂(例如,倍他洛尔、左布诺洛尔和噻吗洛尔),α-2激动剂(例如对氨基可乐定)和碳酸酐酶抑制剂(例如,乙酰唑胺、甲醋唑胺和乙氧苯酰胺)。据信,缩瞳剂和拟交感神经药能通过增加眼房水的流出量来降低眼内压,而β-阻滞剂、α-2激动剂以及碳酸酐酶抑制剂能通过减少房水形成来降低眼内压。所有这5种药物都有潜在的副作用。缩瞳剂,例如毛果芸香碱,会引起视觉模糊和其它视觉副作用,这些副作用要么降低病人的配合性,要么需要中止缩瞳药物治疗。碳酸酐酶抑制剂也会引起严重的副作用,这些副作用会影响病人的配合性和/或需要取消此类药物治疗。至少有一种β-阻滞剂,噻吗洛尔,已经愈加被认为与肺部副作用有关,这是由于其作用于肺组织中的β-2受体所致。
出于上述原因,现在正在研制其它抗青光眼药物,例如,***素衍生物,毒蕈碱拮抗剂等。然而,上述药物没有一种是设计成与视网膜神经节细胞和其相关轴突进行作用的药物。
因此,需要通过不是调节房水动力学并且因而不是调节眼内压的生物学机制,来防止可能与青光眼有关的神经节细胞体和轴突功能的损失。此外,需要直接治疗哺乳动物的视网膜神经节细胞体和轴突来防止由青光眼状态对它们的破坏。
发明概述
令人惊奇的是,依据本发明已经发现,当将能够阻滞哺乳动物视神经非失活性钠离子通道的钠通道阻滞剂给药并且以药物组合物形成应用时,这些钠通道阻滞剂可以有效地防止视网膜神经节细胞的损失。相应地,本发明涉及通过将眼用组合物全身或直接给药到哺乳动物眼睛中以防止与青光眼有关的视网膜神经节细胞和其相关轴突(视神经)功能丧失的方法,其中所述组合物含有一定量的能阻滞所述哺乳动物神经节细胞的非失活性钠离子通道的钠通道阻滞剂。
更具体而言,本发明涉及改变可能与青光眼视神经病有关的视网膜神经节细胞可能的病理过程。此病理过程包括视网膜神经节细胞的病理性去极化,毫摩尔量的钠通过非失活性钠通道内流,以及随后的钠/钙逆交换。由膜的去极化和细胞内钠的增加所介导的钠/钙逆交换引起细胞内钙中毒性蓄积。改变此病理过程的方法包括阻滞视网膜神经节细胞中相关的非失活性钠通道,以阻止钠/钙离子逆交换以及随后的钙离子在视网膜神经节细胞中蓄积到致死水平的步骤。
具体地说,此阻滞是通过将含有具有非失活通道阻滞活性的活性成份的药物组合物施予视网膜神经节细胞来实现的。此组合物可含有抗心律失常剂或化合物如苯并噻唑利鲁唑,芦贝鲁唑,RS6685,联苯乙酰胺如PD85、689,利法利嗪(RS-87476)和二苯基哌嗪抗惊厥剂如苯妥英和卡马西平。拉莫三嗪及其衍生物。
组合物可以含有适于以眼房内注射液的形式施予哺乳动物眼睛的眼用溶液,并且活性成份如抗心率失常剂能以0.001%-约1%(重量体积比)的含量存在于组合物中。
依据本发明的方法,对视网膜神经节细胞的直接作用是一项重要发现。然而,对视觉起决定性作用的神经节细胞的正常电兴奋性则不会受到损害。
此外,依据本发明的药物组合物能用于防止与青光眼有关的视网膜神经节细胞的死亡,其中所述组合物含有一种或多种具有非失活性钠通道阻滞活性的化合物作为其活性成份。
更具体而言,本发明提供在包括人在内的哺乳类动物中防止与青光眼有关的视网膜神经节细胞死亡的方法,包括将药物组合物施予哺乳动物视网膜神经节细胞的步骤,其中所述组合物含有一种或多种具有非失活性钠通道阻滞活性的化合物作为其活性成份。
附图的简要说明
当与附图一起考虑时,通过下面的附图说明可以更好地理解本发明的优点
和特征。
图1是正常条件下,假定的视网膜神经节细胞的相关转运机制图;和
图2是局部缺血条件下,视网膜神经节细胞的构图。
发明详述
虽然不希望受理论的束缚,但是据信,轴突和含有视神经的相关细胞体的死亡或损失是细胞内钙离子浓度(Ca+2)致死性增加的结果,而钙离子浓度增加是由于钠离子(Na+)通过非失活性钠离子通道内流入所致。虽然已经用大鼠的视神经片断进行了一些研究(Stys等,1995;Waxman,1995),但是没有用于神经节细胞。基于早期的大鼠视神经实验,没有提出任何改变视网膜细胞的类似病理过程以阻止缺氧后细胞死亡的预期展望,这是因为在下述方面还是不清楚的:(1)在青光眼期间是否有类似的病理过程发生,或(2)在哺乳动物视网膜神经节细胞中是否存在非失活性钠通道,并且,如果存在的话,这些钠通道在伴随与青光眼有关的视觉损失的视网膜神经节细胞破坏过程中所起的作用是什么。
大鼠视网膜神经节细胞中的生理过程如下所述:
伴随去极化兴奋性电压-依赖性Na通道开放约1毫秒,然后关闭。倘若细胞膜保持去极化状态,钠通道将不会再开放,直到细胞膜朝着其静息状态复极化为止。与正常兴奋性Na通道相反,非失活性Na通道在正常静息膜电位时可以开放,并在去极化电位时仍可以保持开放。在病理生理状态如三磷酸腺苷(ATP)耗尽或持续去极化时,通过非失活性Na通道的Na内流可基本上增加细胞内Na的浓度。细胞内Na的增加引起生电Na/Ca2+交换(Ransom等人,1993;Stys,1995;Waxman等人,1992),这种交换使正常的促使Ca2+由细胞中的外流变成逆向运动,结果导致细胞内Ca2+浓度有很大增加。细胞内Ca2+浓度可以从纳摩尔水平增加到微摩尔水平,结果导致所述神经元细胞死亡。(细胞内Ca2+浓度的大量增加与神经元细胞的死亡有关,并且已经表明,防止细胞内Ca2+浓度的增加能保护中枢神经***的神经元细胞和大鼠视神经。)在视神经标本中,没有测到细胞内的Ca2+,然而,在包括神经元在内的大多数细胞类型中,正常细胞Ca2+浓度约为100-200纳摩尔。当细胞内Ca2+浓度升至微摩尔水平时,它就变得具有毒性。在视神经中,恰好能触发细胞破坏的确切Ca2+水平尚不清楚,或至少还没有报道。
因此,依据本发明方法而使用并且用于本发明组合物的化合物是能阻滞视网膜神经节细胞的非失活性钠通道的钠通道阻滞剂。本发明的钠通道阻滞剂能阻止钠离子通过非失活性钠通道内流进入神经元细胞。本发明的钠通道阻滞剂优选能够选择性地阻滞所述的非失活性钠通道,其中所述的非失活性钠通道与能迅速失活的电压控通的钠离子通道截然相反。
依据本发明,还可以使用钠通道阻滞剂的可药用盐。可药用盐可以是能保持母化合物的活性并且不给其施予者带来任何有害或不利作用,并且在上下文中以此形式给药的盐。
所述可药用盐可以用有机或无极酸或碱来形成。盐可以是单价或多价离子。当考虑酸的功能时,令人特别感兴趣的是无机离子,例如碱离子如钠离子、钾离子等。有机胺盐可以用胺来形成,尤其是铵盐如一烷基胺、二烷基胺和三烷基胺,例如其中每一烷基可包含高达6个碳原子的烷基胺,或乙醇胺。盐还可以用咖啡因、氨基三丁醇和类似分子来形成。唯一重要的是,用于本发明组合物或方法所用的钠通道阻滞剂的任何盐的阳离子应当能够阻滞视网膜神经节细胞的非失活性钠通道。
为了保护哺乳动物眼睛的视网膜神经节细胞免遭损害,尤其为了在患有能引起视神经元损失的疾病的人中防止视网膜神经节细胞损失,将混合有可眼用载体的活性化合物(或混合物或其盐)依据本发明施予眼睛。可以使用任何适宜的例如常规的可眼用载体。如果载体对用其所施予的眼睛基本上没有长期或持久的有害作用的话,那么此载体就是可眼用的。可眼用载体的实例包括水(蒸馏水或去离子水)、盐水和其它水介质。依据本发明,活性化合物优选溶在用于将其给药的载体中,以使活性化合物能以溶液形式施予眼睛。或,也可以使用活性化合物的悬浮液或在适当载体中的化合物(或其盐)。
依据本发明,活性化合物(或混合物或其盐)是以足以使有效量的活性化合物扩散到眼睛视神经位点的浓度在可眼用载体中给药的。眼用治疗溶液优选含有浓度约为0.0001%-约1%(重量体积比),更优选为约0.0005%-约0.1%(重量体积比)的一种或多种活性化合物。
依据本发明,可以采用将药物施予哺乳动物眼睛视网膜神经节细胞位点的任何方法,从而将活性化合物给到欲治疗的眼睛中。术语“施予(adminstration)”包括常用的全身给药方式,例如直接注射到病人的血管中、口服给药以及能使活性化合物全身利用的给药方法。也可以采用眼房内注射的方法将钠通道阻滞剂释放到视网膜神经节细胞位点。将活性化合物直接施予哺乳动物眼睛中对哺乳动物所产生的主要作用是防止视神经损失。优选地,将有效的活性化合物局部施用于眼睛或直接注射到眼睛中。
可以使用眼用制剂的注射剂,例如滴眼剂、眼用凝胶或眼药膏,因为它们施用方便,剂量释放方便并且全身性副作用如心血管性低血压较小。局部施用的眼用制剂的实例呈现在下面的表I中。q.s.(适量)缩写表示足以能影响结果或达到所需体积的量。
表I
成份 含量(%重量体积比)
本发明的活性组分 约0.0001-约1
防腐剂 0-0.10
载体 0-40
张力调节剂 1-10
缓冲剂 0.01-10
pH调节剂 适量,pH4.5-7.5
抗氧化剂 按照需要加
纯化水 按照需要加至100%
在上述表I中所述的眼用制剂中,可以使用多种防腐剂。优选的防腐剂包括但不限于,苯甲烃铵钾、氯丁醇、硫汞撒、乙酸苯汞和硝酸苯汞。同样,在此眼用制剂中也可以使用多种优选的载体。这些载体包括但不限于,聚乙烯醇、聚维酮、羟丙基甲基纤维素、泊咯沙姆、羧甲基纤维素和羟乙基纤维素。
张力调节剂可按照需要量或适当量加入。张力调节剂包括但不限于,盐,尤其是氯化钠、氯化钾等,甘露糖醇和甘油,或其它合适的可眼用张力调节剂。
只要制得的制剂可眼用,可以使用多种用来调节pH值的缓冲剂和手段。相应地,缓冲剂包括但不限于,醋酸盐缓冲剂、柠檬酸盐缓冲剂、磷酸盐缓冲剂和硼酸盐缓冲剂。按照需要,可用酸或碱来调节这些制剂的pH值。
以类似叶脉,可眼用抗氧化剂包括但不限于,焦亚硫酸钠、硫代硫酸钠、乙酰半胱氨酸、叔丁对甲氧酚、和丁化羟基甲苯。
本领域技术人员会认识到,给药频率取决于活性化合物的确实性质和其在眼用制剂中的浓度。作为非失活性钠通道阻滞剂的化合物是I类抗心律失常药,例如苯妥英、利多卡因、拉莫三嗪、美西律、丙缓脉灵、妥卡胺、QX-314、QX-222和其它功能上相关的化合物。与正常的电压控通的Na通道相比,这些活性剂能优先阻滞非失活性Na通道。
在本发明眼用组合物中,用作有效的活性组分的具体实例有奎尼丁、缓脉灵、丙缓脉灵、普鲁卡因胺、丙吡胺、普罗帕酮、利多卡因、妥卡胺、美西律、苯妥英、氟卡胺、氯卡胺、茚丙胺、恩卡胺、QX-314、普鲁卡因、QX-222、丁卡因、苯佐卡因、GEA-968、天青A、泮库铵(pancuronium)、N-甲基***、磷苯妥英、CNS 1237、BW1003C87、BW619C89、U54494A、PD85639、雷利托林、C1953、利法利嗪、唑尼沙胺和利鲁唑。
依据本发明的钠通道阻滞剂可以通过在下述文献中公开的方法来确定:“细胞外膜片钳:解决经过生物膜中单个开放通道的电流的方法”,Neher等人,Pflugers Archiv V375第219-228页(1978);和“为以高分辨率记录细胞和无细胞膜片之间电流的改进的膜片钳技术”,Hamill等人,Pflugers Archiv V391第85-100页(1981)。这些文献全部列入本发明的参考文献,以提供确定能依据本发明而使用的钠通道阻滞剂的方法。
实施例
图1表示在正常条件下的视网膜神经节细胞10,和假设的有关转运机制12、14、16、18,它们分别负责维持钠(Na+)、钾(K+)和钙(Ca2+)的梯度和细胞的电活性。如图所示,在正常条件下,ATP水平是适当的,并且提供驱动Na+/K+泵14所需的能量,其中Na+/K+泵14维持着K+和Na+的梯度,使细胞内K+浓度比其在细胞外的浓度要高,细胞内Na+浓度比其在细胞外的浓度要低。电压控通的Na+和K+通道12、16提供构建动作电位的电流。生电Na+/Ca2+交换器18使细胞的Ca2+水平维持在生理范围(纳摩尔)内。
然而,如果由于一些病生理因素导致ATP水平下降,如图2中处于局部缺血条件下的细胞20所示,轴突就会去极化,并且由于Na+/K+泵14被抑制,会使Na+/K+梯度长时间被破坏。细胞中Na+的增加由不会长时间失活的电压控通的Na+通道所介导。这些Na+通道称为“非失活性”通道。膜的去极化和细胞内Na+浓度增加足以驱动Na+/Ca2+交换器18起反向交换作用(参见图2),由此神经节细胞就负荷有致死水平的Ca2+。假定此变化过程发生在青光眼患者的视网膜神经节细胞中。
相应地,依据本发明,当存在治疗浓度的能选择性地阻滞非失活型Na+通道的Na+通道阻滞剂时,希望发生下述过程。首先,Na+通道阻滞剂对正常动作电位影响很小或没有影响。这对于维护正常神经节细胞的功能至关重要。其次,Na+通道阻滞剂能阻滞细胞内Na+的有害性增加以及随后细胞内Ca2+的致死性增加。由此,将正常神经节细胞的机能障碍降至最小,因而有助于防止与青光眼有关的视野损失。此外,非失活性Na+通道阻滞剂可以产生其它有益作用。这是因为,据认为Na+通道在局部缺血、低氧和其它病理状态期间会阻止神经元组织中致毒性谷氨酸盐的释放。细胞外过高的谷氨酸盐水平具有神经破坏性并且可能也是导致青光视眼神经病的原因。因此,依据本发明,一种药物,即非失活性Na+通道阻滞剂在治疗浓度下,能防止Na+超负荷和细胞外谷氨酸盐的致毒性增加。
综上所述,很明显本发明的保护范围只能由后面的权利要求确定,这些权利要求是根据本发明的公开来阅读和理解的。
Claims (10)
1.使缺氧后的神经节细胞维持正常的细胞内Na+和Ca2+水平的方法,所述方法包括:所述神经节神经元细胞与用于阻滞视网膜神经节细胞非失活性钠通道活性的组合物进行接触。
2.根据权利要求1的方法,其中用于阻滞非失活性钠通道的组合物选自苯并噻唑利鲁唑、芦贝鲁唑、苯基苯并噻唑和利法利嗪。
3.根据权利要求2的方法,其中具有非失活性钠通道阻滞活性的组合物含有抗心律失常剂。
4.根据权利要求1的方法,其中组合物包括适于以眼房内注射液形式施予哺乳动物眼睛的眼用溶液。
5.用于防止哺乳动物眼中与青光眼有关的视网膜神经节细胞死亡的药物组合物,其中所述组合物含有一种或多种具有非失活性钠通道阻滞活性的化合物作为活性组分。
6.根据权利要求5的组合物,其中具有非失活性钠通道阻滞活性的化合物选自苯并噻唑利鲁唑、芦贝鲁唑、苯基苯并噻唑和利法利嗪。
7.根据权利要求5的组合物,其中组合物是适于以眼房内注射液形式施予哺乳动物眼睛的眼用溶液。
8.防止包括人在内的哺乳类动物的与青光眼有关的视网膜神经节细胞死亡的方法,包括将药物组合物施予所述哺乳动物的神经节视神经的步骤,其中所述组合物含有一种或多种具有非失活性钠通道阻滞活性的化合物作为其活性成份。
9.对人眼视网膜神经节细胞提供神经保护作用的方法,包括将含有一种或多种具有非失活性钠通道阻滞活性的化合物作为活性成份的药物组合物施予人。
10.根据权利要求9的方法,其中具有非失活性钠通道阻滞活性的化合物选自苯并噻唑利鲁唑、芦贝鲁唑、苯基苯并噻唑和利法利嗪。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/827,194 US5922746A (en) | 1997-03-27 | 1997-03-27 | Inhibition of noninactivating Na channels of mammalian optic nerve as a means of preventing optic nerve degeneration associated with glaucoma |
US08/827,194 | 1997-03-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1251520A true CN1251520A (zh) | 2000-04-26 |
Family
ID=25248552
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN98803734A Pending CN1251520A (zh) | 1997-03-27 | 1998-03-26 | 钠通道阻滞剂在制备用于防止与青光眼有关的视神经变性的药物中的应用 |
Country Status (13)
Country | Link |
---|---|
US (6) | US5922746A (zh) |
EP (1) | EP0973500A1 (zh) |
JP (1) | JP2001521500A (zh) |
KR (1) | KR100610997B1 (zh) |
CN (1) | CN1251520A (zh) |
AU (1) | AU734432B2 (zh) |
BR (1) | BR9807895A (zh) |
CA (1) | CA2284940A1 (zh) |
HU (1) | HUP0001268A2 (zh) |
IL (1) | IL132001A (zh) |
NO (1) | NO994674L (zh) |
NZ (1) | NZ337604A (zh) |
WO (1) | WO1998043612A1 (zh) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001041756A2 (en) * | 1999-12-02 | 2001-06-14 | University Of South Florida | Method and composition for treatment of ischemic neuronal reperfusion injury |
GB0002666D0 (en) | 2000-02-04 | 2000-03-29 | Univ London | Blockade of voltage dependent sodium channels |
US20060013814A1 (en) * | 2000-08-29 | 2006-01-19 | Davies Collison Cave | Methods for preventing pressure-induced apoptotic neural-cell death |
WO2002042842A2 (en) * | 2000-11-22 | 2002-05-30 | Allergan, Inc. | A high-throughput screen for identifying channel blockers that selectively distinguish transient from persistent sodium channels |
US6479458B1 (en) * | 2001-11-08 | 2002-11-12 | Allergan, Inc. | Targeting the reverse mode of the Na+/Ca2+ exchanger for the treatment of optic neuropathy associated with glaucoma and ischemic optic neuropathy |
US7361478B2 (en) * | 2001-11-20 | 2008-04-22 | Allergan, Inc. | High-throughput screen for identifying selective persistent sodium channels channel blockers |
US20040058313A1 (en) * | 2002-04-24 | 2004-03-25 | Abreu Marcio Marc | Compositions, targets, methods and devices for the therapy of ocular and periocular disorders |
WO2004093814A2 (en) * | 2003-04-22 | 2004-11-04 | Pharmacia Corporation | Compositions of a cyclooxygenase-2 selective inhibitor and a sodium channel blocker |
US7125908B2 (en) * | 2003-08-29 | 2006-10-24 | Allergan, Inc. | Treating pain using selective antagonists of persistent sodium current |
BRPI0413920A (pt) * | 2003-08-29 | 2006-10-24 | Allergan Inc | emprego de antagonistas seletivos de corrente de sódio persistente para tratar distúrbios neurológicos e dor |
US7060723B2 (en) | 2003-08-29 | 2006-06-13 | Allergan, Inc. | Treating neurological disorders using selective antagonists of persistent sodium current |
CA2661448A1 (en) | 2005-08-25 | 2007-03-01 | Steven Michael Weiss | Reducing myocardial damage and the incidence of arrhythmia arising from loss, reduction or interruption in coronary blood flow |
WO2016100209A1 (en) * | 2014-12-15 | 2016-06-23 | The Children's Medical Center Corporation | Non-toxic topical anesthetic ophthalmic compositions |
US10791651B2 (en) | 2016-05-31 | 2020-09-29 | Carbice Corporation | Carbon nanotube-based thermal interface materials and methods of making and using thereof |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH06172176A (ja) * | 1992-12-03 | 1994-06-21 | Rohto Pharmaceut Co Ltd | アジマリンを必須成分とする眼圧降下剤 |
FR2702148B1 (fr) * | 1993-03-05 | 1995-04-07 | Rhone Poulenc Rorer Sa | Application d'anticonvulsivants dans le traitement du neuro-sida. |
GB9326010D0 (en) * | 1993-12-21 | 1994-02-23 | Sandoz Ltd | Improvements in or relating to organic compounds |
FR2714828B1 (fr) * | 1994-01-12 | 1996-02-02 | Rhone Poulenc Rorer Sa | Application du riluzole dans le traitement des maladies mitochondriales. |
JPH09510961A (ja) * | 1994-01-14 | 1997-11-04 | ジュニア シャヒニアン,リー | 持続性および長期間の角膜鎮痛の方法 |
-
1997
- 1997-03-27 US US08/827,194 patent/US5922746A/en not_active Expired - Fee Related
-
1998
- 1998-03-26 HU HU0001268A patent/HUP0001268A2/hu unknown
- 1998-03-26 KR KR1019997008435A patent/KR100610997B1/ko not_active IP Right Cessation
- 1998-03-26 EP EP98913141A patent/EP0973500A1/en not_active Withdrawn
- 1998-03-26 AU AU67762/98A patent/AU734432B2/en not_active Ceased
- 1998-03-26 BR BR9807895-0A patent/BR9807895A/pt not_active Application Discontinuation
- 1998-03-26 WO PCT/US1998/005941 patent/WO1998043612A1/en active IP Right Grant
- 1998-03-26 IL IL13200198A patent/IL132001A/xx active IP Right Grant
- 1998-03-26 NZ NZ337604A patent/NZ337604A/xx unknown
- 1998-03-26 JP JP54179498A patent/JP2001521500A/ja not_active Ceased
- 1998-03-26 CN CN98803734A patent/CN1251520A/zh active Pending
- 1998-03-26 CA CA002284940A patent/CA2284940A1/en not_active Abandoned
-
1999
- 1999-03-22 US US09/273,832 patent/US6326389B1/en not_active Expired - Fee Related
- 1999-09-24 NO NO994674A patent/NO994674L/no not_active Application Discontinuation
-
2001
- 2001-08-21 US US09/935,554 patent/US6420402B2/en not_active Expired - Fee Related
- 2001-09-14 US US09/952,733 patent/US6426358B1/en not_active Expired - Fee Related
- 2001-12-12 US US10/017,660 patent/US20020137777A1/en not_active Abandoned
-
2002
- 2002-04-03 US US10/116,492 patent/US20020183368A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
US6426358B1 (en) | 2002-07-30 |
EP0973500A1 (en) | 2000-01-26 |
BR9807895A (pt) | 2000-02-22 |
NO994674L (no) | 1999-11-25 |
NO994674D0 (no) | 1999-09-24 |
US20020040042A1 (en) | 2002-04-04 |
IL132001A0 (en) | 2001-03-19 |
CA2284940A1 (en) | 1998-10-08 |
US6326389B1 (en) | 2001-12-04 |
AU6776298A (en) | 1998-10-22 |
AU734432B2 (en) | 2001-06-14 |
US5922746A (en) | 1999-07-13 |
US20020013353A1 (en) | 2002-01-31 |
US6420402B2 (en) | 2002-07-16 |
HUP0001268A2 (hu) | 2000-12-28 |
KR20000076334A (ko) | 2000-12-26 |
US20020137777A1 (en) | 2002-09-26 |
JP2001521500A (ja) | 2001-11-06 |
NZ337604A (en) | 2001-03-30 |
US20020183368A1 (en) | 2002-12-05 |
IL132001A (en) | 2005-07-25 |
KR100610997B1 (ko) | 2006-08-10 |
WO1998043612A1 (en) | 1998-10-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU619554B2 (en) | Antiglaucoma compositions containing combinations of alpha-2 agonists and beta-blockers | |
EP1243270B1 (en) | Neuroprotective for the mammalian eye by administration of potassium channel blockers | |
DE3310079C2 (zh) | ||
CA2087420C (en) | Ophthalmic pharmaceutical composition containing n-acetyl-cisteine and polyvinylalcohol | |
CN1251520A (zh) | 钠通道阻滞剂在制备用于防止与青光眼有关的视神经变性的药物中的应用 | |
EP0786994B1 (en) | Use of chloride channel blockers for reducing intraocular pressure | |
CA2132102A1 (en) | Method for reducing intraocular pressure in the mammalian eye by administration of gamma aminobutyric acid (gaba) agonists | |
US9901627B2 (en) | Topical ocular preparation of botulinum toxin for use in ocular surface disease | |
US5612364A (en) | Substantially pure apraclonidine | |
US11484580B2 (en) | Topical ocular preparation of botulinum toxin for use in ocular surface disease | |
AU2002340188B2 (en) | Targeting the reverse mode of the Na+/Ca2+ exchanger for the treatment of optic neuropathy associated with glaucoma and ischemic optic neuropathy | |
US5629345A (en) | Methods and compositions for ATP-sensitive K+ channel inhibition for lowering intraocular pressure | |
MXPA99008771A (en) | Use of sodium channel blocker in the manufacture of a medicament for preventing optic nerve degeneration associated with glaucoma | |
AU2002340188A1 (en) | Targeting the reverse mode of the Na+/Ca2+ exchanger for the treatment of optic neuropathy associated with glaucoma and ischemic optic neuropathy | |
US20090318515A1 (en) | Succinimide derivatives as ocular hypotensive agents | |
EP0277814A2 (en) | Anti-glaucoma use of trifluoromethanesulfonamide | |
de ROETTH | Ophthalmic Pharmacology and Toxicology | |
WO2005082345A2 (en) | Targeting the reverse mode of the na+/ca2+ exchanger for the treatment of neurodegenerative conditions such as alzheimers and parkinsons diseases, multiple sclerosis and amyotropic lateral sclerosis; diabetic retinopathy, epilepsy and ischemia |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
ASS | Succession or assignment of patent right |
Owner name: ALLERGAN INC. Free format text: FORMER OWNER: ALLERGAN SALES, INC. Effective date: 20030917 |
|
C41 | Transfer of patent application or patent right or utility model | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20030917 Address after: American California Applicant after: Allergan Address before: American California Applicant before: Allergan Sales, INC. |
|
C12 | Rejection of a patent application after its publication | ||
RJ01 | Rejection of invention patent application after publication |