CN1889954A - 用类维生素a预防和/或减轻光受体变性的方法 - Google Patents
用类维生素a预防和/或减轻光受体变性的方法 Download PDFInfo
- Publication number
- CN1889954A CN1889954A CNA2004800357329A CN200480035732A CN1889954A CN 1889954 A CN1889954 A CN 1889954A CN A2004800357329 A CNA2004800357329 A CN A2004800357329A CN 200480035732 A CN200480035732 A CN 200480035732A CN 1889954 A CN1889954 A CN 1889954A
- Authority
- CN
- China
- Prior art keywords
- disease
- rar
- tazarotene
- retinal
- retina
- 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
- 230000007850 degeneration Effects 0.000 title claims abstract description 7
- 108091008695 photoreceptors Proteins 0.000 title abstract 2
- 230000002265 prevention Effects 0.000 title description 6
- 229960000565 tazarotene Drugs 0.000 claims abstract description 40
- OGQICQVSFDPSEI-UHFFFAOYSA-N Zorac Chemical compound N1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SCCC2(C)C)C2=C1 OGQICQVSFDPSEI-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 31
- 239000000556 agonist Substances 0.000 claims abstract description 26
- 230000005855 radiation Effects 0.000 claims abstract description 13
- 241000124008 Mammalia Species 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 31
- 201000010099 disease Diseases 0.000 claims description 29
- 238000011282 treatment Methods 0.000 claims description 22
- 208000002780 macular degeneration Diseases 0.000 claims description 19
- 210000001525 retina Anatomy 0.000 claims description 18
- 208000017442 Retinal disease Diseases 0.000 claims description 16
- 206010038923 Retinopathy Diseases 0.000 claims description 15
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 12
- 210000003583 retinal pigment epithelium Anatomy 0.000 claims description 12
- 208000011580 syndromic disease Diseases 0.000 claims description 12
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 8
- 230000001154 acute effect Effects 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 230000002207 retinal effect Effects 0.000 claims description 8
- 208000007014 Retinitis pigmentosa Diseases 0.000 claims description 7
- 201000002563 Histoplasmosis Diseases 0.000 claims description 6
- 206010020880 Hypertrophy Diseases 0.000 claims description 6
- 230000003287 optical effect Effects 0.000 claims description 6
- 208000002720 Malnutrition Diseases 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 230000006378 damage Effects 0.000 claims description 5
- 230000001071 malnutrition Effects 0.000 claims description 5
- 235000000824 malnutrition Nutrition 0.000 claims description 5
- 208000015380 nutritional deficiency disease Diseases 0.000 claims description 5
- 208000014882 Carotid artery disease Diseases 0.000 claims description 4
- 208000005590 Choroidal Neovascularization Diseases 0.000 claims description 4
- 206010060823 Choroidal neovascularisation Diseases 0.000 claims description 4
- 208000002691 Choroiditis Diseases 0.000 claims description 4
- 208000035719 Maculopathy Diseases 0.000 claims description 4
- 208000003971 Posterior uveitis Diseases 0.000 claims description 4
- 201000007527 Retinal artery occlusion Diseases 0.000 claims description 4
- 201000005485 Toxoplasmosis Diseases 0.000 claims description 4
- 208000029977 White Dot Syndromes Diseases 0.000 claims description 4
- 125000005907 alkyl ester group Chemical group 0.000 claims description 4
- 201000005849 central retinal artery occlusion Diseases 0.000 claims description 4
- 210000000981 epithelium Anatomy 0.000 claims description 4
- 210000002189 macula lutea Anatomy 0.000 claims description 4
- 231100000915 pathological change Toxicity 0.000 claims description 4
- 230000036285 pathological change Effects 0.000 claims description 4
- 239000000049 pigment Substances 0.000 claims description 4
- 208000004644 retinal vein occlusion Diseases 0.000 claims description 4
- 208000006379 syphilis Diseases 0.000 claims description 4
- 102100028187 ATP-binding cassette sub-family C member 6 Human genes 0.000 claims description 3
- 208000001351 Epiretinal Membrane Diseases 0.000 claims description 3
- 208000002927 Hamartoma Diseases 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 3
- 201000004613 Pseudoxanthoma elasticum Diseases 0.000 claims description 3
- 208000027073 Stargardt disease Diseases 0.000 claims description 3
- 230000001631 hypertensive effect Effects 0.000 claims description 3
- 208000023558 pseudoxanthoma elasticum (inherited or acquired) Diseases 0.000 claims description 3
- 208000004142 Acute Retinal Necrosis Syndrome Diseases 0.000 claims description 2
- 208000005598 Angioid Streaks Diseases 0.000 claims description 2
- 206010003571 Astrocytoma Diseases 0.000 claims description 2
- 208000003569 Central serous chorioretinopathy Diseases 0.000 claims description 2
- 206010070957 Choroidal haemangioma Diseases 0.000 claims description 2
- 208000021089 Coats disease Diseases 0.000 claims description 2
- 208000035473 Communicable disease Diseases 0.000 claims description 2
- 206010010356 Congenital anomaly Diseases 0.000 claims description 2
- 206010058202 Cystoid macular oedema Diseases 0.000 claims description 2
- 241000555268 Dendroides Species 0.000 claims description 2
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 2
- 208000019878 Eales disease Diseases 0.000 claims description 2
- 208000028506 Familial Exudative Vitreoretinopathies Diseases 0.000 claims description 2
- 206010016654 Fibrosis Diseases 0.000 claims description 2
- 206010058558 Hypoperfusion Diseases 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 206010022557 Intermediate uveitis Diseases 0.000 claims description 2
- 201000000512 Intraocular Lymphoma Diseases 0.000 claims description 2
- 208000016604 Lyme disease Diseases 0.000 claims description 2
- 208000001344 Macular Edema Diseases 0.000 claims description 2
- 206010025412 Macular dystrophy congenital Diseases 0.000 claims description 2
- 208000009857 Microaneurysm Diseases 0.000 claims description 2
- 208000006123 Myiasis Diseases 0.000 claims description 2
- 208000003435 Optic Neuritis Diseases 0.000 claims description 2
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 claims description 2
- 208000008709 Retinal Telangiectasis Diseases 0.000 claims description 2
- 201000007737 Retinal degeneration Diseases 0.000 claims description 2
- 206010038910 Retinitis Diseases 0.000 claims description 2
- 206010038915 Retinitis viral Diseases 0.000 claims description 2
- 201000000582 Retinoblastoma Diseases 0.000 claims description 2
- 206010038934 Retinopathy proliferative Diseases 0.000 claims description 2
- 206010039705 Scleritis Diseases 0.000 claims description 2
- 206010042742 Sympathetic ophthalmia Diseases 0.000 claims description 2
- 206010043189 Telangiectasia Diseases 0.000 claims description 2
- 206010044269 Toxocariasis Diseases 0.000 claims description 2
- 206010044819 Tuberculosis of eye Diseases 0.000 claims description 2
- 208000027076 Uveal disease Diseases 0.000 claims description 2
- 201000005969 Uveal melanoma Diseases 0.000 claims description 2
- 206010046851 Uveitis Diseases 0.000 claims description 2
- 206010047115 Vasculitis Diseases 0.000 claims description 2
- 210000004204 blood vessel Anatomy 0.000 claims description 2
- 238000010322 bone marrow transplantation Methods 0.000 claims description 2
- 210000001715 carotid artery Anatomy 0.000 claims description 2
- 201000005667 central retinal vein occlusion Diseases 0.000 claims description 2
- 230000002490 cerebral effect Effects 0.000 claims description 2
- 210000003161 choroid Anatomy 0.000 claims description 2
- 230000001684 chronic effect Effects 0.000 claims description 2
- 208000006623 congenital stationary night blindness Diseases 0.000 claims description 2
- 201000010206 cystoid macular edema Diseases 0.000 claims description 2
- 230000004340 degenerative myopia Effects 0.000 claims description 2
- 201000011190 diabetic macular edema Diseases 0.000 claims description 2
- 206010014801 endophthalmitis Diseases 0.000 claims description 2
- 201000006902 exudative vitreoretinopathy Diseases 0.000 claims description 2
- 230000004761 fibrosis Effects 0.000 claims description 2
- 201000006321 fundus dystrophy Diseases 0.000 claims description 2
- 229940084434 fungoid Drugs 0.000 claims description 2
- 208000034737 hemoglobinopathy Diseases 0.000 claims description 2
- 206010020718 hyperplasia Diseases 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims description 2
- 230000002757 inflammatory effect Effects 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 208000028867 ischemia Diseases 0.000 claims description 2
- 238000002647 laser therapy Methods 0.000 claims description 2
- 230000017074 necrotic cell death Effects 0.000 claims description 2
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 claims description 2
- 201000002165 neuroretinitis Diseases 0.000 claims description 2
- 210000002445 nipple Anatomy 0.000 claims description 2
- 208000008798 osteoma Diseases 0.000 claims description 2
- 208000001297 phlebitis Diseases 0.000 claims description 2
- 230000000649 photocoagulation Effects 0.000 claims description 2
- 238000002428 photodynamic therapy Methods 0.000 claims description 2
- 201000004849 posterior scleritis Diseases 0.000 claims description 2
- 230000006785 proliferative vitreoretinopathy Effects 0.000 claims description 2
- 239000000790 retinal pigment Substances 0.000 claims description 2
- 210000001957 retinal vein Anatomy 0.000 claims description 2
- 201000007714 retinoschisis Diseases 0.000 claims description 2
- 230000009885 systemic effect Effects 0.000 claims description 2
- 208000009056 telangiectasis Diseases 0.000 claims description 2
- 201000008827 tuberculosis Diseases 0.000 claims description 2
- 210000001745 uvea Anatomy 0.000 claims description 2
- 201000007790 vitelliform macular dystrophy Diseases 0.000 claims description 2
- 241001025261 Neoraja caerulea Species 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- 208000034461 Progressive cone dystrophy Diseases 0.000 claims 1
- 201000008615 cone dystrophy Diseases 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 9
- -1 retinoid compound Chemical class 0.000 abstract description 5
- 108010079850 retinoic acid receptor beta Proteins 0.000 abstract 1
- 108090000064 retinoic acid receptors Proteins 0.000 abstract 1
- 229940096885 Retinoic acid receptor agonist Drugs 0.000 description 15
- 239000005557 antagonist Substances 0.000 description 15
- 241001465754 Metazoa Species 0.000 description 12
- 230000001681 protective effect Effects 0.000 description 7
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 229960003679 brimonidine Drugs 0.000 description 6
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 208000030533 eye disease Diseases 0.000 description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 3
- 239000003889 eye drop Substances 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 229960005280 isotretinoin Drugs 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 3
- 210000004127 vitreous body Anatomy 0.000 description 3
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 2
- 208000002874 Acne Vulgaris Diseases 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 2
- 206010025421 Macule Diseases 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 2
- 206010000496 acne Diseases 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 235000019155 vitamin A Nutrition 0.000 description 2
- 239000011719 vitamin A Substances 0.000 description 2
- 229940045997 vitamin a Drugs 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](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](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- GYTGOLDQGRPDNF-DSSYRYGXSA-N (2e)-hepta-2,4-dienoic acid Chemical class CCC=C\C=C\C(O)=O GYTGOLDQGRPDNF-DSSYRYGXSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- NSTREUWFTAOOKS-UHFFFAOYSA-N 2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1F NSTREUWFTAOOKS-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
- 208000031471 Macular fibrosis Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 206010065700 Ocular sarcoidosis Diseases 0.000 description 1
- 206010065373 Papillophlebitis Diseases 0.000 description 1
- 241000287127 Passeridae Species 0.000 description 1
- 208000034247 Pattern dystrophy Diseases 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000320126 Pseudomugilidae Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000014286 Serpiginous choroiditis Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000022758 Sorsby fundus dystrophy Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- BPMFZUMJYQTVII-UHFFFAOYSA-N alpha-guanidinoacetic acid Natural products NC(=N)NCC(O)=O BPMFZUMJYQTVII-UHFFFAOYSA-N 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000007698 birth defect Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 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
- 244000309464 bull Species 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940064982 ethylnicotinate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000004438 eyesight Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960001238 methylnicotinate Drugs 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 201000002267 posterior uveal melanoma Diseases 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- VSRSQDMWBSKNSF-UHFFFAOYSA-N propan-2-yl pyridine-3-carboxylate Chemical compound CC(C)OC(=O)C1=CC=CN=C1 VSRSQDMWBSKNSF-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000004243 retinal function Effects 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000003786 sclera Anatomy 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001982 uveitic effect Effects 0.000 description 1
- 230000003074 vasoproliferative effect Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000001429 visible spectrum Methods 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
-
- 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
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts 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
- A61K31/33—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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- 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
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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)
- Ophthalmology & Optometry (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及一种减轻和/或预防人类眼中由可见光区辐射引起的光受体变性的方法,所述方法包括将具有 RARβ和/或RARδ选择性激动剂活性的类维生素A化合物、特别是他扎罗汀,向所述哺乳动物给药。
Description
发明背景
1.技术领域
本发明涉及通过将RARβ和/或RARδ选择性类维生素A(retinoid)激动剂向人类给药,来预防和/或减轻由可见光,例如蓝光,引起的光受体损害。
2.背景技术
已经发现,异维甲酸(13-顺式维生素A酸,或ACCUTANE)能够保护大鼠和小鼠的光受体免受光损害。(参见Sparrow,PNAS,2003年4月15日,vol.100,no.8,4353-4354。另外参见Seiving等,PNAS,2001年2月13日,vol.98,no.4,1835-1840。)然而,已公知异维甲酸会导致先天缺陷,并且是非选择性的类维生素A,即,它不具有类维生素A受体亚型选择性。
他扎罗汀(Tazarotene)是一种RARβ和RARδ选择性类维生素A激动剂,已被用于治疗牛皮癣和/或痤疮。(参见美国专利5,089,509。)已公开了他扎罗汀及其它相关的类维生素A用于治疗各种对类维生素A化合物的治疗有反应的其它疾病和病症。(参见美国专利No.5,750,693、6,090,826和6,344,463。)另外,最近还公开了他扎罗汀和某些其它类维生素A激动剂用于预防手术或创伤后的视网膜色素上皮增生,或预防与脉络膜新生血管形成有关的眼病导致的视网膜色素上皮增生,所述眼病包括例如年龄相关黄斑变性以及组织胞浆菌病综合征。(参见美国专利No.5,824,685、6,075,032、6,071,924、6,372,753、5,437,291和5,674,205。)
发明内容
本发明提供一种减轻和/或预防哺乳动物眼中由可见光区,例如蓝光,辐射引起的光受体变性的方法,所述方法包括将具有RARβ和/或RARδ选择性激动剂活性的类维生素A化合物向所述哺乳动物给药。特别是,本发明提供一种治疗因暴露于可见光辐射—特别是可见光谱的蓝色波段的辐射,例如约480nm的辐射—所引起疾病或病症的方法。所述疾病或病症包括,但不限于,非渗出性年龄相关黄斑变性(ARMD)、渗出性年龄相关黄斑变性(ARMD)、脉络膜新生血管形成、糖尿病性视网膜病、中心性浆液性脉络膜视网膜病变、囊样黄斑水肿、糖尿病性黄斑水肿、近视性视网膜变性、急性多灶性鳞状色素上皮病变、贝切特病、鸟枪弹样视网膜脉络膜病变、传染性疾病(梅毒、莱姆病、结核病、弓形体病)、中间葡萄膜炎(睫状体平坦部炎)、多灶性脉络膜炎、多发性一过性白点综合征(multiple evanescent white dotsyndrome,MEWDS)、眼结节病(Ocular Sarcoidosis)、后巩膜炎、匐行性脉络膜炎(serpiginous choroiditis)、视网膜下纤维化和葡萄膜炎综合征、伏-小柳-原田综合征、点状内层(punctate inner)脉络膜病变、急性后极部多灶性鳞状色素上皮病变、急性视网膜色素上皮炎、急性黄斑视神经视网膜病、糖尿病性视网膜病、视网膜中央动脉阻塞病、视网膜中央静脉阻塞、弥散性血管内凝血病、视网膜分支静脉阻塞、高血压性眼底改变(Hypertensive Fundus Changes)、眼缺血综合征、视网膜动脉微动脉瘤、慢性渗出性视网膜病(Coat’sdisease)、旁中心凹毛细血管扩张、半侧视网膜静脉阻塞、视乳头静脉炎(Papillophlebitis)、视网膜中央动脉阻塞、视网膜分支动脉阻塞、颈动脉病(CAD)、霜样树枝状(Frosted Branch)脉管炎、镰状红细胞性视网膜病和其它血红蛋白病、血管样条纹、家族性渗出性玻璃体视网膜病变、伊尔斯病、交感性眼炎、葡萄膜炎性视网膜病(Uveitic Retinal Disease)、视网膜脱离、外伤、视网膜激光治疗、光动力学治疗、光凝固、手术中血流灌注不足、辐射性视网膜病、骨髓移植性视网膜病(Bone Marrow Transplant Retinopathy)、增殖性玻璃体视网膜病以及视网膜前膜(epiretinal membrane)、眼组织胞浆菌病、眼弓蛔虫病、拟眼组织胞浆菌病综合征(PHOS)、眼内炎、弓形体病、与HIV感染相关的视网膜病、与HIV感染相关的脉络膜病、与HIV感染相关的葡萄膜病、病毒性视网膜炎、急性视网膜坏死、进行性视网膜外层(outer retinal)坏死、真菌性视网膜病、眼梅毒、眼结核、弥漫性单侧亚急性视神经视网膜炎、蝇蛆病、视网膜色素变性、伴有视网膜营养不良的全身性疾病、先天性静止性夜盲、锥体(cone)营养不良、斯塔加特病和眼底黄色斑点症(FundusFlavimaculatus)、贝斯特病、视网膜色素上皮的图形营养不良(pattern dystrophy)、X伴性(X-linked)视网膜劈裂症、索斯比眼底营养不良(Sorsby’s Fundus Dystrophy)、良性同心性黄斑病、Bietti结晶样营养障碍、弹性假黄瘤(pseudoxanthoma elasticum)、视网膜脱离、黄斑洞、巨大视网膜撕裂、与肿瘤相关的视网膜病、视网膜色素上皮(RPE)的先天性肥大、后部葡萄膜黑色素瘤(PosteriorUveal Melanoma)、脉络膜血管瘤、脉络膜骨瘤、脉络膜转移、视网膜及视网膜色素上皮的混合性错构瘤(Combined Hamartoma)、视网膜母细胞瘤、眼底的血管增生瘤(Vasoproliferative Tumor)、视网膜星形细胞瘤和眼内淋巴瘤。
优选地,所述类维生素A化合物选自他扎罗汀,即6-[2-(4,4-二甲基-二氢苯并噻喃-6-基)乙基]烟酸乙酯;他扎罗汀酸;以及他扎罗汀酸的其它低级烷基酯,例如他扎罗汀酸的C2-C6烷基酯,例如6-[2-(4,4-二甲基-二氢苯并噻喃-6-基)乙基]烟酸甲酯、6-[2-(4,4-二甲基-二氢苯并噻喃-6-基)乙基]烟酸异丙酯、6-[2-(4,4-二甲基-二氢苯并噻喃-6-基)乙基]烟酸正丁酯等。
附图说明
图1示出了将试验大鼠暴露于波长为480nm的蓝光的影响。特别是,该图表明测试对象的光受体层被严重破坏。
图2与图1相比,示出了将类维生素A或溴莫尼定(brimonidine)向测试大鼠给药对其光受体层的保护作用。
图3示出了由ERG测定的将RAR激动剂或RXR激动剂向测试大鼠给药对其光受体层的保护作用。
图4示出了用类维生素A或溴莫尼定给药的测试大鼠的光受体层的测定的ERG的相对应答。
图5示出了当与RAR拮抗剂结合给药时,RAR激动剂的保护作用的丧失。
具体实施方式
他扎罗汀已被用于治疗痤疮和/或牛皮癣,以及对类维生素A的治疗有反应的其它疾病。最近还公开了他扎罗汀和其它类维生素A激动剂可用于预防手术或创伤后的视网膜色素上皮增生,或预防与脉络膜新生血管形成有关的眼病导致的视网膜色素上皮增生,所述眼病包括例如年龄相关黄斑变性以及组织胞浆菌病综合征。
现已出人意料地发现,他扎罗汀可用于治疗因暴露于可见光辐射,例如光谱的蓝色波段的辐射,而引起的眼部疾病和/或病症。虽然不希望被理论所束缚,但是可推测他扎罗汀之所以有效是因为它能够充当RARβ和/或RARγ选择性类维生素A激动剂。(优选地,本发明方法中使用的RARβ和/或RARγ选择性类维生素A对任何RXR受体不具有激动剂活性,并且,按美国专利6,075,032的实施例1的共转染检测进行测定,所述RARβ和/或RARγ选择性类维生素A具有大于15的RARα/RARβ效能和/或大于30的RARα/RARγ效能。更优选地,本方法中使用的类维生素A具有大于15的RARα/RARβ效能和大于30的RARα/RARγ效能。参见美国专利6,075,032的表1。)
本发明的一个优选实施方案是将他扎罗汀用于治疗因所述辐射引起的年龄相关黄斑变性、糖尿病性视网膜病和/或视网膜色素变性,所述治疗是通过将患所述疾病的人眼与治疗有效量的他扎罗汀接触而进行。治疗有效量是活性剂的能够达到所需治疗效果的量。已知治疗有效量取决于给药方式、待治疗个体的病症等。
为达到本发明方法的RARβ和/或RARγ选择性类维生素A的治疗效果,可将类维生素A全身给药,例如口服,或者局部给药,例如通过滴眼剂或位置选择性注射给药至眼内,这取决于待治疗的病症、对位置选择性治疗的需要、类维生素A的给药量以及其它考虑因素。
本发明还涉及他扎罗汀或其它RARβ和/或RARγ选择性类维生素A用于制备眼用组合物的用途,所述眼用组合物用于治疗ARMD、糖尿病性视网膜病和/或视网膜色素变性。也就是说,将他扎罗汀与常规的可眼用赋形剂混合,例如,水溶液例如生理盐水,油溶液,或药膏。赋形剂可含有可眼用的防腐剂例如氯化苄烷铵,表面活性剂例如聚山梨醇酯80,脂质体,或者聚合物例如甲基纤维素、聚乙烯醇、聚乙烯吡咯烷酮以及透明质酸,所述聚合物可用于增加粘度。
这里使用的术语—他扎罗汀或其它RARβ或RARγ选择性类维生素A激动剂的“治疗有效量”,是计算得到的这样的量,即它能够在人体或动物体内、在所需的时间段内,达到并维持眼内或血流内的治疗浓度,例如能够有效治疗不良病症的浓度,如果将所述激动剂直接给至玻璃体腔或眼周间隙内,则所述浓度指眼内浓度,如果所述激动剂通过外周给药,则所述浓度指血流内浓度。治疗有效量将会随着以下因素变化:各个RARβ和/或RARγ选择性类维生素A激动剂的效能,预期的治疗或其它效果所需要的量,所述物质一旦进入玻璃体腔或血流后被身体排除或分解的速度,以及制剂中RAR激动剂的量。按照常规的谨慎给药惯例,通常首先使用特定药剂的接近有效范围下限的剂量,然后根据所观察到的反应增大或减小剂量,这正是医生的常规程序。
对于直接给药至眼的玻璃体腔内,可将50至150μg范围内的量一次或分多次给药,以达到所需的治疗效果。或者,类维生素A的给药可采用玻璃体内和结膜下注射相结合的方式进行,并且可同时或间歇进行。对于玻璃体内注射,优选采用局部或眼球后麻醉将RAR激动剂注射入前玻璃体腔。在一个可选的实施方案中,采用药物递送载体将RAR激动剂给至玻璃体内。例如,可将RAR激动剂溶解于生物惰性流体中,所述流体也可用作机械填塞以帮助固定视网膜,所述流体优选类维生素A可溶的油,例如硅油。然而,对于具有部分溶混性的RAR激动剂,也可使用除油之外的液体。
已发现本发明的类维生素A的治疗作用可以被延迟起效并且是可逆的。因此,采用一种缓释方法将类维生素A给药是有利的,例如将封装于诸如脂质体的微泡内的类维生素A药剂进行玻璃体内注射,药剂从所述微泡中经过数天时间释放出来,优选3至20天之间。或者,可将药物制成缓释制剂,例如容纳于缓释聚合物中,药物从所述聚合物中经过数天时间缓慢释放,例如2至30天。可通过玻璃体内、结膜下、眼周、巩膜内或视网膜下注射将缓释制剂置于眼中。可将类维生素A容纳于生物可降解聚合物中,例如聚乳酸-羟基乙酸共聚物,例如Oculex。
本发明的眼用组合物可以多种方式给药。通过一种给药方式,所述眼用组合物局部施用于眼部。对于局部施用,可将所述眼用组合物和与眼相容的赋形剂进行配制,并优选以此促进他扎罗汀向眼内渗透。对于这样的施用方式,可将所述活性药剂配制为滴眼剂形式(其中将他扎罗汀或其它RARβ和/或RARγ选择性类维生素A激动剂溶于生理溶液中)、药膏形式、脂质体溶液形式等。
本发明的滴眼剂中所使用的他扎罗汀的剂量水平可以根据缺乏响应、所需的响应速度、他扎罗汀溶液的强度等因素的需要而调整。
本发明的方法可单独或与其它治疗相结合实施。
本发明可由下列实施例进一步说明,所述实施例是实施本发明的具体方式的说明,其目的不是对所附的权利要求的范围进行限制。
将成年雄性abino Sprague-Dawley大鼠(重400±30g)用于下列实施例。适应黑暗18小时后,将动物装于特别设计的丙烯酸笼中,并暴露于高强度(12000LUX)蓝色荧光(480nm)中8小时。用数字测光表测量光强。将每只动物分开装笼。实验过程中将室温保持在73。使动物口服5天适当的类维生素A,或阳性对照即溴莫尼定,最后一次给药在暴露于蓝光之前2小时。曝光之后,将动物保存于暗室中,并进行另外5天的恢复。用闪烁ERG分析评价视网膜功能。通过组织学评价视网膜结构。
实施例1
如图1所示,没有进行类维生素A或其它神经保护剂给药的动物的光受体层在本实验中被蓝光的照射严重损害。
实施例2
评价下列类维生素A对受蓝光照射大鼠的光受体层损害的预防作用。
受测类维生素A化合物/受体选择性/剂量
他扎罗汀/(RAR激动剂)/3mg/kg/天
化合物A/(RXR激动剂)/10mg/kg/天
化合物B/(RXR拮抗剂)/50mg/kg/天
化合物C/(RAR拮抗剂)/3mg/kg/天
化合物A
3,7-二甲基-6(S),7(S)-亚甲基-7-[1,1,4,4-四甲基-1,2,3,4-四氢萘-7-基]-2E,4E-庚二烯酸
化合物B
(2E,4E,6E)-7-(3,5-二异丙基-2-丙氧基-苯基)-6-氟-3-甲基-壬-2,4,6-三烯酸
化合物C
4-2(6-(2,2-二甲基-(1H)-4-(4-乙基苯基)-1-苯并噻喃))乙炔基]苯甲酸
如图2所示,给与了公知的神经保护剂溴莫尼定的动物的光受体层厚度,远大于仅给与了赋形剂或RAR拮抗剂或RXR拮抗剂的动物的光受体层厚度。给与了RXR激动剂的动物的光受体层厚度大于给与了RAR或RXR拮抗剂的动物的光受体层厚度,而给与了RAR激动剂的动物的光受体层是所测试的类维生素A中最好的,几乎相当于溴莫尼定的效果。(RAR激动剂他扎罗汀是RARβ和RARδ选择性类维生素A。RXR激动剂也具有一定的RAR激动剂活性。)
另外,图3是ERG波-时间图,其中表明,当用ERG测量时,RAR激动剂和RXR激动剂表现出对光受体层的保护作用。
图4以柱状图示出了上述动物在受蓝光照射后的ERG波的相对应答。
实施例3
在本实施例中,用RAR拮抗剂重复上述实验,所述RAR拮抗剂在与RAR激动剂和RXR激动剂结合给药时,在α、β和δ类维生素A受体亚型上具有拮抗剂活性。
图5表明,RAR拮抗剂严重降低RAR激动剂和RXR激动剂的效果,因而表明,RXR拮抗剂的效果来自于其RAR激动剂活性,而不是其RXR拮抗剂活性。
实施例4
将下列类维生素A化合物按上述方法进行测试,结果如下所示。
维生素A化合物/受体选择性 保护活性
他扎罗汀/(RARβ,γ激动剂) ***
化合物A/(具有RAR活性的RXRα,β,γ激动剂) **
化合物C/(RARα,β,γ拮抗剂) X
化合物B/(RXRα,β,γ拮抗剂) X
化合物D/(RARα拮抗剂) X
化合物E/(RARα激动剂) **
化合物F/(RXRα,β,γ激动剂) X
*表示使光受体层避免因受蓝光照射而损伤的保护作用。*的
数目增加表明保护作用增大。
X表示没有上述保护作用。
化合物D
2-氟-4-[6’-(2”,2”-二甲基-4”-甲苯基苯并二氢吡喃基)-8’-溴]氨基甲酰苯甲酸
化合物E
4-[(4-氯-3-羟基-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-羰基)-氨基]-2,6-二氟-苯甲酸
化合物F
3-甲基-7-丙基-6(S),7(S)-亚甲基-7[1,1,4,4-四甲基-1,2,3,4-四氢-7-基]-2(E),4(E)-庚二烯酸
实施例5
在一个根据上述优选实施方案的治疗实施例中,一位蓝眼睛的64岁男性患者被诊断为持续了约10年的年龄相关黄斑变性。在两眼中发现许多玻璃疣。获取了眼底图像。在左眼中开始根据本说明书所述的优选使用方法用他扎罗汀进行治疗。
在治疗两年后,受治眼的视觉敏锐性与治疗开始前所测相比没有变化。与治疗开始前所获取的图像相比,眼底也没有变化,例如玻璃疣的数目或范围没有增加。因此,根据本发明的方法用他扎罗汀进行的治疗,防止了受治眼中黄斑变性的进一步发展。这一点很重要,因为正如以上所述,黄斑变性的正常病程导致视力随时间持续不断地丧失。
以上公开内容阐明了本发明的一个实施方案。未详细阐述的其它实施方案可在本发明的教导下实施。
虽然就治疗年龄相关黄斑变性对本发明进行了描述,但是他扎罗汀也可用于治疗视网膜色素变性、糖尿病性视网膜病,因手术例如激光或机械手术,以及光动力治疗引起的局部缺血性视网膜损伤,以及以上公开的任何疾病和/或病症。
此外,虽然本发明描述的是用他扎罗汀治疗视网膜色素变性,但是也可使用相应的酸即他扎罗汀酸,以及他扎罗汀酸的其它C1至C6低级烷基酯,例如他扎罗汀酸的甲酯和异丙酯。
以上公开内容阐明了本发明的某些优选实施方案。未详细阐述的其它实施方案可在本发明的教导下实施。
Claims (16)
1.减轻和/或预防人类眼中由可见光区辐射引起的光受体变性的方法,所述方法包括将具有RARβ和/或RARδ选择性激动剂活性的类维生素A化合物向所述哺乳动物给药。
2.权利要求1的方法,其中所述辐射是蓝光辐射。
3.权利要求1的方法,其中所述类维生素A化合物是他扎罗汀酸,或其低级烷基酯或盐。
4.权利要求3的方法,其中所述化合物是他扎罗汀酸或他扎罗汀。
5.权利要求4的方法,其中所述化合物是他扎罗汀。
6.治疗哺乳动物因暴露于可见光辐射而引起的疾病或病症的方法,所述方法包括将具有RARβ和/或RARδ选择性激动剂活性的类维生素A化合物向所述哺乳动物给药。
7.权利要求6的方法,其中所述辐射是蓝光辐射。
8.权利要求6的方法,其中所述类维生素A化合物是他扎罗汀酸,或其低级烷基酯或盐。
9.权利要求6的方法,其中所述化合物是他扎罗汀酸或他扎罗汀。
10.权利要求6的方法,其中所述化合物是他扎罗汀。
11.权利要求1的方法,其中所述哺乳动物具有一种选自以下所述的病症:非渗出性年龄相关黄斑变性(ARMD)、渗出性年龄相关黄斑变性(ARMD)、脉络膜新生血管形成、糖尿病性视网膜病、中心性浆液性脉络膜视网膜病变、囊样黄斑水肿、糖尿病性黄斑水肿、近视性视网膜变性、急性多灶性鳞状色素上皮病变、贝切特病、鸟枪弹样视网膜脉络膜病变、传染性疾病(梅毒、莱姆病、结核病、弓形体病)、中间葡萄膜炎(睫状体平坦部炎)、多灶性脉络膜炎、多发性一过性白点综合征(MEWDS)、眼结节病、后巩膜炎、匐行性脉络膜炎、视网膜下纤维化和葡萄膜炎综合征、伏-小柳-原田综合征、点状内层脉络膜病变、急性后极部多灶性鳞状色素上皮病变、急性视网膜色素上皮炎、急性黄斑视神经视网膜病、糖尿病性视网膜病、视网膜中央动脉阻塞病、视网膜中央静脉阻塞、弥散性血管内凝血病、视网膜分支静脉阻塞、高血压性眼底改变、眼缺血综合征、视网膜动脉微动脉瘤、慢性渗出性视网膜病、旁中心凹毛细血管扩张、半侧视网膜静脉阻塞、视乳头静脉炎、视网膜中央动脉阻塞、视网膜分支动脉阻塞、颈动脉病(CAD)、霜样树枝状脉管炎、镰状红细胞性视网膜病和其它血红蛋白病、血管样条纹、家族性渗出性玻璃体视网膜病变、伊尔斯病、交感性眼炎、葡萄膜炎性视网膜病、视网膜脱离、外伤、视网膜激光治疗、光动力学治疗、光凝固、手术中血流灌注不足、辐射性视网膜病、骨髓移植性视网膜病、增殖性玻璃体视网膜病以及视网膜前膜、眼组织胞浆菌病、眼弓蛔虫病、拟眼组织胞浆菌病综合征(PHOS)、眼内炎、弓形体病、与HIV感染相关的视网膜病、与HIV感染相关的脉络膜病、与HIV感染相关的葡萄膜病、病毒性视网膜炎、急性视网膜坏死、进行性视网膜外层坏死、真菌性视网膜病、眼梅毒、眼结核、弥漫性单侧亚急性视神经视网膜炎、蝇蛆病、视网膜色素变性、伴有视网膜营养不良的全身性疾病、先天性静止性夜盲、锥体营养不良、斯塔加特病和眼底黄色斑点症、贝斯特病、视网膜色素上皮的图形营养不良、X伴性视网膜劈裂症、索斯比眼底营养不良、良性同心性黄斑病、Bietti结晶样营养障碍、弹性假黄瘤、视网膜脱离、黄斑洞、巨大视网膜撕裂、与肿瘤相关的视网膜病、视网膜色素上皮(RPE)的先天性肥大、后部葡萄膜黑色素瘤、脉络膜血管瘤、脉络膜骨瘤、脉络膜转移、视网膜及视网膜色素上皮的混合性错构瘤、视网膜母细胞瘤、眼底的血管增生瘤、视网膜星形细胞瘤和眼内淋巴瘤。
12.权利要求11的方法,其中所述病症是年龄相关黄斑变性。
13.权利要求11的方法,其中所述病症是视网膜色素变性。
14.权利要求11的方法,其中所述病症是糖尿病性视网膜病。
15.权利要求11的方法,其中所述病症是外伤。
16.权利要求11的方法,其中所述病症是激光引起的损伤。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US52650503P | 2003-12-02 | 2003-12-02 | |
US60/526,505 | 2003-12-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1889954A true CN1889954A (zh) | 2007-01-03 |
Family
ID=34676622
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2004800357329A Pending CN1889954A (zh) | 2003-12-02 | 2004-11-30 | 用类维生素a预防和/或减轻光受体变性的方法 |
Country Status (9)
Country | Link |
---|---|
US (1) | US20070112032A1 (zh) |
EP (1) | EP1689396A1 (zh) |
JP (1) | JP2007513161A (zh) |
KR (1) | KR20070051768A (zh) |
CN (1) | CN1889954A (zh) |
AU (1) | AU2004296748B2 (zh) |
BR (1) | BRPI0417057A (zh) |
CA (1) | CA2549161A1 (zh) |
WO (1) | WO2005056010A1 (zh) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005087210A2 (en) * | 2004-03-17 | 2005-09-22 | Lars Michael Larsen | Prevention of retinopathy by inhibition of the visual cycle |
US20090281184A1 (en) * | 2005-09-27 | 2009-11-12 | Sapporo Medical University | Pharmaceutical for prevention and treatment of ophthalmic disease induced by in-crease in vasopermeability |
GB2433180B (en) * | 2005-12-09 | 2008-01-30 | Oracle Int Corp | Communications method |
US20120238623A1 (en) * | 2011-03-14 | 2012-09-20 | Chandraratna Roshantha A | Inflammation and Autoimmune Disorder Treatment using RARa Selective Agonists |
EP3650045A4 (en) * | 2017-07-04 | 2021-07-07 | Daiichi Sankyo Company, Limited | MEDICINAL PRODUCTS FOR RETINA DEGENERATIVE DISEASE ASSOCIATED WITH PHOTORECEPTOR DEGENERATION |
WO2019099949A1 (en) * | 2017-11-17 | 2019-05-23 | The Regents Of The University Of California | Manipulation of the retinoic acid signaling pathway |
TW202039421A (zh) * | 2018-12-25 | 2020-11-01 | 日商第一三共股份有限公司 | 具有稠環結構之對酞酸衍生物 |
WO2023150560A1 (en) * | 2022-02-01 | 2023-08-10 | Baylor College Of Medicine | Rxr agonists in eye disorders |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5089509A (en) * | 1988-09-15 | 1992-02-18 | Allergan, Inc. | Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity |
US5264578A (en) * | 1987-03-20 | 1993-11-23 | Allergan, Inc. | Disubstituted acetylenes bearing heterobicyclic groups and heteroaromatic or phenyl groups having retinoid like activity |
US5602130A (en) * | 1987-03-20 | 1997-02-11 | Allergan | Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity |
US5437291A (en) * | 1993-08-26 | 1995-08-01 | Univ Johns Hopkins | Method for treating gastrointestinal muscle disorders and other smooth muscle dysfunction |
US5824685A (en) * | 1995-02-01 | 1998-10-20 | The Johns Hopkins University School Of Medicine | Method of preventing proliferation of retinal pigment epithelium by retinoic acid receptor agonists |
US5919970A (en) * | 1997-04-24 | 1999-07-06 | Allergan Sales, Inc. | Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity |
CA2300154C (en) * | 1997-08-11 | 2008-07-08 | Allergan Sales, Inc. | Sterile bioerodible implant device with improved biocompatability and method |
US20050009910A1 (en) * | 2003-07-10 | 2005-01-13 | Allergan, Inc. | Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug |
-
2004
- 2004-11-30 CN CNA2004800357329A patent/CN1889954A/zh active Pending
- 2004-11-30 JP JP2006542667A patent/JP2007513161A/ja active Pending
- 2004-11-30 AU AU2004296748A patent/AU2004296748B2/en not_active Ceased
- 2004-11-30 WO PCT/US2004/039987 patent/WO2005056010A1/en not_active Application Discontinuation
- 2004-11-30 CA CA002549161A patent/CA2549161A1/en not_active Abandoned
- 2004-11-30 EP EP04812497A patent/EP1689396A1/en not_active Withdrawn
- 2004-11-30 BR BRPI0417057-1A patent/BRPI0417057A/pt not_active IP Right Cessation
- 2004-11-30 KR KR1020067010776A patent/KR20070051768A/ko active Search and Examination
- 2004-11-30 US US10/580,879 patent/US20070112032A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
EP1689396A1 (en) | 2006-08-16 |
AU2004296748B2 (en) | 2010-12-23 |
JP2007513161A (ja) | 2007-05-24 |
BRPI0417057A (pt) | 2007-03-13 |
KR20070051768A (ko) | 2007-05-18 |
CA2549161A1 (en) | 2005-06-23 |
WO2005056010A1 (en) | 2005-06-23 |
US20070112032A1 (en) | 2007-05-17 |
AU2004296748A1 (en) | 2005-06-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR102312186B1 (ko) | 안 질환 및 장애 치료용 화합물 | |
CA2703000C (en) | Water-immiscible materials as vehicles for drug delivery | |
JP6487848B2 (ja) | ヒト被験体における眼部障害の処置のための方法およびデバイス | |
RU2353393C2 (ru) | Доставка активного лекарства к дальней области глаза посредством субконъюнктивальной или периокулярной доставки пролекарства | |
JP2010536797A5 (zh) | ||
CN1882339A (zh) | 黄斑变性和其他眼科疾病的缓解 | |
CA2702761A1 (en) | Non-aqueous water-miscible materials as vehicles for drug delivery | |
KR101933610B1 (ko) | 5-아미노레불린산 염산염용 경피 치료 시스템 | |
CN1889954A (zh) | 用类维生素a预防和/或减轻光受体变性的方法 | |
JPH04221322A (ja) | 眼病用製剤 | |
US20130046003A1 (en) | Pharmaceutical compositions comprising 4-bromo-n-(imidazolidin-2-ylidene)-1h-benzimidazol-5-amine for treating retinal diseases | |
MXPA06006024A (es) | Prevencion y/o reduccion, con retinoides de la degeneracion de fotorreceptores | |
JP2013501794A (ja) | 目の疾患を治療するためのイソチオゾール | |
Schallhorn | Noninfectious Uveitis: Emerging Therapies | |
TW202345804A (zh) | 治療濕性老年黃斑部病變(Wet Age-related Macular Degeneration)之方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |