CN113768929B - Fdi化合物在眼科疾病中的用途 - Google Patents
Fdi化合物在眼科疾病中的用途 Download PDFInfo
- Publication number
- CN113768929B CN113768929B CN202110346039.9A CN202110346039A CN113768929B CN 113768929 B CN113768929 B CN 113768929B CN 202110346039 A CN202110346039 A CN 202110346039A CN 113768929 B CN113768929 B CN 113768929B
- Authority
- CN
- China
- Prior art keywords
- fdi
- surgery
- ocular
- group
- eye
- 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.)
- Active
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 30
- 201000010099 disease Diseases 0.000 title claims description 20
- 239000003112 inhibitor Substances 0.000 claims abstract description 14
- ZATJMMZPGVDUOM-UHFFFAOYSA-N 3-amino-n-(4-fluorophenyl)-6-thiophen-2-yl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide Chemical compound C=1C(C(F)(F)F)=C2C(N)=C(C(=O)NC=3C=CC(F)=CC=3)SC2=NC=1C1=CC=CS1 ZATJMMZPGVDUOM-UHFFFAOYSA-N 0.000 claims description 89
- 238000001356 surgical procedure Methods 0.000 claims description 51
- 239000003814 drug Substances 0.000 claims description 42
- 238000011282 treatment Methods 0.000 claims description 27
- 206010016654 Fibrosis Diseases 0.000 claims description 21
- 230000004761 fibrosis Effects 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 15
- 206010061218 Inflammation Diseases 0.000 claims description 12
- 230000004054 inflammatory process Effects 0.000 claims description 12
- 208000010412 Glaucoma Diseases 0.000 claims description 11
- 208000002177 Cataract Diseases 0.000 claims description 6
- 208000021957 Ocular injury Diseases 0.000 claims description 6
- 239000007943 implant Substances 0.000 claims description 5
- 230000002207 retinal effect Effects 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 4
- 206010038848 Retinal detachment Diseases 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 150000004677 hydrates Chemical class 0.000 claims description 3
- 230000004264 retinal detachment Effects 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 210000004561 lacrimal apparatus Anatomy 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000008439 repair process Effects 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 claims description 2
- 238000002399 angioplasty Methods 0.000 claims 1
- 230000037431 insertion Effects 0.000 claims 1
- 238000003780 insertion Methods 0.000 claims 1
- 230000002787 reinforcement Effects 0.000 claims 1
- 208000030533 eye disease Diseases 0.000 abstract description 8
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 50
- 210000001508 eye Anatomy 0.000 description 34
- 108010008599 Forkhead Box Protein M1 Proteins 0.000 description 32
- 235000002639 sodium chloride Nutrition 0.000 description 32
- 230000014509 gene expression Effects 0.000 description 30
- 241000283973 Oryctolagus cuniculus Species 0.000 description 28
- 108090000623 proteins and genes Proteins 0.000 description 27
- 102100023374 Forkhead box protein M1 Human genes 0.000 description 26
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 26
- 229940079593 drug Drugs 0.000 description 25
- 210000002950 fibroblast Anatomy 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 230000000694 effects Effects 0.000 description 22
- 239000003513 alkali Substances 0.000 description 19
- 208000002352 blister Diseases 0.000 description 18
- 239000011780 sodium chloride Substances 0.000 description 18
- 210000001519 tissue Anatomy 0.000 description 18
- 210000004087 cornea Anatomy 0.000 description 17
- 238000002474 experimental method Methods 0.000 description 17
- 238000002347 injection Methods 0.000 description 15
- 239000007924 injection Substances 0.000 description 15
- 208000027418 Wounds and injury Diseases 0.000 description 14
- 210000004204 blood vessel Anatomy 0.000 description 14
- 208000014674 injury Diseases 0.000 description 14
- 238000003753 real-time PCR Methods 0.000 description 13
- 238000010186 staining Methods 0.000 description 13
- 230000004410 intraocular pressure Effects 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- 230000006378 damage Effects 0.000 description 10
- 238000001514 detection method Methods 0.000 description 10
- 239000000499 gel Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 210000000795 conjunctiva Anatomy 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- 102000004315 Forkhead Transcription Factors Human genes 0.000 description 8
- 108090000852 Forkhead Transcription Factors Proteins 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 206010055665 Corneal neovascularisation Diseases 0.000 description 7
- 102000007237 Forkhead Box Protein M1 Human genes 0.000 description 7
- 206010029113 Neovascularisation Diseases 0.000 description 7
- 201000000159 corneal neovascularization Diseases 0.000 description 7
- 239000003889 eye drop Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 102000008186 Collagen Human genes 0.000 description 6
- 108010035532 Collagen Proteins 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 210000005252 bulbus oculi Anatomy 0.000 description 6
- 238000010609 cell counting kit-8 assay Methods 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229920001436 collagen Polymers 0.000 description 6
- 229940012356 eye drops Drugs 0.000 description 6
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- -1 isomers Chemical class 0.000 description 6
- 210000000651 myofibroblast Anatomy 0.000 description 6
- 238000001262 western blot Methods 0.000 description 6
- 206010012689 Diabetic retinopathy Diseases 0.000 description 5
- 108010087230 Sincalide Proteins 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 206010052428 Wound Diseases 0.000 description 5
- 230000004888 barrier function Effects 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- 230000002980 postoperative effect Effects 0.000 description 5
- 210000003786 sclera Anatomy 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 5
- 150000003384 small molecules Chemical class 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 230000008733 trauma Effects 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 208000022873 Ocular disease Diseases 0.000 description 4
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 4
- 230000006838 adverse reaction Effects 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000033115 angiogenesis Effects 0.000 description 4
- 230000001447 compensatory effect Effects 0.000 description 4
- 210000002889 endothelial cell Anatomy 0.000 description 4
- 230000003176 fibrotic effect Effects 0.000 description 4
- 229940020947 fluorescein sodium Drugs 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 238000003119 immunoblot Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 230000005012 migration Effects 0.000 description 4
- 238000013508 migration Methods 0.000 description 4
- 229960001699 ofloxacin Drugs 0.000 description 4
- 239000003002 pH adjusting agent Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 230000035897 transcription Effects 0.000 description 4
- 206010067484 Adverse reaction Diseases 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 102100033601 Collagen alpha-1(I) chain Human genes 0.000 description 3
- 208000028006 Corneal injury Diseases 0.000 description 3
- 206010011033 Corneal oedema Diseases 0.000 description 3
- 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 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 3
- 238000011529 RT qPCR Methods 0.000 description 3
- 206010038934 Retinopathy proliferative Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 206010064930 age-related macular degeneration Diseases 0.000 description 3
- 108010029483 alpha 1 Chain Collagen Type I Proteins 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 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 3
- 239000011230 binding agent Substances 0.000 description 3
- 238000010805 cDNA synthesis kit Methods 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 3
- 229960002327 chloral hydrate Drugs 0.000 description 3
- 230000001886 ciliary effect Effects 0.000 description 3
- 239000000512 collagen gel Substances 0.000 description 3
- 201000004778 corneal edema Diseases 0.000 description 3
- NJDNXYGOVLYJHP-UHFFFAOYSA-L disodium;2-(3-oxido-6-oxoxanthen-9-yl)benzoate Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=CC(=O)C=C2OC2=CC([O-])=CC=C21 NJDNXYGOVLYJHP-UHFFFAOYSA-L 0.000 description 3
- 230000003828 downregulation Effects 0.000 description 3
- 210000000981 epithelium Anatomy 0.000 description 3
- 230000003325 follicular Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 206010023332 keratitis Diseases 0.000 description 3
- 208000002780 macular degeneration Diseases 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 229940023490 ophthalmic product Drugs 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 229960001412 pentobarbital Drugs 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 210000001525 retina Anatomy 0.000 description 3
- 210000003583 retinal pigment epithelium Anatomy 0.000 description 3
- 230000037390 scarring Effects 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000002103 transcriptional effect Effects 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 108010022452 Collagen Type I Proteins 0.000 description 2
- 102000012422 Collagen Type I Human genes 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 230000004568 DNA-binding Effects 0.000 description 2
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 2
- 206010013774 Dry eye Diseases 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- 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 2
- 208000020564 Eye injury Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 206010019668 Hepatic fibrosis Diseases 0.000 description 2
- 101000907578 Homo sapiens Forkhead box protein M1 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 239000004677 Nylon Substances 0.000 description 2
- 208000007950 Ocular Hypotension Diseases 0.000 description 2
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 2
- 208000003435 Optic Neuritis Diseases 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- 208000037273 Pathologic Processes Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 208000019155 Radiation injury Diseases 0.000 description 2
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 2
- 206010038933 Retinopathy of prematurity Diseases 0.000 description 2
- 206010039705 Scleritis Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010066902 Surgical failure Diseases 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003732 agents acting on the eye Substances 0.000 description 2
- 210000003484 anatomy Anatomy 0.000 description 2
- 210000002159 anterior chamber Anatomy 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 210000002469 basement membrane Anatomy 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 239000000872 buffer Substances 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
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 229960002143 fluorescein Drugs 0.000 description 2
- 238000012757 fluorescence staining Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 201000003142 neovascular glaucoma Diseases 0.000 description 2
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- 201000002740 oral squamous cell carcinoma Diseases 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 230000004792 oxidative damage Effects 0.000 description 2
- 230000009054 pathological process Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 201000006366 primary open angle glaucoma Diseases 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000006785 proliferative vitreoretinopathy Effects 0.000 description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 208000004644 retinal vein occlusion Diseases 0.000 description 2
- 238000010839 reverse transcription Methods 0.000 description 2
- 238000003757 reverse transcription PCR Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000015424 sodium Nutrition 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 230000003827 upregulation Effects 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 239000012224 working solution Substances 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- QAPSNMNOIOSXSQ-YNEHKIRRSA-N 1-[(2r,4s,5r)-4-[tert-butyl(dimethyl)silyl]oxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C1 QAPSNMNOIOSXSQ-YNEHKIRRSA-N 0.000 description 1
- LSIXBBPOJBJQHN-UHFFFAOYSA-N 2,3-Dimethylbicyclo[2.2.1]hept-2-ene Chemical compound C1CC2C(C)=C(C)C1C2 LSIXBBPOJBJQHN-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 208000022309 Alcoholic Liver disease Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 101100328883 Arabidopsis thaliana COL1 gene Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000029402 Bulbospinal muscular atrophy Diseases 0.000 description 1
- 208000008516 Capsule Opacification Diseases 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- 208000005590 Choroidal Neovascularization Diseases 0.000 description 1
- 206010060823 Choroidal neovascularisation Diseases 0.000 description 1
- 208000002691 Choroiditis Diseases 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 208000031973 Conjunctivitis infective Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 206010011844 Dacryocystitis Diseases 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
- 206010012688 Diabetic retinal oedema Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010015084 Episcleritis Diseases 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 206010015946 Eye irritation Diseases 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- 208000027761 Hepatic autoimmune disease Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-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
- 208000027747 Kennedy disease Diseases 0.000 description 1
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 206010065062 Meibomian gland dysfunction Diseases 0.000 description 1
- 102100025751 Mothers against decapentaplegic homolog 2 Human genes 0.000 description 1
- 101710143123 Mothers against decapentaplegic homolog 2 Proteins 0.000 description 1
- 102100025748 Mothers against decapentaplegic homolog 3 Human genes 0.000 description 1
- 101710143111 Mothers against decapentaplegic homolog 3 Proteins 0.000 description 1
- 206010048654 Muscle fibrosis Diseases 0.000 description 1
- 208000006550 Mydriasis Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010072139 Ocular rosacea Diseases 0.000 description 1
- 206010061323 Optic neuropathy Diseases 0.000 description 1
- 208000012868 Overgrowth Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 1
- 206010063381 Polypoidal choroidal vasculopathy Diseases 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 208000003971 Posterior uveitis Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241001085205 Prenanthella exigua Species 0.000 description 1
- 208000034461 Progressive cone dystrophy Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 208000029091 Refraction disease Diseases 0.000 description 1
- 201000001949 Retinal Vasculitis Diseases 0.000 description 1
- 201000007527 Retinal artery occlusion Diseases 0.000 description 1
- 201000007737 Retinal degeneration Diseases 0.000 description 1
- 206010038910 Retinitis Diseases 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 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 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 201000001028 acute contagious conjunctivitis Diseases 0.000 description 1
- 201000011101 acute retrobulbar neuritis Diseases 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 230000004430 ametropia Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 102000001307 androgen receptors Human genes 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003510 anti-fibrotic effect Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 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
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 208000010217 blepharitis Diseases 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000009530 blood pressure measurement Methods 0.000 description 1
- 230000004378 blood-retinal barrier Effects 0.000 description 1
- 210000004155 blood-retinal barrier Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 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
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000008004 cell lysis buffer Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 201000005667 central retinal vein occlusion Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 210000003161 choroid Anatomy 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940096422 collagen type i Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 201000008615 cone dystrophy Diseases 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 238000007596 consolidation process Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 210000003683 corneal stroma Anatomy 0.000 description 1
- 230000004453 corneal transparency Effects 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000002638 denervation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 201000011190 diabetic macular edema Diseases 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000001819 effect on gene Effects 0.000 description 1
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010014801 endophthalmitis Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007705 epithelial mesenchymal transition Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 208000016245 inborn errors of metabolism Diseases 0.000 description 1
- 201000001371 inclusion conjunctivitis Diseases 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000000138 intercalating agent Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000002647 laser therapy Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 238000013187 longer-term treatment Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000001617 migratory effect Effects 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000009701 normal cell proliferation 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
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 208000020911 optic nerve disease Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 210000003668 pericyte Anatomy 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000011422 pharmacological therapy Methods 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000649 photocoagulation Effects 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 238000005375 photometry Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 208000014733 refractive error Diseases 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 208000022670 retrobulbar neuritis Diseases 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 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
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 206010044325 trachoma Diseases 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 230000003845 vascular endothelial function Effects 0.000 description 1
- 230000006426 vascular sprouting Effects 0.000 description 1
- 201000002282 venous insufficiency Diseases 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 208000005494 xerophthalmia Diseases 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Images
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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Ophthalmology & Optometry (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及药物活性成分叉头结构域抑制剂FDI的新用途,用于眼部疾病。
Description
技术领域
本申请涉及一种叉头结构域抑制剂FDI在制备治疗眼部损伤性疾病的药物中的应用,尤其涉及其在眼部纤维化及眼部炎症性和新生血管性疾病中的应用。
背景技术
视觉器官是机体的重要感官之一,也是人类最敏感的器官。眼部疾病覆盖的人群较为广泛,从易患干眼症、屈光不正的青年人,到易患青光眼及白内障的老年人,且随着人类用眼方式的改变、用眼过度的普遍以及老龄化的进一步加剧,眼部疾病正严重困扰着人们的生活。在诸多眼科疾病的治疗方法中,药物治疗无疑发挥着重要作用。
由于眼睛具有精密的结构,受到解剖、生理屏障作用以及体循环的保护作用,使得眼科用药表现出独特的药代动力学特点。以局部或全身给药必须克服这种屏障作用才能到达视网膜和玻璃体。由于眼部存在血眼屏障,包括血—房水屏障和血—视网膜屏障等特殊的组织解剖结构,眼科用药除了严格掌握适应证外,还需要考虑药物在眼局部的独特的药动学和药效学特征。药物可从眼表结构中的血管如角膜缘血管和结膜血管吸收通过血循环进入眼球内,或经结膜、筋膜和巩膜渗透至眼球内。由眼球表面进入眼球内组织的主要途径是经角膜转运,首先分布到泪膜,由泪膜转运入角膜,再由角膜转运至眼球内。其中,角膜上皮细胞层和内皮细胞层的细胞之间均有紧密连接,药物不能经细胞外间隙进入,只能由细胞膜转运。因而可用于其他组织或器官的药物通常无法直接作用于眼发挥相应的治疗作用。此外,泪液、角膜、结膜、前房、玻璃体、巩膜和眼后其他区域与药物相互作用也各有不同。同时,影响药物透过角膜的因素也有很多,如药物浓度、粘滞性、脂溶性、溶解度、表面活性等,pH值和渗透压的不适宜也会造成眼部刺激或引起反射泪液分泌。药物在眼部代谢后经房水或直接如静脉回流***,其独特的代谢途径对药物能否安全作用于眼部也有较大影响。且由于角膜上皮细胞和内皮细胞均有脂性屏障,而泪液和角膜基质为水溶性,因此对眼部用药的要求十分特殊。需找新的安全、有效的眼部用药十分不易。
原发性开角型青光眼(Primary open angle glaucoma,POAG)是一种累及终生的、以眼压升高为主要危险因素的视神经病变,需要终生治疗。目前青光眼治疗仍以降眼压为主。而药物治疗、激光治疗、青光眼滤过手术(如小梁切除术)等降低眼压的治疗手段已被证明是治疗青光眼的有效干预手段。其中,小梁切除术是治疗中重度青光眼最常见的手术,其手术原理是从眼前房到结膜下之间产生一个新的房水流出通道,从而降低眼压。然而,这种手术的长期效果并不总是令人满意,因为滤过部位结膜下组织纤维化和瘢痕形成可能会导致人工流出通道阻塞,最终导致手术失败。
结膜下纤维化是一个复杂的、多阶段的病理过程。在手术后的最初阶段,结膜下成纤维细胞分化成肌成纤维细胞。然后,该分化的细胞增殖迁移,并合成细胞外基质,如Ⅰ型胶原蛋白和纤连蛋白,这一系列改变可能会导致手术部位的疤痕组织产生扭曲和非功能性聚合,最终阻塞人工流出通道,从而导致手术失败。目前的抗增殖药物,如5-氟尿嘧啶和丝裂霉素C已广泛应用于临床预防滤过术后的结膜下纤维化。但这些药物的非特异性作用可能导致角膜和眼内组织毒性、眼压过低、渗漏或与滤过泡相关的感染等副作用。
此外,眼部纤维化疾病还包括角膜的瘢痕化、后发性白内障及增生性玻璃体视网膜病变等。与结膜下纤维化病理过程相似,其特征同样是眼部细胞通过上皮间质转化为肌成纤维细胞。由于病因复杂,目前临床上所使用的常规药物、手术或激光等治疗方法效果往往不令人满意。因此迫切需要更有效、更安全的化合物来特异性抑制术后结膜下纤维化和其他眼部纤维化疾病。眼部新生血管(Ocular neovascularization, NV)是许多眼部疾病致盲的主要原因,包括糖尿病视网膜病变(DR)、年龄相关性黄斑变性(AMD)、早产儿视网膜病变(ROP)、视网膜中央和分支静脉阻塞(CRVO和BRVO)、感染性角膜炎、外伤和各种炎症性眼病等。在眼部不同组织中,视网膜、脉络膜和角膜是眼部NV最常见的部位,虹膜NV也见于严重的缺血性眼病和新生血管性青光眼。新生血管由于周细胞覆盖不完全以及血管内皮功能改变等而致血管通透性增加,最终造成血管渗漏增加。同时,过度生长的新生血管长入无血管区的视网膜外层造成其结构紊乱,共同造成机体不同程度的视觉损害。
新生血管性眼病的发生机制尚未完全阐明。越来越多的研究表明,在各种病理条件下,如缺氧、缺血、炎症、感染、创伤等,血管生成刺激因子和血管生成抑制因子之间的平衡被打破,正常血管基底膜首先被降解,进而血管内皮细胞游走、穿出基底膜,并向损伤部位迁移,同时血管内皮细胞的增殖能力增强,加速血管出芽,导致异常的血管腔产生,是眼部新生血管发生的共同机制。目前临床治疗新生血管性眼病的方式包括玻璃体手术、激光光凝、光动力疗法以及玻璃体腔注射抗VEGF药物等,尤其是抗VEGF治疗更是显著改变治疗的结果。然而,这些治疗方式都存在各自的弊端,并且治疗效果有限。据报道,长期使用抗VEGF治疗存在视网膜萎缩、视网膜色素上皮(RPE)撕裂、***性不良反应等。为此,深入研究新生血管性眼病的分子机制、开发新的抗新生血管的药物具有极其重要的临床意义。
叉头盒M1转录因子(forkhead box M1,FOXM1)是叉头/翼螺旋(forkhead/winged-helix)转录因子家族中的一员,主要负责正常的细胞增殖、生存和自我更新,以及肿瘤的发生、进展和耐药性。目前,许多研究结果已证实,FOXM1的异常过表达是许多人类癌症的肿瘤发生和发展的关键特征。WO2018026776A 记载了FOXM1抑制剂用于治疗个体的雄激素受体活性相关的疾病或脊髓延髓性肌萎缩等,具有神经保护作用。Increased FOXM1Expression by Cisplatin Inhibits Paclitaxel-Related Apoptosis in Cisplatin-Resistant Human Oral Squamous Cell Carcinoma (OSCC) Cell Lines(Hyeong SimChoi等,2020年)通过实时qPCR和Western印迹测定检测了在口腔鳞状细胞癌(OSC)细胞系上forkhead盒蛋白M1 (FOXM1) mRNA和蛋白表达,顺铂诱导的FOXM1的过表达仅在顺铂抗性细胞系中显示相同的趋势,表明它与紫杉醇相关的细胞凋亡的抑制有关。同时,FOXM1在肺纤维化表现出一定程度地升高,如Loss of FOXM1 in macrophages promotes pulmonaryfibrosis by activating p38 MAPK signaling pathway. PLoS Genet.(Goda C 等,2020年)记载的。
叉头结构域抑制剂FDI(Forkhead Domain Inhibitory)属于FOXM1抑制剂,是一种小分子抑制剂,相关抑制剂涉及化合物的披露主要有FDI-2、FDI-4、FDI-6、FDI-7、FDI-10或FDI-11及其盐。如叉头结构域抑制剂FDI-6能选择性结合到FOXM1蛋白的DNA结合域上,使FOXM1从染色质中移位,从而广泛抑制FOXM1所调控基因的转录。Suppression of theFOXM1 transcriptional program via novel small molecule inhibition(Michael V.Gormally等,2014)记载了从高处理量出发应用于54,211小分子文库的筛选鉴定了阻断DNA结合的FOXM1的新小分子抑制剂,其中FDI6特征在于可深度结合,且能直接结合FOXM1蛋白,从MCF7乳腺癌细胞的基因组靶标置换FOXM1,并诱导伴随的转录下调。MCF7的全局转录谱,通过RNAeq的细胞显示FDI6特异性下调FOXM1激活的基因。这种小分子介导的效应对FOXM1控制的基因是选择性的,对由同源Forkhead家族因子调节的基因没有影响。CN109432091A(2018年)记载了FDI-6在制备治疗结肠癌的药物中的用途。CN108210494A(2018年)记载了FDI-6作为FOXM1抑制剂发挥相应的抗肝纤维化作用,其所述的造成肝纤维化的疾病主要包括但不限于:慢性病毒性肝炎、酒精性肝病、非酒精性脂肪性肝病、毒素和药物、自身免疫性肝病、肝淤血、遗传代谢性疾病等。Reciprocal Regulation Between Forkhead Box M1/NF-κB and Methionine Adenosyltransferase 1A Drives Liver Cancer(Yuan Li等,2020年)发现在肝细胞癌和胆管癌中,都诱导了FOXM1表达,检测了FDI-6在体外和在肝脏内对异种移植物和同系模型中的癌症的作用,发现FDI-6抑制体外和体内肝癌细胞生长,且在不表达MAT1A的肝癌细胞中具有最小的影响。Dual inhibition of FOXM1 and itscompensatory signaling pathway decreased the survival of ovarian cancer cells(Dae Woo Lee等,2021年)通过分析在卵巢癌细胞中由FDI6诱导的补偿信号传导途径,评价FOXM1和补偿信号传导途径同时抑制卵巢癌细胞存活的有效性,确定了FDI-6和补偿性信号传导途径对癌细胞活力的影响。
可见,目前对FDI的研究主要集中在抗肿瘤活性的方面;尚无其在眼部疾病的应用如眼部损伤性疾病;尤其未见在眼部纤维化或炎性疾病以及新生血管性疾病领域的应用报道。
发明内容
为了克服现有技术中眼部损伤性疾病的治疗效果不满意的现状,寻求新的安全的有效的眼部治疗药物,提出本发明。本发明有效扩展了药物活性成分叉头结构域抑制剂FDI的应用领域,提供了FDI的新用途。
一方面,本发明提供一种式(I)FDI化合物及其盐、异构体、水合物在制备治疗和或预防眼部损伤性疾病的药物中的用途,所述式(I)化合物具有如下结构:
式(I)
其中R1、R2、R3、R4分别独立的选自H、卤素或C1-2烷基;
进一步的,其中R1、R2、R3、R4分别独立的选自卤素;进一步的,分别独立的选自F、Cl、Br、I;
进一步的,其中R1、R2、R3、R4为F。
进一步的,提供一种式(II)FDI化合物及其盐、异构体、水合物在制备治疗和或预防眼部损伤性疾病的药物中的用途,所述式(II)化合物具有如下结构:
本发明提供一种式I 结构的FDI或其盐、异构体、水合物在制备治疗和或预防眼部损伤性疾病的药物中的用途。
第二方面,本发明提供化合物FDI-2、FDI-4、FDI-7、FDI-10或FDI-11及其异构体或其盐在制备治疗和或预防眼部损伤性疾病的药物中的用途,所述式化合物具有如下结构:
进一步的,所述眼部损伤性疾病选自炎性损伤、氧化损伤、物理损伤(如外伤、手术、辐射损伤)或免疫损伤;进一步的,选自眼部纤维化、眼部炎症或眼部新生血管性疾病;进一步的,选自眼部外科手术相关的眼部纤维化、眼部炎症或眼部新生血管性疾病。
本发明药物可以抑制角膜损伤后的炎症反应和新生血管形成,以及显著减轻人工流出通道的纤维化瘢痕形成。在整个实验监测过程中,本发明药物本身也并未引起任何的不良反映。本发明药物在眼科领域的创新性应用,既能提高手术的成功率、减少瘢痕形成又具有抗眼科炎症性和新生血管性疾病的作用,且无明显不良反应。因此,其将成为眼科相关疾病治疗中一个非常有潜力的药物。
附图说明
图1:Western blot检测不同浓度FDI-6(2.5、5、10、20、30、40μM)处理原代兔结膜囊成纤维细胞后FOXM1蛋白的表达
图2:不同浓度FDI-6(2.5、5、10、20、40μM)下的细胞增殖能力,以及相应的细胞数量
图3:FDI-6处理原代兔结膜囊成纤维细胞后第0、12和24小时划痕愈合情况及其定量分析
图4:FDI-6处理原代兔结膜囊成纤维细胞后第0、12和24小时凝胶收缩情况及其定量分析
图5:FDI-6处理原代兔结膜囊成纤维细胞后α-SMA、COL1A1和FN 的mRNA表达分析
图6:FDI-6处理原代兔结膜囊成纤维细胞后FN、COL1A1、α-SMA、p-Smad2/3和总Smad3的蛋白表达水平
图7:各组不同时间点的眼压(IOP)变化情况(POD表示手术后天数)
图8:术后第7和14天各组滤过泡代表性形态学图像及其滤过泡评分
图9:术后第14天角膜荧光素钠染色及眼前段的代表性图像
图10:术后第14天滤泡区结膜上皮、浅层间质和深层间质的激光共聚焦生物显微镜图像
图11:术后第14天各组术区(滤过泡)组织的苏木素-伊红染色、Masson三色染色和α-SMA免疫组化
图12:角膜荧光素钠染色及眼前段的代表性图像
图13:FDI-6对角膜FOXM1、CD31、VEGF、IL-6、α-SMA和MMP-9基因转录水平的影响
实施方式
本发明所述眼部损伤性疾病选自炎性损伤、氧化损伤、物理损伤(如外伤、手术、辐射损伤)、免疫损伤等;进一步的,选自各种原发或继发性眼部疾病带来的病理损伤或眼部手术带来的损伤;包括眼部纤维化、眼部炎症或眼部新生血管性疾病等;选自眼部外科手术相关的眼部纤维化、眼部炎症或眼部新生血管性疾病;进一步的,选自青光眼、视网膜血管炎、葡萄膜炎(如后葡萄膜炎)、干燥性角膜结膜炎、结膜炎、青光眼继发视网膜炎、表层巩膜炎、巩膜炎、角膜炎、泪囊炎、泪腺炎、视神经炎、球后视神经炎、糖尿病视网膜病变(DR)、眼部红斑痤疮、年龄相关黄斑变性、新生血管性青光眼、角膜新生血管形成、视网膜脉络膜新生血管形成、息肉状脉络膜血管病变、糖尿病性视网膜病变、糖尿病性黄斑水肿、缺血性增殖性视网膜病变、色素性视网膜炎、视锥细胞营养不良、增生性玻璃体视网膜病变、视网膜动脉阻塞、视网膜静脉阻塞、视网膜脱离、视网膜色素上皮脱离;眼部外科手术后的眼部炎症、由物理性眼外伤引起的眼部炎症、白内障、眼部过敏、干眼症、睑缘炎、睑板腺功能障碍、视网膜特异性疾患,诸如视网膜色素变性和年龄相关性损伤等,以及微生物感染引起的眼部疾病,如沙眼、红眼病、眼部疱疹等;以及伴有这些疾病的眼部疾病。
进一步的,特别是在进行眼科外科手术的情况下,预防措施可以包括手术后纤维化的预防和治疗,以及术后炎症和新生血管性疾病的最小化。进一步的,所述眼科外科手术选自激光眼科外科手术、屈光外科手术、角膜移植术、角膜切开术、角膜磨镶术、白内障外科手术、青光眼外科手术、青光眼滤过手术、小梁切除术、管道成形术、卡姆拉嵌体(KarmraInlays)、巩膜加固外科手术、角膜外科手术、玻璃体视网膜外科手术、视网膜脱离修复、视网膜固定外科手术、充气性视网膜固定术、眼肌外科手术、涉及泪器的外科手术,将植入物***眼内以及眼睛摘除、眼内容物摘除或其他眼科外科手术如巩膜切开术、表层角膜镜片术、睫状体切开术、睫状体切除术、睫状神经切断术、虹膜切除术等。
本发明所述药物可通过眼部局部给药、注射给药或口服给药或经皮给药等途径施用;进一步的,局部给药包括滴眼剂,或其它适于眼睛直接给药的局部制剂,如洗剂、凝胶剂、软膏剂等;注射给药包括结膜下注射、巩膜内注射、眼周注射、玻璃体内注射、眼用***剂、外科手术植入剂如缓释植入剂等局部注射,以及肌注、静注、皮下注射等注射剂或粉针剂;口服给药包括片剂、胶囊、丸剂、颗粒剂、粉末剂、液体制剂如溶液剂、乳剂、混悬剂等。
本发明所述药物中,有效成分的浓度为0.5-500µM,进一步的,有效成分的浓度为1µM、1.5µM、2µM、2.5µM、3µM、3.5µM、4µM、4.5µM、5µM、5.5µM、6µM、7µM、8µM、9µM、10µM、15µM、20µM、25µM、30µM、35µM、40µM、45µM、50µM、55µM、60µM、65µM、70µM、75µM、80µM、85µM、90µM、100µM、110µM、120µM、130µM、140µM、150µM、160µM、170µM、180µM、200µM、220µM、250µM、275µM、300µM、325µM、350µM、375µM、400µM、425µM、450µM、475µM、500µM;优选的,有效成分的浓度为1-400µM;优选的,有效成分的浓度为2-300µM;优选的,有效成分的浓度为5-250µM;优选的,有效成分的浓度为10-200µM;优选的,有效成分的浓度为20-150µM;优选的,有效成分的浓度为30-100µM;优选的,有效成分的浓度为40-80µM。
本发明所述化合物的盐为药学上可接受的盐的形式,如酸加成盐或碱加成盐;酸加成盐能够由合适的无机酸或合适的有机酸进行制备。这种无机酸的例子包括盐酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸及磷酸。这种有机酸的例子选自脂肪族、环脂族、芳香族、芳脂族、杂环类、羧酸类及磺酸类的有机酸,例如甲酸、乙酸、丙酸、琥珀酸、乙醇酸、葡糖酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、葡糖醛酸、马来酸、富马酸、丙酮酸、天冬氨酸、谷氨酸、苯甲酸、邻氨基苯甲酸、甲磺酸、水杨酸、4-羟基苯甲酸、苯乙酸、扁桃酸、帕莫酸、扑酸、甲磺酸、乙磺酸、苯磺酸、泛酸、2-羟基乙磺酸、甲苯磺酸、对氨基苯磺酸、环己氨基磺酸、硬脂酸、海藻酸、β-羟基丁酸、半乳糖二酸及半乳糖醛酸。碱加成盐包括:金属盐,诸如由铝、钙、锂、镁、钾、钠及锌制成的盐;或由有机碱制成的盐,所述有机碱包括伯胺、仲胺及叔胺、取代的胺,所述取代的胺包括诸如咖啡因、精氨酸、二乙胺、N-乙基哌啶、组氨酸、葡糖胺、异丙胺、赖氨酸、吗啉、N-乙基吗啉、哌嗪、哌啶、三乙胺及三甲胺之类的环胺。
本发明所述药物可与本领域常规的辅料制成相应的剂型。
例如,滴眼剂可根据需要适当地选用以下来进行制备:张度剂,诸如氯化钠、甘油、甘露醇或葡萄糖;缓冲剂,诸如磷酸钠或乙酸钠;表面活性剂,诸如聚氧乙烯脱水山梨醇单油酸酯、硬脂酸聚烃氧40酯或聚氧乙烯氢化蓖麻油;稳定剂,诸如柠檬酸钠或乙二胺四乙酸钠;防腐剂,诸如苯扎氯铵或对羟基苯甲酸酯;等。滴眼剂的pH只要在眼用制剂可接受的范围内即可,优选在4至8的范围,优选在5至7、5.5至6.5的范围。作为pH调节剂,可以使用通常的pH调节剂。
例如,注射剂可根据需要适当地选用张度剂,诸如氯化钠、甘油、甘露醇或葡萄糖;缓冲剂,诸如磷酸钠或乙酸钠;表面活性剂,诸如聚氧乙烯脱水山梨醇单油酸酯;增稠剂,诸如甲基纤维素的等,来进行制备。
例如,眼软膏能够使用诸如白色凡士林或液体石蜡之类的广泛使用的基剂来进行制备;***剂能够使用诸如羟丙基纤维素、羟丙基甲基纤维素、羧基乙烯基聚合物或聚丙烯酸之类的可生物降解的聚合物,并在需要时适当地选用赋形剂、粘合剂、稳定剂、pH调节剂等来进行制备;眼内植入剂能够使用诸如聚乳酸、聚乙醇酸、乳酸-乙醇酸共聚物或羟丙基纤维素之类的可生物降解的聚合物,并在需要时适当地选用赋形剂、粘合剂、稳定剂、pH调节剂等来进行制备。
例如,在片剂、胶囊剂、颗粒剂、粉末剂等的情况下,这种制剂可根据需要适当地选用以下来进行制备:赋形剂,诸如乳糖、葡萄糖、D-甘露醇、无水磷酸氢钙、淀粉或蔗糖;崩解剂,诸如羧甲基纤维素、羧甲基纤维素钙、交联羧甲基纤维素钠、交联聚维酮、淀粉、部分糊化淀粉或低取代的羟丙基纤维素;粘合剂,诸如羟丙基纤维素、乙基纤维素、***树胶、淀粉、部分糊化淀粉、聚乙烯吡咯烷酮或聚乙烯醇;润滑剂,诸如,硬脂酸镁、硬脂酸钙、滑石、含水二氧化硅或氢化油;包衣剂,诸如精制蔗糖、羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、乙基纤维素或聚乙烯吡咯烷酮;矫味剂,诸如柠檬酸、阿斯巴甜、抗坏血酸或薄荷醇;等。
本发明所述药物可单独给药,或与其他药物活性成分联合用药。所述其他药物活性成分为抗炎药(如类固醇或非类固醇抗炎药)、抗生素、抗病毒剂、抗真菌剂、***、止疼药等眼科用药或全身用药物。可同时施用,或依次施用;可单独制剂或可制成联合制剂或试剂盒。试剂盒包含用于容纳分离的组合物的容器,诸如分开的瓶或分开的箔包,然而,分离的组合物也可装在单一、未分开的容器中。
实施例1. FDI-6对原代兔结膜囊成纤维细胞的作用
(1) 材料
1)实验所用的FDI-6药物浓度为:2.5、5、10、20和40 µM。
2)原代兔结膜囊成纤维细胞(Rabbit Tenon's Fibroblasts)及其原代成纤维细胞培养基(赛百慷生物技术股份有限公司,中国)。
3)检测所用的主要生化试剂(盒):Cell counting kit-8 (CCK-8;DojindoMolecular Technologies, Kumamoto, Japan),Neutral type I collagen from rattail (A10483-01, Gibco, Thermo Fisher Scientific, former savant, MA, USA),RevertAid First Strand cDNA Synthesis Kit (Fermentas, Thermo FisherScientific, Pittsburgh, PA, USA),SYBR Green Real-Time PCR Master Mix (Toyobo,Osaka, Japan),TGF-β1 (PeproTech, NJ, USA)。
4)检测所用的主要抗体及其工作浓度:FOXM1 (ab207298, rabbit monoclonalantibody, 1:1,000; Abcam, cambridge, MA, USA), ꭤ-SMA (ab7817, mousemonoclonal antibody, 1:200; Abcam, cambridge, MA, USA), COL1A1 (ab6308, mousemonoclonal antibody, 1-2 µg/ml; Abcam, cambridge, MA, USA), FN (ab6328, mousemonoclonal antibody, 1-5 µg/ml; Abcam, cambridge, MA, USA), Smad3 (#9523,Rabbit monoclonal antibody, 1:1000, Cell Signaling Technology, Danvers, MA,USA), Phospho-Smad2/smad3 (#8828, Rabbit monoclonal antibody, 1:1000, CellSignaling Technology, Danvers, MA, USA) or GAPDH (AF5718, goat polyclonalantibody, 1 mg/mL; R&D Systems, Minneapolis, MN, USA)。
5)检测所用的主要仪器:Fluor ChemE (92-14860-00; ProteinSimple, SanJose, CA, USA),flame atomic absorption spectrophotometry (PerkinElmer,Boston, MA, USA),Leica DM4 microscope (DM400B; Leica, Wetzlar, Germany),Rotor-Gene Q cycler (QIAGEN, Germantown, MD, USA)。
(2)实验方法
1)细胞培养与各浓度FDI-6工作液处理
①原代兔结膜囊成纤维细胞于37℃,5% CO2培养箱中进行培养。配套的细胞培养基每天更换一次。待细胞传代至第3 ~ 6代时进行后续实验。
②细胞实验共进行了5组,按下列方法处理:空白对照组,仅用培养基处理细胞;二甲亚砜组(DMSO,用培养基稀释至0.04%的浓度);TGF-β1组,先用0.04% DMSO预处理细胞1小时,然后用20 ng/mL TGF-β1再处理24小时;FDI-6+TGF-β1组,10 M FDI-6预处理细胞1 h,然后用20 ng/mL TGF-β1再预处理24 h;FDI-6组,用2.5、5、10、20和40 µM浓度的FDI-6处理细胞(筛选实验),或者10 µM浓度的FDI-6处理细胞24小时。
2)CCK-8检测与细胞计数
将原代兔结膜囊成纤维细胞以4.5×103/孔的数量接种在96孔板中,用2.5、5、10、20和40 µM浓度的FDI-6或20 ng / ml TGF -β1分别处理细胞24小时。弃去废培养基,用含有CCK-8试剂(10µl/孔)的新培养基添加至到每个孔中,孵化3小时。最后使用Fluor ChemE检测每个孔在450nm波长处的吸光度值。与此同时,对每组(每孔)贴壁细胞进行计数。
3)划痕实验
将原代兔结膜囊成纤维细胞接种至12孔板中。待细胞生长至80-90%的融合度时,用200μl无菌移液管尖端刮取细胞培养物。磷酸盐缓冲盐水(DPBS)清除刮下的细胞碎屑,然后分别加入无血清培养基稀释的FDI-6(10 µM)或TGF -β1(20 ng / ml)。分别于0、12和24小时拍摄细胞迁移图像,并用ImageJ软件分析各组创面愈合率(原始创面面积-实际创面面积)/原始创面面积×100%。在治疗后,细胞会以不同的速度向伤口内生长。当划痕边缘两侧的细胞相互接触并愈合缝隙时,即达到愈合(伤口闭合)。
4)凝胶收缩试验
根据说明书制备Neutral type I collagen from rat tail工作液,并与2.5×105 cells/ml的原代兔结膜囊成纤维细胞悬浮液以体积比9:1于冰上混合。将24孔板用1%牛血清白蛋白(BSA)于培养箱中孵育1小时,然后每孔加入0.5 ml细胞混合物,再孵育1小时使其凝固。凝固的胶原凝胶用10μl移液管尖端从孔壁分离,然后分别在每个凝胶表面加入含TGF-β1、DMSO或FDI-6(10 µM)的无血清培养基(0.5 ml/孔)。Fluor ChemE拍摄胶原凝胶收缩图像。用Image J软件测量凝胶大小。各组收缩面积百分比评价公式:(初始凝胶面积-各时间点的凝胶面积)/初始凝胶面积×100%。
5)蛋白质免疫印迹(Western blot)
将原代兔结膜囊成纤维细胞接种至6孔板中。待细胞生长至80-90%的融合度时,用含TGF-β1、DMSO或FDI-6(10 µM)的培养基分别进行处理一段时间。收集细胞,使用RIPA细胞裂解缓冲液提取总蛋白。所得的各组蛋白质样品,按20-40 μg/孔在梯度浓度的聚丙烯酰胺凝胶(4%-20%)中进行上样,电泳分离,并转移到PVDF膜上。用含5%脱脂奶粉中将PVDF膜封闭1小时,然后在对应的一抗稀释液中分别于4℃孵育过夜。用1×TBS-T洗涤30分钟后,用相应的二抗稀释液于室温中孵育1小时。用Fluor ChemE显影蛋白条带,并使用ImageJ软件对进行分析。
6)实时荧光定量PCR(qRT-PCR)
将原代兔结膜囊成纤维细胞接种至6孔板中。待细胞生长至80-90%的融合度时,用含TGF-β1、DMSO或FDI-6(10 µM)的培养基分别进行处理一段时间。用Trizol试剂(Invitrogen, CA, USA)从细胞中提取总RNA,并检测RNA含量。用RevertAid First StrandcDNA Synthesis kit进行逆转录反应(RT-PCR)。采用SYBR Green Real-Time PCR MasterMix试剂盒于Rotor-Gene Q cycler中进行实时荧光定量PCR,检测各组相应基因的转录水平。利用2-ΔΔCt法计算靶基因的相对表达量。
(3)实验结果
1)蛋白质免疫印迹检测FOXM1蛋白表达水平
为了检测FDI-6对原代兔结膜囊成纤维细胞中FOXM1表达的影响,我们检测了不同浓度的FDI-6处理细胞的FOXM1蛋白的表达水平。结果显示,空白对照、DMSO组和2.5 µM的FDI-6组之间,FOXM1蛋白的表达无显著差异(图1;n = 3,p>0.05)。与DMSO组相比,FDI-6处理组其细胞内FOXM1的表达呈显著的剂量依赖性下调(图1;n = 3,p<0.05)。结果表明,所述浓度的FDI-6成功诱导了原代兔结膜囊成纤维细胞内FOXM1蛋白水平的减少。
2)CCK-8检测与细胞计数
采用CCK-8法和细胞计数测定细胞总代谢活性或细胞增殖能力,以排除药物毒性对FOXM1表达的影响并优化FDI-6浓度。如图2所示,FDI-6显著抑制了原代兔结膜囊成纤维细胞的细胞代谢/增殖活力。随着FDI-6浓度的增加,其抑制程度增加(n=3,p<0.05)。经5 µM FDI-6处理24小时后,细胞数量持续增加(n=3,p<0.05);在10 µM时仍有轻微但不显著的增加(n=3,p<0.05);然而在较高浓度(20和40 µM)组中,细胞数量明显减少,表明细胞死亡(n=3,p<0.05)。结果表明,FDI-6能有效抑制FOXM1的表达,而10 µM浓度的FDI-6似乎是后续细胞实验研究的最佳浓度,预期的患者依从性较好,可以在眼部实现较为长期的治疗效果。
3)划痕实验
该实验的目的为观察10 µM FDI-6对原代兔结膜囊成纤维细胞迁移能力的影响。为了进一步研究FDI-6在细胞中的抗纤维化作用,因此建立了一个TGF-β1(20 ng/ml)处理模型,用于在体外模拟纤维化病变。如图3所示,空白对照组与DMSO组之间迁移面积(%)的差异无统计学意义(n=3,p>0.05)。与DMSO组相比,10 µM FDI-6组细胞的迁移面积减少了22.8%(n=3,p<0.05)。TGF-β1组细胞的迁移面积增加了11.5%(n=3,p<0.05),而FDI-6则显著扭转了这一增幅(n=3,p<0.05)。结果表明,FDI-6对原代兔结膜囊成纤维细胞的迁移和增殖功能具有很强的抑制作用。
4)凝胶收缩实验
成纤维细胞收缩胶原凝胶的能力是其分化成肌成纤维细胞表型的重要标志。如图4所示,原代兔结膜囊成纤维细胞的平均收缩面积(%)在DMSO组和空白对照组之间无显著性差异(n=3,p>0.05)。与DMSO组比较,FDI-6组的平均收缩面积显著减少了11.6%(n=3,p<0.05),表明有调节肌成纤维细胞活性的能力。此外,TGF-β1组的平均收缩面积增加了7.7%(n=3,p<0.05),而FDI-6逆转了这种促收缩能力。结果表明,FDI-6对原代兔结膜囊成纤维细胞的收缩性具有很强的抑制作用。
5)蛋白质免疫印迹和实时荧光定量PCR检测纤维化相关基因的表达
观察FDI-6对纤维化相关基因,如α-SMA、COL1A1和FN表达的影响。如图5和图6所示,这些基因在DMSO组与空白对照组之间的表达无显著差异(实时荧光定量PCR的n=4;免疫印迹实验的n=3;p>0.05)。与DMSO组相比,FDI-6显著降低了上述基因在mRNA和蛋白水平上的表达(实时荧光定量PCR的n=4;免疫印迹实验的n=3;p<0.05)。与DMSO组相比,TGF-β1组中上述基因在mRNA和蛋白上的表达均增加(实时荧光定量PCR的n=4;免疫印迹实验的n=3;p<0.05),但FDI-6同样逆转了这种升高作用(实时荧光定量PCR的n=4;免疫印迹实验的n=3;p<0.05)。如图6所示,FDI-6可显著降低细胞中Smad2/3蛋白的磷酸化水平(n=3;p<0.05)。结果表明,FDI-6通过调控原代兔结膜囊成纤维细胞中这些纤维化相关基因的表达。
实施例2. FDI-6抗兔眼部纤维化的作用
(1)材料
1)实验所用的FDI-6药物浓度为40 µM。
2)成年新西兰大白兔(雌雄各5只,10-12周龄,1.5-2 kg,四川省医学科学院成都实验动物研究所)。
3)主要的试剂材料:BD舒锐一次性无菌胰岛素注射器(BD,U-100,0.5ml,0.33mm/29G×12.7mm),0.3% ofloxacin ophthalmic ointment (Santen, Inc., Tokyo, Japan),0.3% ofloxacin eye drops (Minsheng Pharma, Hangzhou, China),3% pentobarbitalsodium (30 mg/kg, Sanofi, Paris, France),formaldehyde, acetic acid, andsaline (FAS) fixative (Wuhan Servicebio, Wuhan, China),。
4)检测所用的主要仪器:TonoVet® rebound tonometer (Icare, Finland,Espoo, Finland),slit lamp biomicroscope (S350; Shanghai Medi Works PrecisionInstruments, Hangzhou, China),In vivo confocal microscopy (HRT II/RCM,Heidelberg Engineering GmbH, Heidelberg, Germany),Leica DM4 microscope(DM400B; Leica, Wetzlar, Germany)。
(2)分组方式
10只兔随机分配至以下各组中
备注:手术方式为小梁切除术;注射方式为结膜下注射。
(3)实验方法
1)小梁切除术
按照上述表格分组情况进行小梁切除术。兔通过耳缘静脉注射3%戊巴比妥钠进行麻醉。眼周皮肤消毒后,用开睑器撑开手术侧眼睑,用8-0缝合线穿过外周角膜基质,并将眼球提拉旋转至一侧,使术区充分暴露。在鼻上象限建立以角膜缘为基础的结膜瓣,并暴露巩膜。然后制作约3×3毫米的方形巩膜瓣。在切除约0.5×1毫米的小梁网区域组织后,再进行外周虹膜切除术。采用10-0尼龙缝线缝合巩膜瓣。结膜用10-0尼龙线进行缝合。通过胰岛素注射器将40 µM的FDI-6或生理盐水注射于手术眼或非手术眼的颞上结膜下,推注时针头朝向手术区。术毕,以0.3% ofloxacin ophthalmic ointment涂布术区。次日开始以0.3%ofloxacin eye drops进行滴眼,每日4次,连续1周。
2)眼压测量
动物在清醒状态下,使用TonoVet回弹式眼压计于术后每隔两天测量一次眼压,为期14天。先训练兔子在安静放松状态下接受测量。研究者于每天下午2点到4点的同一时间进行。
3)临床检查项目
①兔通过耳缘静脉注射3%戊巴比妥钠进行麻醉,然后进行如下检查项目。
②术后通过裂隙灯每天观察术区滤过泡形态及眼前节段情况,并于第7和14天拍摄图片。对第7和14天滤过泡的高度和大小等情况进行Krofeld评分,评分细则如下:
1+,最小高度,结膜增厚,无滤过泡;
2+,可见滤过泡;
3+,升高的滤过泡覆盖眼球3到4个时钟方向的面积;
4+,显著升高的滤过泡覆盖超过眼球5个时钟方向的面积。
0,表示没有可观察到的水泡。
③用荧光素钠眼条进行角膜荧光染色,在第14天下用裂隙灯生物显微镜蓝光检查每只兔的角膜,分析药物本身对角膜是否有不良影响。
④激光共聚焦生物显微镜用于检查术后第14天时滤过泡以及处滤泡区上皮下***情况。
⑤上述临床检查项目均由经验丰富的眼科临床医师按制造商推荐的程序进行,未发现与这些检查相关的副作用。
4)组织学分析
术后第14天,3%戊巴比妥钠过量麻醉以处死动物,立即摘除双侧眼球,术区以及滤过泡组织均用品红进行标记。标记后眼球置入formaldehyde, acetic acid, and saline(FAS) fixative内于4℃固定48小时。然后进行常规石蜡包埋,4μm厚度组织切片。切片常规处理后,分别进行苏木素-伊红染色进行组织形态学分析,Masson三色染色评价胶原蛋白表达,α-SMA免疫组化染色观察组织肌纤维化程度。用胶原体积分数(Collagen volumefraction,CVF)定量结膜层和巩膜层胶原表达,计算为蓝染组织面积与总面积的比值(%)。
(4)实验结果
1)眼压监测
如图7所示,各组术前眼压值无显著性差异。非手术组(空白对照组、生理盐水组和FDI-6组)之间的眼压也无显著性差异(n=4;p>0.05)。手术组(手术+生理盐水组和手术+FDI-6组)眼压在术后均明显降低,但手术+ FDI-6组眼压于第12天开始显著低于手术+生理盐水组(n=4;p<0.05)。
结果提示,FDI-6可以稳定小梁切除术后下降的眼压。
2)临床检查项目
(1)如图8所示,手术+FDI-6组在第14天时的滤过泡评分显著优于手术+生理盐水组(n=4;p<0.05)。与滤过泡评分结果相对应的是,第7和第14天时手术+生理盐水组的滤过泡小而平,术区的血管化丰富,而手术+FDI-6组的滤过泡轻度***,术区血管化较少。
(2)角膜荧光素钠染色结果如图9所示,所有兔眼均未见荧光素钠着色,表明FDI-6治疗后无不良反应或毒性反应。此外,所有组均未观察到明显的并发症,如角膜或结膜上皮缺损、滤过泡渗漏、眼压过低、白内障和眼内炎。除瘢痕形成的差异之外,手术+生理盐水组与手术+FDI-6组之间无其他明显差异。
(3)激光共聚焦生物显微镜分析结果如图10所示,手术+盐水组结膜上皮有明显的炎性细胞浸润,可见多个亮白色细胞核,而手术+FDI-6组无明显的炎性细胞浸润。此外,非手术组的结膜上皮下***间隙疏松。手术+生理盐水组结膜的浅层和深层间质中可见大量致密的纤维组织,而FDI-6的治疗降低了小梁切除术后纤维密度增加,导致小梁切除术后出现功能性滤过泡。
结果表明,FDI-6治疗可以显著减少结膜下纤维化,并进一步促进了功能性滤过泡的形成。
3)组织形态学分析
(1)苏木素-伊红染色结果显示,手术组(手术+生理盐水组和手术+FDI-6组)结膜和巩膜之间的厚度增加(n=3;p<0.05),而手术组+FDI-6组的平均厚度明显薄于手术组+生理盐水组,但组间差异无统计学意义(n=3;p>0.05)。
(2) Masson三色染色结果显示,手术组结膜下聚集了大量胶原蛋白。手术组+FDI-6组胶原体积分数明显低于手术组+生理盐水组(n=3;p<0.05)。
(3)α-SMA蛋白免疫组化结果显示,手术组的结膜和巩膜组织间存在阳性表达,非手术组阴性表达,而手术+FDI-6组α-SMA表达弱于手术+生理盐水组,提示肌成纤维细胞较少。
结果显示(见图11),FDI-6可以通过减少肌成纤维细胞分化和细胞外基质合成(包括FN和COL1A1),从而预防小梁切除术后结膜下纤维化。
实施例3. FDI-6对大鼠眼部新生血管的作用
1 材料
(1)实验所用的FDI-6药物浓度为40 µM。
(2)Sprague-Dawley大鼠(SD大鼠),雄性,体重175 ~ 200 g(北京维通利华实验动物技术有限公司,中国)。
(3)检测所用的主要生化试剂(盒):Sodium hydroxide (Sigma Aldrich, St.Louis, MO, USA), Chloral hydrate (Sigma Aldrich, St. Louis, MO, USA),RevertAid First Strand cDNA Synthesis Kit (Fermentas, Thermo FisherScientific, Pittsburgh, PA, USA),SYBR Green Real-Time PCR Master Mix (Toyobo,Osaka, Japan)。
(4)检测所用的主要仪器:slit lamp biomicroscope (S350; Shanghai MediWorks Precision Instruments, Hangzhou, China),Rotor-Gene Q cycler (QIAGEN,Germantown, MD, USA)。
2 分组方式
备注:碱烧伤为角膜碱烧伤模型;注射方式为结膜下注射。
3 实验方法
(1)角膜碱烧伤模型的构建
SD大鼠以10%水合氯醛腹腔麻醉后,右眼予以散瞳及眼表麻醉,将3.5×3.5mm的滤纸浸入1N(mol/L)氢氧化钠中约10秒,蘸去多余液体后将其放在大鼠角膜中央45s,后立即用20ml的0.9%氯化钠注射液冲洗角膜1min,然后于上侧球结膜下注射20 µl 40 µM FDI-6或生理盐水,左眼仅结膜下注射20 µl 40 µM FDI-6或生理盐水。
术后用1ml注射器抽取40 µM FDI-6或生理盐水对大鼠进行滴眼。滴眼方式为每天3次,每次给予一滴(每次给药维持时间2min),持续至术后第7天。
(2)临床检查项目
1)大鼠通过腹腔注射10%水合氯醛进行麻醉,然后进行如下检查项目。
2)通过裂隙灯于术后第1、4和7天观察角膜形态、通透度和血管生成情况,以及眼前节情况,并拍摄图片。其中角膜新生血管的观察指标如下:
①长度:即计算从角巩膜缘伸入角膜的新生血管长度。
②面积:采用公式S=(C/12)×3.1416×[R2-(R-r)2]分析角膜新生血管生长的面积;其中C为角膜新生血管时钟数;R为角膜半径,统一为3.5mm;r为角膜新生血管长度。
3)用荧光素钠眼条进行角膜荧光染色,在第7天下用裂隙灯生物显微镜蓝光检查每只大鼠的角膜,分析角膜损伤程度,以及药物对损伤的影响。
(3)实时荧光定量PCR(qRT-PCR)
术后第7天,10%水合氯醛过量麻醉以处死动物,立即摘除双侧眼球,沿角巩膜缘剪下角膜组织。用Trizol试剂从角膜组织中提取总RNA,并检测RNA含量。用RevertAid FirstStrand cDNA Synthesis kit进行逆转录反应(RT-PCR)。采用SYBR Green Real-Time PCRMaster Mix试剂盒于Rotor-Gene Q cycler中进行实时荧光定量PCR,检测各组相应基因的转录水平。利用2-ΔΔCt法计算靶基因的相对表达量。
4 实验结果
1)临床检查项目
如图12所示,未碱烧伤组(空白对照组、生理盐水组和FDI-6组)的眼前节均未见明显异常,角膜透明,无新生血管长入。而碱烧伤组均可见明显的角膜水肿、角膜新生血管长入和结膜充血,但碱烧伤+FDI-6组的情况明显轻于碱烧伤+生理盐水组。尤其在第7天时角膜水肿的情况以及新生血管的长度和面积均显著低于手术+生理盐水组(p<0.05)。
角膜荧光素钠染色结果显示,术后第7天时未碱烧伤组均未见荧光素钠着色,而碱烧伤组可见荧光素着色。但碱烧伤+FDI-6组的着色情况明显轻于碱烧伤+生理盐水组。说明FDI-6缓解了角膜上皮溃疡的形成。
结果说明,FDI-6可以显著抑制角膜碱烧伤后的新生血管长入,缓解角膜水肿和上皮溃疡的形成。
2)实时荧光定量PCR
观察FDI-6对角膜炎症和新生血管相关基因表达的影响,如CD31、VEGF、IL-6、α-SMA和MMP-9。
如图13所示,这些基因在未碱烧伤组(空白对照组、生理盐水组和FDI-6组)之间的表达无显著差异(p>0.05),但在碱烧伤组(碱烧伤+生理盐水组和碱烧伤+FDI-6组)均有显著的上调(p<0.05)。碱烧伤+FDI-6组上述基因的mRNA水平显著低于碱烧伤+生理盐水组(p<0.05),说明FDI-6显著逆转了角膜碱烧伤后上述基因表达的上调。
结果表明,FDI-6可能通过抑制血管诱导因子和炎症因子,从而在角膜损伤后发挥抗炎症和抗新生血管的作用。
综上,在碱烧伤诱导的角膜新生血管模型中,FDI-6 处理后能显著抑制角膜新生血管的生长、炎症以及纤维化的发生,表现在裂隙灯下观察到角膜新生血管的面积以及长度、角膜透明度等均较未处理组改善。病理结果表明,FDI-6处理后血管相关标志物CD31、纤维化相关标志物α-平滑肌肌动蛋白(α-SMA)等表达较未处理组明显减少。
以上显示和描述了本发明的基本原理和主要特征,而非用于限制本发明。本领域技术人员应该了解,在不脱离本发明构思和范围的前提下,举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变,仍应由本发明所涵盖。
Claims (4)
2.根据权利要求1所述的用途,其中R1、R2、R3、R4分别独立的选自F、Cl、Br或I。
3.根据权利要求2所述的用途,其中R1、R2、R3、R4分别独立的选自F。
4.根据权利要求1所述的用途,其中式(I)化合物为叉头结构域抑制剂FDI-6。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110346039.9A CN113768929B (zh) | 2021-03-31 | 2021-03-31 | Fdi化合物在眼科疾病中的用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110346039.9A CN113768929B (zh) | 2021-03-31 | 2021-03-31 | Fdi化合物在眼科疾病中的用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113768929A CN113768929A (zh) | 2021-12-10 |
CN113768929B true CN113768929B (zh) | 2023-03-31 |
Family
ID=78835606
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110346039.9A Active CN113768929B (zh) | 2021-03-31 | 2021-03-31 | Fdi化合物在眼科疾病中的用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113768929B (zh) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108210494B (zh) * | 2018-03-23 | 2019-09-27 | 南华大学 | Foxm1抑制剂fdi-6抗肝纤维化的应用 |
-
2021
- 2021-03-31 CN CN202110346039.9A patent/CN113768929B/zh active Active
Also Published As
Publication number | Publication date |
---|---|
CN113768929A (zh) | 2021-12-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7234283B2 (ja) | 翼状片を治療するための組成物及び方法 | |
EP3441069B1 (en) | Treatment of diabetic retinopathy using pharmaceutical agents that eliminate senescent cells | |
US11865123B2 (en) | Methods of inhibiting pathological angiogenesis | |
JP5557408B1 (ja) | 眼底疾患治療剤 | |
JP2012524073A (ja) | 眼球瘢痕化を抑制するための形質転換成長因子−β受容体阻害剤の使用 | |
US20130189246A1 (en) | Treatment of ophthalmic conditions with fluorenone derivatives | |
BR112020015567A2 (pt) | medicamento para prevenir ou tratar doença oftálmica associada com neovascularização intraocular e/ou permeabilidade vascular intraocular realçadas | |
CN113768929B (zh) | Fdi化合物在眼科疾病中的用途 | |
US20200179482A1 (en) | Composition for and method of facilitating corneal tissue repair | |
RU2815482C2 (ru) | Лечение глазных болезней типа дегенерации желтого пятна, глаукомы и диабетической ретинопатии с помощью лекарственных средств, устраняющих стареющие клетки | |
JP7429500B2 (ja) | 角膜上皮障害治療剤 | |
Wang et al. | Celastrol alleviates subconjunctival fibrosis induced by silicone implants mimicking glaucoma surgery | |
WO2023201312A2 (en) | Methods of treating ocular fibrotic pathologies | |
JP2023035973A (ja) | ナノ低分子ペプチドfh及びその眼底血管疾患の治療や予防用薬物の調製への応用 |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
TR01 | Transfer of patent right |
Effective date of registration: 20240527 Address after: No. 336, Xiahe Road, Siming District, Xiamen City, Fujian Province, 361000 Patentee after: Xiamen Eye Center Co.,Ltd. Country or region after: China Address before: 361016 floor 10, building 3, wuyuanyuan District, Xiamen Eye Center, No. 989, Wutong West Road, Huli District, Xiamen City, Fujian Province Patentee before: Liu Xuyang Country or region before: China |
|
TR01 | Transfer of patent right |