JP6526570B2 - 炎症及び血管形成を減少させるcyp450脂質メタボライト - Google Patents
炎症及び血管形成を減少させるcyp450脂質メタボライト Download PDFInfo
- Publication number
- JP6526570B2 JP6526570B2 JP2015552772A JP2015552772A JP6526570B2 JP 6526570 B2 JP6526570 B2 JP 6526570B2 JP 2015552772 A JP2015552772 A JP 2015552772A JP 2015552772 A JP2015552772 A JP 2015552772A JP 6526570 B2 JP6526570 B2 JP 6526570B2
- Authority
- JP
- Japan
- Prior art keywords
- lcpufa
- omega
- cnv
- mice
- edp
- 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
- 230000033115 angiogenesis Effects 0.000 title claims description 45
- 239000002207 metabolite Substances 0.000 title description 59
- 150000002632 lipids Chemical class 0.000 title description 22
- 206010061218 Inflammation Diseases 0.000 title description 18
- 230000004054 inflammatory process Effects 0.000 title description 18
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 68
- 208000002780 macular degeneration Diseases 0.000 claims description 62
- 210000001525 retina Anatomy 0.000 claims description 61
- 206010028980 Neoplasm Diseases 0.000 claims description 44
- 238000011282 treatment Methods 0.000 claims description 39
- 210000003161 choroid Anatomy 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 35
- 201000011510 cancer Diseases 0.000 claims description 29
- 210000001508 eye Anatomy 0.000 claims description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 208000017442 Retinal disease Diseases 0.000 claims description 17
- 230000002792 vascular Effects 0.000 claims description 17
- 208000030533 eye disease Diseases 0.000 claims description 12
- 210000004087 cornea Anatomy 0.000 claims description 11
- 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 10
- 208000006011 Stroke Diseases 0.000 claims description 10
- 210000000554 iris Anatomy 0.000 claims description 10
- 208000022873 Ocular disease Diseases 0.000 claims description 9
- 206010003246 arthritis Diseases 0.000 claims description 8
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 7
- 230000008728 vascular permeability Effects 0.000 claims description 7
- 206010029113 Neovascularisation Diseases 0.000 claims description 6
- 210000001745 uvea Anatomy 0.000 claims description 6
- 206010064714 Radiation retinopathy Diseases 0.000 claims description 5
- 206010038935 Retinopathy sickle cell Diseases 0.000 claims description 5
- 208000027073 Stargardt disease Diseases 0.000 claims description 5
- 210000000744 eyelid Anatomy 0.000 claims description 5
- 208000004644 retinal vein occlusion Diseases 0.000 claims description 5
- 210000000795 conjunctiva Anatomy 0.000 claims description 4
- 238000007911 parenteral administration Methods 0.000 claims description 4
- 238000011200 topical administration Methods 0.000 claims description 4
- 230000000699 topical effect Effects 0.000 claims description 4
- 210000004127 vitreous body Anatomy 0.000 claims description 4
- 208000005590 Choroidal Neovascularization Diseases 0.000 description 208
- 206010060823 Choroidal neovascularisation Diseases 0.000 description 207
- 235000020667 long-chain omega-3 fatty acid Nutrition 0.000 description 172
- 241000699670 Mus sp. Species 0.000 description 163
- 230000006698 induction Effects 0.000 description 80
- 235000005911 diet Nutrition 0.000 description 78
- 230000003902 lesion Effects 0.000 description 74
- 210000000265 leukocyte Anatomy 0.000 description 74
- 238000000034 method Methods 0.000 description 67
- 230000037213 diet Effects 0.000 description 66
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 63
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 59
- 201000010099 disease Diseases 0.000 description 55
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 description 52
- 230000000694 effects Effects 0.000 description 45
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 40
- 102000009524 Vascular Endothelial Growth Factor A Human genes 0.000 description 39
- 239000003981 vehicle Substances 0.000 description 39
- 108010016731 PPAR gamma Proteins 0.000 description 36
- 239000004593 Epoxy Substances 0.000 description 35
- 230000014509 gene expression Effects 0.000 description 35
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 33
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 32
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 32
- 101710151710 Vascular endothelial growth factor A-A Proteins 0.000 description 31
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 30
- 238000004458 analytical method Methods 0.000 description 30
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 30
- 229940090949 docosahexaenoic acid Drugs 0.000 description 26
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 25
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 25
- 102100022338 Integrin alpha-M Human genes 0.000 description 25
- 102100025390 Integrin beta-2 Human genes 0.000 description 25
- 108010035766 P-Selectin Proteins 0.000 description 25
- 102100023472 P-selectin Human genes 0.000 description 25
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 24
- 230000002207 retinal effect Effects 0.000 description 24
- 235000018823 dietary intake Nutrition 0.000 description 22
- GPQVVJQEBXAKBJ-JPURVOHMSA-N 17(18)-EpETE Chemical compound CCC1OC1C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O GPQVVJQEBXAKBJ-JPURVOHMSA-N 0.000 description 21
- 150000001875 compounds Chemical class 0.000 description 21
- 235000021342 arachidonic acid Nutrition 0.000 description 20
- 229940114079 arachidonic acid Drugs 0.000 description 20
- 210000002966 serum Anatomy 0.000 description 19
- 230000003828 downregulation Effects 0.000 description 18
- 210000002540 macrophage Anatomy 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
- 239000003112 inhibitor Substances 0.000 description 16
- 108010024212 E-Selectin Proteins 0.000 description 15
- 102100023471 E-selectin Human genes 0.000 description 15
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 14
- 210000004204 blood vessel Anatomy 0.000 description 14
- 230000000875 corresponding effect Effects 0.000 description 13
- 235000014113 dietary fatty acids Nutrition 0.000 description 13
- 229930195729 fatty acid Natural products 0.000 description 13
- 239000000194 fatty acid Substances 0.000 description 13
- 239000003446 ligand Substances 0.000 description 13
- 238000003753 real-time PCR Methods 0.000 description 13
- 239000002253 acid Substances 0.000 description 12
- 230000000378 dietary effect Effects 0.000 description 12
- 150000004665 fatty acids Chemical class 0.000 description 12
- 239000005090 green fluorescent protein Substances 0.000 description 12
- 108020004999 messenger RNA Proteins 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 210000005259 peripheral blood Anatomy 0.000 description 11
- 239000011886 peripheral blood Substances 0.000 description 11
- 210000001519 tissue Anatomy 0.000 description 11
- -1 EDP) Chemical class 0.000 description 10
- 238000002965 ELISA Methods 0.000 description 10
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 10
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 10
- 102000004856 Lectins Human genes 0.000 description 10
- 108090001090 Lectins Proteins 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 239000007928 intraperitoneal injection Substances 0.000 description 10
- 238000012014 optical coherence tomography Methods 0.000 description 10
- 238000004445 quantitative analysis Methods 0.000 description 10
- 238000010186 staining Methods 0.000 description 10
- 230000003827 upregulation Effects 0.000 description 10
- DVSZKTAMJJTWFG-SKCDLICFSA-N (2e,4e,6e,8e,10e,12e)-docosa-2,4,6,8,10,12-hexaenoic acid Chemical class CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C=C\C(O)=O DVSZKTAMJJTWFG-SKCDLICFSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 9
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000003937 drug carrier Substances 0.000 description 9
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 9
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 9
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 9
- 230000000649 photocoagulation Effects 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 230000001629 suppression Effects 0.000 description 9
- OSXOPUBJJDUAOJ-MBYQGORISA-N (4Z,7Z,10Z,13Z,16Z)-19,20-epoxydocosapentaenoic acid Chemical compound CCC1OC1C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O OSXOPUBJJDUAOJ-MBYQGORISA-N 0.000 description 8
- 101150062345 CX3CR1 gene Proteins 0.000 description 8
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 8
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 8
- 230000002491 angiogenic effect Effects 0.000 description 8
- 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 8
- 238000013534 fluorescein angiography Methods 0.000 description 8
- 239000002953 phosphate buffered saline Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 230000007306 turnover Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- YUFFSWGQGVEMMI-JLNKQSITSA-N (7Z,10Z,13Z,16Z,19Z)-docosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCCCC(O)=O YUFFSWGQGVEMMI-JLNKQSITSA-N 0.000 description 7
- AVUQWNIWFSWLIY-UHFFFAOYSA-N 2,3-dihydroxyicosa-2,4,6-trienoic acid Chemical compound CCCCCCCCCCCCCC=CC=CC(O)=C(O)C(O)=O AVUQWNIWFSWLIY-UHFFFAOYSA-N 0.000 description 7
- 235000021294 Docosapentaenoic acid Nutrition 0.000 description 7
- 102000015271 Intercellular Adhesion Molecule-1 Human genes 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 230000001419 dependent effect Effects 0.000 description 7
- 238000000684 flow cytometry Methods 0.000 description 7
- 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 7
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
- 210000004379 membrane Anatomy 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- 210000005087 mononuclear cell Anatomy 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 6
- 150000002066 eicosanoids Chemical class 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 229940012843 omega-3 fatty acid Drugs 0.000 description 6
- 230000000144 pharmacologic effect Effects 0.000 description 6
- 230000007115 recruitment Effects 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- WLCZTRVUXYALDD-IBGZPJMESA-N 7-[[(2s)-2,6-bis(2-methoxyethoxycarbonylamino)hexanoyl]amino]heptoxy-methylphosphinic acid Chemical compound COCCOC(=O)NCCCC[C@H](NC(=O)OCCOC)C(=O)NCCCCCCCOP(C)(O)=O WLCZTRVUXYALDD-IBGZPJMESA-N 0.000 description 5
- 208000010412 Glaucoma Diseases 0.000 description 5
- 201000006165 Kuhnt-Junius degeneration Diseases 0.000 description 5
- 206010027476 Metastases Diseases 0.000 description 5
- 108091008605 VEGF receptors Proteins 0.000 description 5
- 208000000208 Wet Macular Degeneration Diseases 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000001772 anti-angiogenic effect Effects 0.000 description 5
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 210000004443 dendritic cell Anatomy 0.000 description 5
- 230000004438 eyesight Effects 0.000 description 5
- 238000003119 immunoblot Methods 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 230000009545 invasion Effects 0.000 description 5
- 230000009401 metastasis Effects 0.000 description 5
- 229960003407 pegaptanib Drugs 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- 210000003786 sclera Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 5
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 4
- XTNOEYFQXCQKLC-UHFFFAOYSA-N 18-(oxiren-2-yl)octadeca-15,17-dienoic acid Chemical compound C1=C(C=CC=CCCCCCCCCCCCCCC(=O)O)O1 XTNOEYFQXCQKLC-UHFFFAOYSA-N 0.000 description 4
- GZJLLYHBALOKEX-UHFFFAOYSA-N 6-Ketone, O18-Me-Ussuriedine Natural products CC=CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O GZJLLYHBALOKEX-UHFFFAOYSA-N 0.000 description 4
- 108091023037 Aptamer Proteins 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
- 201000004569 Blindness Diseases 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 102100034925 P-selectin glycoprotein ligand 1 Human genes 0.000 description 4
- 108010054395 P-selectin ligand protein Proteins 0.000 description 4
- 108020004459 Small interfering RNA Proteins 0.000 description 4
- 108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 description 4
- 206010052428 Wound Diseases 0.000 description 4
- 238000009825 accumulation Methods 0.000 description 4
- 210000001775 bruch membrane Anatomy 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- KAUVQQXNCKESLC-UHFFFAOYSA-N docosahexaenoic acid (DHA) Natural products COC(=O)C(C)NOCC1=CC=CC=C1 KAUVQQXNCKESLC-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 208000024519 eye neoplasm Diseases 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 230000003463 hyperproliferative effect Effects 0.000 description 4
- 210000002865 immune cell Anatomy 0.000 description 4
- 230000008595 infiltration Effects 0.000 description 4
- 238000001764 infiltration Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 206010061289 metastatic neoplasm Diseases 0.000 description 4
- 210000000274 microglia Anatomy 0.000 description 4
- 235000021590 normal diet Nutrition 0.000 description 4
- 235000016709 nutrition Nutrition 0.000 description 4
- 201000008106 ocular cancer Diseases 0.000 description 4
- 239000006014 omega-3 oil Substances 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 4
- CRDZYJSQHCXHEG-SFVBTVKNSA-N protectin D1 Chemical compound CC\C=C/C[C@H](O)\C=C/C=C/C=C/[C@H](O)C\C=C/C\C=C/CCC(O)=O CRDZYJSQHCXHEG-SFVBTVKNSA-N 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 238000011002 quantification Methods 0.000 description 4
- 210000003583 retinal pigment epithelium Anatomy 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 239000004055 small Interfering RNA Substances 0.000 description 4
- 230000000007 visual effect Effects 0.000 description 4
- 150000000266 14,15-EET derivatives Chemical class 0.000 description 3
- PNYUUUKFXBYULF-UHFFFAOYSA-N 2,3-dihydroxydocosa-2,4,6,8,10-pentaenoic acid Chemical compound CCCCCCCCCCCC=CC=CC=CC=CC(O)=C(O)C(O)=O PNYUUUKFXBYULF-UHFFFAOYSA-N 0.000 description 3
- 102000007469 Actins Human genes 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- 206010070957 Choroidal haemangioma Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010061818 Disease progression Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- 102000000536 PPAR gamma Human genes 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- 208000007135 Retinal Neovascularization Diseases 0.000 description 3
- 206010038923 Retinopathy Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940120638 avastin Drugs 0.000 description 3
- 229960000397 bevacizumab Drugs 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 238000004891 communication Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000005750 disease progression Effects 0.000 description 3
- 239000002612 dispersion medium Substances 0.000 description 3
- 239000006196 drop Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- IQLUYYHUNSSHIY-HZUMYPAESA-N eicosatetraenoic acid Chemical compound CCCCCCCCCCC\C=C\C=C\C=C\C=C\C(O)=O IQLUYYHUNSSHIY-HZUMYPAESA-N 0.000 description 3
- 210000002889 endothelial cell Anatomy 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 201000011066 hemangioma Diseases 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000000370 laser capture micro-dissection Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 230000001394 metastastic effect Effects 0.000 description 3
- 230000009826 neoplastic cell growth Effects 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000010412 perfusion Effects 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 229960003876 ranibizumab Drugs 0.000 description 3
- 239000000790 retinal pigment Substances 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000003595 spectral effect Effects 0.000 description 3
- 230000035882 stress Effects 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 230000005747 tumor angiogenesis Effects 0.000 description 3
- DXOYQVHGIODESM-KROJNAHFSA-N 11,12-EET Chemical compound CCCCC\C=C/CC1OC1C\C=C/C\C=C/CCCC(O)=O DXOYQVHGIODESM-KROJNAHFSA-N 0.000 description 2
- 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
- DBWQSCSXHFNTMO-TYAUOURKSA-N 8,9-EET Chemical compound CCCCC\C=C/C\C=C/CC1OC1C\C=C/CCCC(O)=O DBWQSCSXHFNTMO-TYAUOURKSA-N 0.000 description 2
- 102000001381 Arachidonate 5-Lipoxygenase Human genes 0.000 description 2
- 108010093579 Arachidonate 5-lipoxygenase Proteins 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 208000003163 Cavernous Hemangioma Diseases 0.000 description 2
- 102100031162 Collagen alpha-1(XVIII) chain Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 108010079505 Endostatins Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 208000004413 Eyelid Neoplasms Diseases 0.000 description 2
- 206010050497 Eyelid tumour Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 2
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010065630 Iris neovascularisation Diseases 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 2
- 208000010415 Low Vision Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 208000014245 Ocular vascular disease Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 206010046851 Uveitis Diseases 0.000 description 2
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 2
- 208000032594 Vascular Remodeling Diseases 0.000 description 2
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 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
- 235000021068 Western diet Nutrition 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000003070 absorption delaying agent Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000003732 agents acting on the eye Substances 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 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 2
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 102000036639 antigens Human genes 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
- 208000006673 asthma Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 210000001715 carotid artery Anatomy 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 201000000787 conjunctival cancer Diseases 0.000 description 2
- 208000017903 conjunctival tumor Diseases 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 2
- 239000003599 detergent Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 235000015872 dietary supplement Nutrition 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 230000002222 downregulating effect Effects 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 230000000004 hemodynamic effect Effects 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 230000036737 immune function Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000002085 irritant Substances 0.000 description 2
- 231100000021 irritant Toxicity 0.000 description 2
- 210000004731 jugular vein Anatomy 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 230000004303 low vision Effects 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
- 206010027191 meningioma Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- 201000003142 neovascular glaucoma Diseases 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 235000020665 omega-6 fatty acid Nutrition 0.000 description 2
- 229940033080 omega-6 fatty acid Drugs 0.000 description 2
- 229940023490 ophthalmic product Drugs 0.000 description 2
- 210000001328 optic nerve Anatomy 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 210000000608 photoreceptor cell Anatomy 0.000 description 2
- 108091008695 photoreceptors Proteins 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 235000004252 protein component Nutrition 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004263 retinal angiogenesis Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 230000009469 supplementation Effects 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 230000009897 systematic effect Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- YFDSDPIBEUFTMI-UHFFFAOYSA-N tribromoethanol Chemical compound OCC(Br)(Br)Br YFDSDPIBEUFTMI-UHFFFAOYSA-N 0.000 description 2
- 229950004616 tribromoethanol Drugs 0.000 description 2
- 230000004304 visual acuity Effects 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
- 230000029663 wound healing Effects 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- BCTXZWCPBLWCRV-ZYADFMMDSA-N (4Z,7Z,10Z,13Z,19Z)-16,17-epoxydocosapentaenoic acid Chemical compound CC\C=C/CC1OC1C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O BCTXZWCPBLWCRV-ZYADFMMDSA-N 0.000 description 1
- SYAWGTIVOGUZMM-ILYOTBPNSA-N (5Z,8Z,11Z)-14,15-dihydroxyicosatrienoic acid Chemical compound CCCCCC(O)C(O)C\C=C/C\C=C/C\C=C/CCCC(O)=O SYAWGTIVOGUZMM-ILYOTBPNSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- NNDIXBJHNLFJJP-KVJJYFOZSA-N 20-HETE-d6 Chemical compound OCCC([2H])([2H])C([2H])([2H])C([2H])([2H])\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O NNDIXBJHNLFJJP-KVJJYFOZSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-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
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 241000321096 Adenoides Species 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- 239000012114 Alexa Fluor 647 Substances 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 208000016623 Choroid neoplasm Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 1
- 208000032972 Conjunctival malignant melanoma Diseases 0.000 description 1
- 206010066384 Conjunctival melanoma Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 238000001061 Dunnett's test Methods 0.000 description 1
- 108010041308 Endothelial Growth Factors Proteins 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 206010051045 Eye naevus Diseases 0.000 description 1
- 101150070880 Ffar4 gene Proteins 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 208000008069 Geographic Atrophy Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000219726 Griffonia simplicifolia Species 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 101000599852 Homo sapiens Intercellular adhesion molecule 1 Proteins 0.000 description 1
- 101000808011 Homo sapiens Vascular endothelial growth factor A Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 101000668058 Infectious salmon anemia virus (isolate Atlantic salmon/Norway/810/9/99) RNA-directed RNA polymerase catalytic subunit Proteins 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 206010073086 Iris melanoma Diseases 0.000 description 1
- 206010057412 Iris neoplasm Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 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
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 108090000128 Lipoxygenases Proteins 0.000 description 1
- 102000003820 Lipoxygenases Human genes 0.000 description 1
- 206010025219 Lymphangioma Diseases 0.000 description 1
- 102100037611 Lysophospholipase Human genes 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102100027159 Membrane primary amine oxidase Human genes 0.000 description 1
- 101710132836 Membrane primary amine oxidase Proteins 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 1
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 1
- 206010057269 Mucoepidermoid carcinoma Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 101100136062 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) PE10 gene Proteins 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000007792 Orbital Pseudotumor Diseases 0.000 description 1
- 208000035452 Orbital pseudotumour Diseases 0.000 description 1
- 208000017678 Ota naevus Diseases 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 101150014691 PPARA gene Proteins 0.000 description 1
- 208000034038 Pathologic Neovascularization Diseases 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108010058864 Phospholipases A2 Proteins 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 230000021839 RNA stabilization Effects 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 238000011530 RNeasy Mini Kit Methods 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000034541 Rare lymphatic malformation Diseases 0.000 description 1
- 208000016624 Retinal neoplasm Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 206010038934 Retinopathy proliferative Diseases 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 241000669326 Selenaspidus articulatus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 208000002847 Surgical Wound Diseases 0.000 description 1
- 201000005969 Uveal melanoma Diseases 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 210000002534 adenoid Anatomy 0.000 description 1
- 208000002517 adenoid cystic carcinoma Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 108010081667 aflibercept Proteins 0.000 description 1
- 208000038018 age-related macular disease Diseases 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 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
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000002137 anti-vascular effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 208000021780 appendiceal neoplasm Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 208000027439 benign eyelid neoplasm Diseases 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 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 1
- PRYZSLKPMFOUNL-MHIBGBBJSA-N bevasiranib Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2CO)N2C3=NC=NC(N)=C3N=C2)O)N2C(N=C(N)C=C2)=O)O)N2C(N=C(N)C=C2)=O)O)N2C(NC(=O)C=C2)=O)O)N2C(N=C(N)C=C2)=O)O)N2C3=NC=NC(N)=C3N=C2)O)N2C(N=C(N)C=C2)=O)O)N2C(N=C(N)C=C2)=O)O)N2C3=NC=NC(N)=C3N=C2)O)N2C3=NC=NC(N)=C3N=C2)O)N2C3=C(C(NC(N)=N3)=O)N=C2)O)N2C3=C(C(NC(N)=N3)=O)N=C2)O)N2C(N=C(N)C=C2)=O)O)N2C(N=C(N)C=C2)=O)O)N2C3=NC=NC(N)=C3N=C2)O)N2C3=C(C(NC(N)=N3)=O)N=C2)O)N2C(N=C(N)C=C2)=O)O)N2C3=NC=NC(N)=C3N=C2)O)N2C(N=C(N)C=C2)=O)O)[C@@H](O)C1 PRYZSLKPMFOUNL-MHIBGBBJSA-N 0.000 description 1
- 229950006615 bevasiranib Drugs 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 235000019577 caloric intake Nutrition 0.000 description 1
- 208000001969 capillary hemangioma Diseases 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- WNRZHQBJSXRYJK-UHFFFAOYSA-N carboxyamidotriazole Chemical compound NC1=C(C(=O)N)N=NN1CC(C=C1Cl)=CC(Cl)=C1C(=O)C1=CC=C(Cl)C=C1 WNRZHQBJSXRYJK-UHFFFAOYSA-N 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 201000002588 choroid cancer Diseases 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000001609 comparable effect Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000006059 cover glass Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 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 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007159 enucleation Effects 0.000 description 1
- 208000017338 epidermoid cysts Diseases 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 206010015831 extraocular retinoblastoma Diseases 0.000 description 1
- 208000026043 eyelid cancer Diseases 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical class O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000003633 gene expression assay Methods 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000011544 gradient gel Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 230000003118 histopathologic effect Effects 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 102000058223 human VEGFA Human genes 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229940027941 immunoglobulin g Drugs 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- UHEBDUAFKQHUBV-UHFFFAOYSA-N jspy-st000261 Chemical compound C1=CC=C2C3=C(C(=O)NC4)C4=C(C=4C(=CC=C(C=4)COC(C)C)N4CCCOC(=O)CN(C)C)C4=C3CC2=C1 UHEBDUAFKQHUBV-UHFFFAOYSA-N 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 229960004488 linolenic acid Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 235000010598 long-chain omega-6 fatty acid Nutrition 0.000 description 1
- 235000020978 long-chain polyunsaturated fatty acids Nutrition 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229940076783 lucentis Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 201000002576 malignant conjunctival melanoma Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000002406 microsurgery Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 238000002552 multiple reaction monitoring Methods 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 208000004942 nevus of Ota Diseases 0.000 description 1
- 229940080607 nexavar Drugs 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 230000035764 nutrition 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
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 208000027500 optic nerve neoplasm Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 208000025303 orbit neoplasm Diseases 0.000 description 1
- 201000000890 orbital cancer Diseases 0.000 description 1
- 201000010668 orbital plasma cell granuloma Diseases 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 208000008798 osteoma Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- YIYBQIKDCADOSF-UHFFFAOYSA-N pent-2-enoic acid Chemical compound CCC=CC(O)=O YIYBQIKDCADOSF-UHFFFAOYSA-N 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000003873 peroxisome proliferator activated receptor gamma antagonist Substances 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920003207 poly(ethylene-2,6-naphthalate) Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 239000011112 polyethylene naphthalate Substances 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001023 pro-angiogenic effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000001210 retinal vessel Anatomy 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 235000020807 short-term diet Nutrition 0.000 description 1
- 238000001877 single-ion monitoring Methods 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 239000008181 tonicity modifier Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 239000003656 tris buffered saline Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 201000011531 vascular cancer Diseases 0.000 description 1
- 206010055031 vascular neoplasm Diseases 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 229950000578 vatalanib Drugs 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- LLDWLPRYLVPDTG-UHFFFAOYSA-N vatalanib succinate Chemical compound OC(=O)CCC(O)=O.C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 LLDWLPRYLVPDTG-UHFFFAOYSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—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
- A61K31/202—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 having three or more double bonds, e.g. linolenic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
- A61P35/00—Antineoplastic 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
-
- 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
-
- 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
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- 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
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Ophthalmology & Optometry (AREA)
- Rheumatology (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Urology & Nephrology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、国立衛生研究所が付与したGrantNos.R01EY022084−01/S1、T32EY007145及びP30EY014104の下、政府の支援で行われた。政府は、本発明に特定の権利を持つ。
いくつかの実施形態における疾患は、癌である。
いくつかの実施形態における疾患は、癌、卒中または関節炎である。
治療方法。
加齢性黄斑変性
血管透過性
炎症
ω−3LCPUFAのエポキシメタボライト。
栄養学的AMD治療2(NAT2)は、特に、DHAサプリメントと、CNVの病的進展におけるそれの役割を査定した。この二重盲検で、ランダムな、平行比較トライアルでは、一つの眼球内に血管新生AMDを有する患者が、3年に渡って経口DHAまたはプラセボの投与を受け、そして被験眼球におけるCNV発生時期の査定を受けた(Souied et al.,OPHTHA,120(8):1619−1631(2013))。高EPAプラスDHAレベルを受けた患者では、その3年間、CNV進展に関して有意な減少(−68%)があることが観察された。これらのデータは、これらの分子が強力な抗血管新生特性を持つことを示す。網膜LCPUFA組織の状態は食餌摂取に依存し、また、西洋型の食事ではω−3LCPUFA摂取量が比較的に低いことを考慮して、本発明者は、これらの栄養分が、血管新生AMDに対する合理的な治療的処置になると仮定した。
組合せ治療、抗VEGF剤
物質及び方法
マウス。本研究は、視力及び眼科学研究協会の眼科視力研究における動物の使用規範に従い、また、マサチューセッツ目耳診療所の動物ケア委員会の承認を受けて行われた。生後6週目の雄C57BL/6マウス(ストック番号000664)を、ジャクソン実験室から取得した。Cx3cr1GFP/+マウス(ストック番号005582)を、ジャクソン実験室から取得した。このマウスは、特に単核細胞、樹状細胞及び小膠細胞内に緑色蛍光タンパク質(GFP)を発現させるものである。C57BL/6マウスと同じ食餌を投与した。
フルオレセイン・アンジオグラフィー。レーザー光凝固後5日及び7日に、カメラ及びイメージング・システム(TRC50VTカメラ及びIMAGEnet1.53システム、トプコン)で、フルオレセイン・アンジオグラフィーを実行した。写真は、0.1mLの2%フルオレセインナトリウム(Akorn)を腹腔内注射後、眼底カメラ・レンズに接触した20−ジオプトリー・レンズでキャプチャした。レーザー光凝固またはアンジオグラフィーには関わらなかった2人の網膜専門医(J.S.及びD.G.V)が、覆面方式で、1回の作業として蛍光血管造影図を評価した。病変は、予め既定したスキームに従って、以下の通りに等級分けした。0(漏れない)、漏出のない、かすかな過蛍光か、まだら蛍光。1(疑わしい漏出)、サイズまたは強度に漸進的増加がない過蛍光病変。2A(漏れやすい)、サイズではなく強度が増加している過蛍光。2B(臨床的に有意な漏出)、強度及びサイズにおいて増加している過蛍光42。
CYPエイコサノイド及び脂肪酸分析。ω−6及びω−3LCPUFAを与えたマウスから、CNV誘発後7日に、組織及び血清サンプルを採集し、前述したCYP−エイコサノイド・プロフィールのLC−MS/MS分析のために準備した28。手短に、サンプルを、内部標準(カイマン・ケミカルからの、20−HETE−d6、14,15−EET−d8及び14,15−DHETE−d11の各々10ng)と混合し、アルカリ加水分解させてから、アジレント・ボンド溶出認証IIコラムを使用して、メタボライトの固相抽出を行った。メタボライトは、水性蟻酸(0.1%)及びアセトニトリルの溶媒系を使用して、Phenomenex Kinetex−C18コラム(2.6μm、2.1x150mm)上のアジレント1200HPLCシステムで分析した。勾配溶離を、5%のアセトニトリルで開始し、10分以内に90%へ増加し、10分間そこに維持した。流速は、0.3mL/分に設定した。HPLCは、エレクトロスプレー・イオン化源を持つアジレント6460三連四重質量スペクトロメータに結合した。CYPエイコサノイドの分析は、ネガティブ・モードにある多重反応モニタリングで、前述の通り実行した28。結果は、アジレント質量ハンター・ソフトウェアを使用して計算した。メタボライト濃度は、ローリー法で測定されるままの、血清に対するng/mLで、また、網膜タンパク質に対するng/mgで示す。
[実施例1]ω−3長鎖多価不飽和脂肪酸のチトクロームP450依存エポキシメタボライトは、脈絡膜新生血管の溶解を促進する。
[実施例2]ω−3あるいはω−6LCPUFA食餌を与えたマウスにおける、LC−MS/MSによって有意に規制されたCYPメタボライトの識別。
[実施例3]ω−3LCPUFA由来のチトクロームP450脂質メタボライトは、CNV病変サイズを減少させる。
[実施例4]PPARγ発現及び活性は、ω−3LCPUFAを与えたマウスで上昇する。
[実施例5]ω−3LCPUFA食餌摂取は、CNV病変におけるICAM−1及びE−セレクチン発現を抑制する。
[実施例6]内皮細胞へのICAM−1と白血球表面へのICAM−1リガンドの両方の機能的な下方制御は、ω−3LCPUFA摂取によって仲介される。
[実施例7]ω−3LCPUFAを与えたマウスにおけるCNV病変の脈絡膜及び網膜内では、Cx3Cr1陽性細胞の侵入が抑制される。
[実施例8]ω−3LCPUFA食餌は、網膜及び脈絡膜内のVEGF発現を抑制する。
[実施例9]メタボライトによるサプリメントは、炎症を減少させる。
参考文献。
2.Zhang,K.,Zhang,L.&Weinreb,R.N.Ophthalmic drug discovery:novel targets and mechanisms for retinal diseases and glaucoma.Nat.Rev.Drug Discov.11,541−559(2012)(眼科薬剤の発見:網膜疾患及び緑内障の新規標的及びメカニズム)。
3.Friedman,D.S. et al.Prevalence of age−related macular degeneration in the United States.Arch.Ophthalmol.122,564−572(2004)(合衆国における加齢性黄斑変性の流行)。
4.SanGiovanni,J.P. et al.The relationship of dietary lipid intake and age−related macular degeneration in a case−control study:AREDS Report No.20.Arch.Ophthalmol.125,671−679(2007)(症例コントロール研究における食餌脂質摂取量と加齢性黄斑変性の関係)。
5.SanGiovanni,J.P. et al.The relationship of dietary omega−3 long−chain polyunsaturated fatty acid intake with incident age−related macular degeneration:AREDS report no.23.Arch.Ophthalmol.126,1274−1279(2008)(食餌のオメガ−3長鎖不飽和脂肪酸摂取と加齢性黄斑変性発症の関係)。
6.Chew,E.Y.Fatty acids and retinopathy.N.Engl.J.Med.364,1970−1971(2011)(脂肪酸と網膜疾患)。
7.Sangiovanni,J.P. et al.ω−3Long−chain polyunsaturated fatty acid intake and 12−y incidence of neovascular age−related macular degeneration and central geographic atrophy:AREDS report30,a prospective cohort study from the Age−Related Eye Disease Study.Am.J.Clin.Nutr.90,1601−1607(2009)(ω−3長鎖不飽和脂肪酸摂取と血管新生加齢性黄斑変性の12−y発生、及び中央地図状萎縮:加齢性眼疾患試験からの前向きコホート試験)。
8.Bhutto,I.&Lutty,G.Understanding age−related macular degeneration(AMD):relationships between the photoreceptor/retinal pigment epithelium/Bruch’s membrane/choriocapillaris complex.Mol.Aspects Med.33,295−317(2012)(加齢性黄斑変性(AMD)の理解:光レセプター/網膜色素上皮/ブルッフ膜/脈絡毛細管複合体の関係)。
9.Guyer,D.R. et al.Subfoveal choroidal neovascular membranes in age−related macular degeneration.Visual prognosis in eyes with relatively good initial visual acuity.Arch.Ophthalmol.104,702−705(1986)(加齢性黄斑変性の中心窩下脈絡膜血管新生膜。比較的に良い初期視力を有する眼の視覚予測)。
10.Wang,L. et al.Abundant lipid and protein components of drusen.PLoSOne.5,e10329(2010)(ドルーゼンの大量な脂質及びタンパク質要素)。
11.Curcio,C.A.,Rudolf,M.&Wang,L.Histochemistry and lipid profiling combine for insights into aging and age−related maculopathy.Methods Mol.Biol.580,267−281(2009)(組織化学と脂質プロファイリングとの組合せが、エージングと加齢性黄斑症への洞察をもたらす)。
12.Wong,T.Y. et al.Prevalence and causes of low vision and blindness in an urban Malay population:the Singapore Malay Eye Study.Arch.Ophthalmol.126,1091−1099(2008)(マレー半島都市部に住む人々の低視力及び失明の罹患及び原因:シンガポール・マレー眼研究)。
13.Gragoudas,E.S.,Adamis,A.P.,Cunningham,E.T.,Jr.,Feinsod,M.&Guyer,D.R.Pegaptanib for neovascular age−related macular degeneration.N.Engl.J.Med.351,2805−2816(2004)(血管新生加齢性黄斑変性に対するペガプタニブ)。
14.Ng,E.W.&Adamis,A.P.Anti−VEGF aptamer (pegaptanib) therapy for ocular vascular diseases.Ann.N.Y.Acad.Sci.1082,151−171(2006)(眼球血管疾患に対する抗VEGFアプタマー(ペガプタニブ)療法)。
15.Rosenfeld,P.J. et al.Ranibizumab for neovascular age−related macular degeneration.N.Engl.J.Med.355,1419−1431(2006)(血管新生加齢性黄斑変性に対するラニビズマブ)。
16.Sapieha,P. et al.5−Lipoxygenase metabolite4−HDHA is a mediator of the antiangiogenic effect of omega−3 polyunsaturated fatty acids.Sci.Transl.Med.3,69ra12(2011)(5−リポキシゲナーゼ・メタボライト4−HDHAは、オメガ−3多価不飽和脂肪酸の抗血管新生効果のメディエーターである)。
17.Connor,K.M. et al.Increased dietary intake of omega−3−polyunsaturated fatty acids reduces pathological retinal angiogenesis.Nat.Med.13,868−873(2007)(オメガ−3−多価不飽和脂肪酸の食餌摂取の増加が、病的網膜血管形成を減少させる)。
18.Bazan,N.G.Homeostatic regulation of photoreceptor cell integrity:significance of the potent mediator neuroprotectin D1 biosynthesized from docosahexaenoic acid:the Proctor Lecture.Invest.Ophthalmol.Vis.Sci.48,4866−4881(2007)(光受容細胞健全性のホメオスタシス規制:ドコサヘキサエン酸から生合成した強力なメディエーター・ニューロプロテクチンD1の有意性)。
19.Stahl,A. et al.Short communication:PPAR gamma mediates a direct antiangiogenic effect of omega3−PUFAs in proliferative retinopathy.Circ.Res.107,495−500(2010)(コミュニケーションの短絡:PPARガンマは、増殖網膜疾患におけるオメガ3−PUFAの直接的な抗血管新生効果を媒介する)。
20.Kang,J.X. et al.The role of the tissure omega6/omega−3 fatty acid ratio in regulating tumor angiogenesis.Cancer Metast.Rev.In press (腫瘍血管形成を規制する組織オメガ6/オメガ−3脂肪酸の比率の役割)。
21.Sheets K.G. et al.Neuroprotectin D1 attenuates laser−induced choroidal neovascularization in mouse.Mol Vis.16,320−329(2010)(ニューロプロテクチンD1は、マウスでレーザー誘発された脈絡膜血管新生を減衰させる)。
22.SanGiovanni,J.P.&Chew,E.Y.The role of omega−3 long−chain polyunsaturated fatty acids in health and disease of the retina.Prog.Retin.Eye Res.24,87−138(2005)(網膜の健康及び疾患におけるオメガ−3長鎖不飽和脂肪酸の役割)。
23.Montezuma,S.R.,Vavvas,D.&Miller,J.W.Review of the ocular angiogenesis animal models.Semin.Ophthalmol.24,52−61(2009)(眼球血管形成動物モデルのレビュー)。
24.Afzal,A. et al.Targeting retinal and choroid neovascularization using the small molecule inhibitor carboxyamidotriazole.Brain Res.Bull.81,320−326(2010)(小型分子阻害剤カルボキシアミドトリアゾールを使用して、網膜及び脈絡膜血管新生を標的とする)。
25.Giani,A. et al.Spectral−domain optical coherence tomography as an indicator of fluorescein angiography leakage from choroidal neovascularization.Invest.Ophthalmol.Vis.Sci.52,5579−5586(2011)(脈絡膜血管新生からのフルオレセイン・アンジオグラフィー漏出の指標としてのスペクトル・ドメイン光干渉断層法)。
26.Sulzbacher,F. et al.Correlation of SD−OCT features and retinal sensitivity in neovascular age−related macular degeneration.Invest.Ophthalmol.Vis.Sci.53,6448−6455(2012)(血管新生加齢性黄斑変性におけるSD−OCT機能と網膜感度の相関関係)。
27.Arnold,C.,Konkel,A.,Fischer,R.&Schunck,W.H.Cytochrome P450−dependent metabolism of omega−6 and omega−3 long−chain polyunsaturated fatty acids.Pharmacol.Rep.62,536−547(2010)(オメガ−6及びオメガ−3長鎖不飽和脂肪酸のチトクロームP450依存代謝)。
28.Arnold,C. et al.Arachidonic acid−metabolizing cytochrome P450 enzymes are targets of ω−3 fatty acids.J.Biol.Chem.285,32720−32733(2010)(アラキドン酸代謝チトクロームP450酵素は、ω−3脂肪酸の標的である)。
29.Konkel,A.&Schunck,W.H.Role of cytochromeP450enzymesinthebioactivation of polyunsaturated fatty acids.Biochim.Biophys.Acta1814,210−222(2011)(多価不飽和脂肪酸の生理活性におけるチトクロームP450酵素の役割)。
30.Serhan,C.N.&Devchand,P.R.Novel antiinflammatory targets for asthma.A role for PPARgamma?Am.J.Respir.Cell Mol.Biol.24,658−661(2001)(喘息のための新規消炎性標的。PPARガンマの役割?)。
31.Ambati,J.&Fowler,B.J.Mechanisms of age−related macular degeneration.Neuron75,26−39(2012)(加齢性黄斑変性のメカニズム)。
32.Noda,K. et al.Vascular adhesion protein−1 blockade suppresses choroidal neovascularization.FASEBJ.22,2928−2935(2008)(血管付着タンパク質−1封鎖は、脈絡膜血管新生を抑制する)。
33.Almulki,L. et al.Surprising up−regulation of P−selectin glycoprotein ligand−1(PSGL−1) in endotoxin−induced uveitis.FASEBJ.23,929−939(2009)(エンドトキシンによって誘発されたブドウ膜炎におけるP−セレクチン・グリコプロテイン・リガンド−1(PSGL−1)の驚くべき上方制御)。
34.Cherepanoff,S.,McMenamin,P.,Gillies,M.C.,Kettle,E.&Sarks,S.H.Bruch’s membrane and choroidal macrophages in early and advanced age−related macular degeneration.Br.J.Ophthalmol.94,918−925(2010)(初期型及び進行型加齢性黄斑変性におけるブルック膜及び脈絡膜マクロファージ)。
35.Zarbin,M.A.Current concepts in the pathogenesis of age−related macular degeneration.Arch.Ophthalmol.122,598−614(2004)(加齢性黄斑変性発病の最新概念)。
36.Ishida,S. et al.Leukocytes mediate retinal vascular remodeling during development and vaso−obliteration in disease.Nat.Med.9,781−788(2003)(白血球は、疾患の進行及び脈管遮断中の、網膜血管リモデリングを媒介する)。
37.Daviglus,M.L. et al.Fish consumption and the 30−year risk of fatal myocardial infarction.N Engl J Med.336,1046−1053(1997)(魚の消費と、致命的な心筋梗塞の30年リスク)。
38.Berson,E.L.,Rosner,B.,Sandberg,M.A.,Weigel−DiFranco,C.&Willett,W.C.ω−3 intake and visual acuity in patients with retinitis pigmentosa receiving vitamin A.Arch.Ophthalmol.130,707−711(2012)(ビタミンAを受ける色素性網膜炎患者におけるω−3摂取及び視力)。
39.Miles,E.A.&Calder,P.C.Influence of marine n−3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis.Br.J.Nutr.107(suppl.2),S171−S184(2012)(免疫機能へのマリーンn−3多価不飽和脂肪酸の影響と、それらの、リウマチ様関節炎における臨床結果に対する影響の系統的なレビュー)。
40.Simopoulos AP.Omega−3 fatty acids in inflammation and autoimmune diseases.J Am.Coll.Nutr.21,495−505(2002)(炎症及び自己免疫疾患におけるオメガ−3脂肪酸)。
41.Nakai,K. et al.Dendritic cells augment choroidal neovascularization.Invest.Ophthalmol.Vis.Sci.49,3666−3670(2008)(樹状細胞は脈絡膜血管新生を増大させる)。
42.Marneros,A.G.Endogenous endostatin inhibits choroidal neovascularization.FASEB J.21,3809−3818(2007)(内在性エンドスタチンは、脈絡膜血管新生を阻止する)。
43.Hafezi−Moghadam,A.,Thomas,K.L.&Cornelssen,C.A novel mouse−driven ex vivo flow chamber for the study of leukocyte and platelet function.Am.J.Physiol.Cell Physiol.286,C876−C892(2004)(白血球及び血小板機能の試験のための、新規なマウス駆動生体外フローチャンバー)。
他の実施形態。
また、本発明は以下を提供する。
[1] 対象者における血管新生に関連する疾患の治療方法あるいはリスクの減少方法であって、ドコサヘキサエン酸(DHA)またはエイコサペンタエン酸(EPA)の一つ以上のエポキシメタボライトと医薬的に許容可能な担体を含む医薬組成物を治療的に有効な量で、それを必要とする対象者へ投与することを含む、前記方法。
[2] 対象者における血管新生に関連する疾患の治療方法への、ドコサヘキサエン酸(DHA)及びエイコサペンタエン酸(EPA)のエポキシメタボライトの使用。
[3] 前記治療が血管後退に至る、[1]の方法または[2]の使用。
[4] 前記疾患が、血管新生に関連する眼の疾患である、[1]の方法または[2]の使用。
[5] 前記眼の疾患が、角膜、網膜、脈絡膜、ブドウ膜あるいは虹彩の血管新生に関連する、[3]の方法または使用。
[6] 前記血管新生に関連する眼の疾患が加齢性黄斑変性である、[5]の方法または使用。
[7] 前記血管新生に関連する眼の疾患がシュタルガルト病である、[5]の方法または使用。
[8] 前記血管新生に関連する眼の疾患が網膜疾患である、[5]の方法または使用。
[9] 前記網膜疾患が、未熟児網膜症(ROP)、糖尿病性網膜症、網膜静脈閉塞症、鎌状赤血球網膜症及び放射線網膜症からなる群から選択される、[8]の方法または使用。
[10] 前記投与が、眼球への局所投与、すなわち非経口投与である、[4]の方法または使用。
[11] 前記投与が、角膜、網膜、ガラス体液、葡萄膜、眼球孔、眼瞼、結膜または虹彩への、あるいは、その近くへの局所注入による、[10]の方法または使用。
[12] 前記疾患が癌である、[1]の方法または[2]の使用。
[13] 対象者における炎症に関連する疾患の治療方法あるいはリスクの減少方法であって、ω−3LCPUFAの一つ以上のエポキシメタボライトと医薬的に許容可能な担体を含む医薬組成物を、治療的に有効な量で投与することを含む、前記方法。
[14] 対象者における炎症に関連する疾患の治療方法への、ドコサヘキサエン酸(DHA)及びエイコサペンタエン酸(EPA)のエポキシメタボライトの使用。
[15] 前記疾患が関節炎である、[13]の方法または[14]の使用。
[16] 対象者における血管からの漏れに関連する疾患の治療方法あるいはリスクの減少方法であって、ω−3LCPUFAの一つ以上のエポキシメタボライトと医薬的に許容可能な担体を含む医薬組成物を、治療的に有効な量で投与することを含む、前記方法。
[17] 対象者における血管からの漏れに関連する疾患の治療方法への、ドコサヘキサエン酸(DHA)及びエイコサペンタエン酸(EPA)のエポキシメタボライトの使用。
[18] 前記疾患が卒中である、[16]の方法または[17]の使用。
[19] 前記ω−3LCPUFAの一つ以上のエポキシメタボライトが、表Aにリストされている、[1]、[2]、[13]、[14]、[16]または[17]のいずれかの方法または使用。
[20] 前記組成物が、ω−3LCPUFAを含み、17,18−EEQ及び/または19,20−EDPである、[1]、[2]、[13]、[14]、[16]または[17]のいずれかの方法または使用。
[21] 前記17,18−EEQ及び/または19,20−EDPが実質的に精製される、[20]の方法または使用。
[22] 前記ω−3LCPUFAの一つ以上のエポキシメタボライトが、表Aにリストされている、[3]から[12]、[15]または[18]のいずれかの方法または使用。
[23] 前記組成物が、ω−3LCPUFAを含み、17,18−EEQ及び/または19,20−EDPである、[3]から[12]、[15]または[18]のいずれかの方法または使用。
[24] 前記17,18−EEQ及び/または19,20−EDPが実質的に精製される、[23]の方法または使用。
Claims (14)
- 17,18−EEQおよび/または19,20−EDPを含む、対象者における血管新生の抑制あるいは血管新生のリスクの減少のための医薬組成物。
- 血管後退を生じさせる、請求項1に記載の組成物。
- 前記対象者が、血管新生に関連する眼の疾患を有する、請求項1または2に記載の組成物。
- 前記眼の疾患が、角膜、網膜、脈絡膜、ブドウ膜あるいは虹彩の血管新生に関連する、請求項3に記載の組成物。
- 前記血管新生に関連する眼の疾患が加齢性黄斑変性である、請求項3に記載の組成物。
- 前記血管新生に関連する眼の疾患がシュタルガルト病である、請求項3に記載の組成物。
- 前記血管新生に関連する眼の疾患が網膜疾患である、請求項3に記載の組成物。
- 前記網膜疾患が、未熟児網膜症(ROP)、糖尿病性網膜症、網膜静脈閉塞症、鎌状赤血球網膜症及び放射線網膜症からなる群から選択される、請求項7に記載の組成物。
- 眼球への局所投与または非経口投与のための、請求項3に記載の組成物。
- 角膜、網膜、ガラス体液、ブドウ膜、眼球孔、眼瞼、結膜または虹彩への、あるいは、その近くへの局所注入のための、請求項9に記載の組成物。
- 19,20−EDPを含む、癌の治療のための医薬組成物。
- 17,18−EEQおよび/または19,20−EDPを含む、関節炎の治療のための医薬組成物。
- 17,18−EEQおよび/または19,20−EDPを含む、対象者における血管透過性の減少あるいは血管透過性上昇のリスクの減少のための医薬組成物。
- 17,18−EEQおよび/または19,20−EDPを含む、血管透過性上昇に関連する卒中の治療のための医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361751617P | 2013-01-11 | 2013-01-11 | |
US61/751,617 | 2013-01-11 | ||
PCT/US2014/010880 WO2014110261A1 (en) | 2013-01-11 | 2014-01-09 | Cyp450 lipid metabolites reduce inflammation and angiogenesis |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2016505016A JP2016505016A (ja) | 2016-02-18 |
JP2016505016A5 JP2016505016A5 (ja) | 2018-05-10 |
JP6526570B2 true JP6526570B2 (ja) | 2019-06-12 |
Family
ID=51167370
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015552772A Active JP6526570B2 (ja) | 2013-01-11 | 2014-01-09 | 炎症及び血管形成を減少させるcyp450脂質メタボライト |
Country Status (6)
Country | Link |
---|---|
US (2) | US9770426B2 (ja) |
EP (1) | EP2943190B1 (ja) |
JP (1) | JP6526570B2 (ja) |
AU (1) | AU2014205369B2 (ja) |
CA (1) | CA2930987A1 (ja) |
WO (1) | WO2014110261A1 (ja) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK2755647T3 (en) | 2011-09-12 | 2015-10-12 | Tassos Georgiou | Use of omega fatty acid for medical care |
AU2016356767A1 (en) * | 2015-11-17 | 2018-06-07 | Massachusetts Eye And Ear Infirmary | Stable analogs of CYP450 lipid metabolites and inhibitors of soluble epoxide hydrolase |
US20180228764A1 (en) * | 2017-02-13 | 2018-08-16 | Indiana University Research And Technology Corporation | Soluble epoxide hydrolase as a target for ocular neovascularization |
CA3136137A1 (en) * | 2019-04-04 | 2020-10-08 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Very-long-chain polyunsaturated fatty acids, elovanoid hydroxylated derivatives, and methods of use |
WO2024010896A1 (en) * | 2022-07-08 | 2024-01-11 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Very-long-chain polyunsaturated fatty acids (vlcpufa) for improving retina/cognitive functions and atherosclerosis |
WO2024044666A2 (en) * | 2022-08-24 | 2024-02-29 | University Of Oregon | Methods of increasing mesenchymal stromal cell biosynthesis of specialized pro-resolving mediators and methods of use |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
US5858784A (en) | 1991-12-17 | 1999-01-12 | The Regents Of The University Of California | Expression of cloned genes in the lung by aerosol- and liposome-based delivery |
JPH05286956A (ja) * | 1992-04-06 | 1993-11-02 | Nippon Suisan Kaisha Ltd | ドコサペンタエン酸モノエポキシ体、及びその製造法 |
DK0666868T4 (da) | 1992-10-28 | 2006-09-18 | Genentech Inc | Anvendelse af anti-VEGF-antistoffer til behandling af cancer |
ES2230542T3 (es) | 1993-03-25 | 2005-05-01 | MERCK & CO., INC. | Inhibidor del factor de crecimiento celular endotelial vascular. |
US6811779B2 (en) | 1994-02-10 | 2004-11-02 | Imclone Systems Incorporated | Methods for reducing tumor growth with VEGF receptor antibody combined with radiation and chemotherapy |
JP3957765B2 (ja) | 1997-04-07 | 2007-08-15 | ジェネンテク・インコーポレイテッド | 抗vegf抗体 |
US20020032315A1 (en) | 1997-08-06 | 2002-03-14 | Manuel Baca | Anti-vegf antibodies |
NZ514918A (en) | 1999-04-28 | 2003-11-28 | Univ Texas | Compositions and methods for cancer treatment by selectively inhibiting VEGF |
US7582785B2 (en) | 2002-04-01 | 2009-09-01 | University Of Southern California | Trihydroxy polyunsaturated eicosanoid derivatives |
WO2004065417A2 (en) | 2003-01-23 | 2004-08-05 | Genentech, Inc. | Methods for producing humanized antibodies and improving yield of antibodies or antigen binding fragments in cell culture |
EP1629010A1 (en) | 2003-05-30 | 2006-03-01 | Genentech, Inc. | Treatment with anti-vegf antibodies |
BRPI0516803A (pt) * | 2004-11-19 | 2008-09-23 | Martek Biosciences Corp | oxilipinas de ácidos graxos polinsaturados de cadeia longa e métodos de produção e uso dos mesmos |
JP5909183B2 (ja) * | 2010-08-19 | 2016-04-26 | 国立大学法人 東京大学 | オメガ3系脂肪酸由来の新規抗炎症性代謝物 |
DK2755647T3 (en) | 2011-09-12 | 2015-10-12 | Tassos Georgiou | Use of omega fatty acid for medical care |
-
2014
- 2014-01-09 EP EP14737722.0A patent/EP2943190B1/en not_active Not-in-force
- 2014-01-09 CA CA2930987A patent/CA2930987A1/en not_active Abandoned
- 2014-01-09 AU AU2014205369A patent/AU2014205369B2/en not_active Ceased
- 2014-01-09 WO PCT/US2014/010880 patent/WO2014110261A1/en active Application Filing
- 2014-01-09 US US14/758,724 patent/US9770426B2/en not_active Expired - Fee Related
- 2014-01-09 JP JP2015552772A patent/JP6526570B2/ja active Active
-
2017
- 2017-08-23 US US15/684,251 patent/US10413518B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
CA2930987A1 (en) | 2014-07-17 |
US20180133187A1 (en) | 2018-05-17 |
AU2014205369A1 (en) | 2015-08-27 |
EP2943190B1 (en) | 2019-01-02 |
US10413518B2 (en) | 2019-09-17 |
US20150335603A1 (en) | 2015-11-26 |
AU2014205369B2 (en) | 2018-08-09 |
US9770426B2 (en) | 2017-09-26 |
JP2016505016A (ja) | 2016-02-18 |
EP2943190A1 (en) | 2015-11-18 |
EP2943190A4 (en) | 2016-08-31 |
WO2014110261A1 (en) | 2014-07-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6526570B2 (ja) | 炎症及び血管形成を減少させるcyp450脂質メタボライト | |
Koto et al. | Eicosapentaenoic acid is anti-inflammatory in preventing choroidal neovascularization in mice | |
Amer et al. | Exudative retinal detachment | |
Ooi et al. | Statins in ophthalmology | |
Holz et al. | Geographic atrophy: clinical features and potential therapeutic approaches | |
Cusick et al. | Histopathology and regression of retinal hard exudates in diabetic retinopathy after reduction of elevated serum lipid levels | |
Boscia | Current approaches to the management of diabetic retinopathy and diabetic macular oedema | |
Chan et al. | Sympathetic ophthalmia: immunopathological findings | |
KR20190124704A (ko) | 아포지질단백질 모방체를 이용하는, 나이 관련 황반 변성 및 기타 안질환의 치료 | |
KR101629670B1 (ko) | 질환을 치료하기 위한 오메가 지방산의 용도 | |
JP2008515778A (ja) | 眼の状態を13−シス−レチニル誘導体で処置するための組み合わせ方法、組成物および治療 | |
Kusari et al. | Effect of brimonidine on retinal and choroidal neovascularization in a mouse model of retinopathy of prematurity and laser-treated rats | |
JP2016539098A (ja) | 網膜の血管障害を治療又は予防する方法 | |
Costagliola et al. | Effect of palmitoylethanolamide on visual field damage progression in normal tension glaucoma patients: results of an open-label six-month follow-up | |
Kim et al. | Comparison between intravitreal bevacizumab and triamcinolone for macular edema secondary to branch retinal vein occlusion | |
Shah et al. | Verteporfin combination regimens in the treatment of neovascular age-related macular degeneration | |
US20170224815A1 (en) | Method of Preventing and Treating Retinal Microvasculature Inflammation Using C-Met Signaling Pathway Inhibition | |
Peters et al. | Immunohistochemical localisation of intravitreally injected bevacizumab in the anterior chamber angle, iris and ciliary body of the primate eye | |
JP2018530586A (ja) | 加齢黄斑変性のための高用量スタチン | |
Pastore et al. | Vitreous prostaglandin e2 changes after topical administration of diclofenac 0.1%, Indomethacin 0.5%, Nepafenac 0.3%, and Bromfenac 0.09% | |
Thompson et al. | Diabetic macular edema: a review of past, present, and future therapies | |
Beyazyıldız et al. | Comparison of prednisolone acetate and loteprednol etabonate for the treatment of benzalkonium chloride-induced dry eye syndrome in rats | |
AU2016356767A1 (en) | Stable analogs of CYP450 lipid metabolites and inhibitors of soluble epoxide hydrolase | |
Fathima et al. | Omega-3 Polyunsaturated Fatty Acids and Their Anti-Oxidant, Anti-Inflammatory and Neuroprotective Effects in Diabetic Retinopathy: A Narrative Review | |
Gupta et al. | Macular Oedema |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20161214 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20170912 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20171122 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180312 |
|
A524 | Written submission of copy of amendment under article 19 pct |
Free format text: JAPANESE INTERMEDIATE CODE: A524 Effective date: 20180312 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20180724 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20181016 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20181225 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20190409 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20190508 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6526570 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |