JP6559357B2 - ブチリデンフタリドの使用 - Google Patents
ブチリデンフタリドの使用 Download PDFInfo
- Publication number
- JP6559357B2 JP6559357B2 JP2018534811A JP2018534811A JP6559357B2 JP 6559357 B2 JP6559357 B2 JP 6559357B2 JP 2018534811 A JP2018534811 A JP 2018534811A JP 2018534811 A JP2018534811 A JP 2018534811A JP 6559357 B2 JP6559357 B2 JP 6559357B2
- Authority
- JP
- Japan
- Prior art keywords
- oral
- butylidenephthalide
- pharmaceutical composition
- cells
- gene
- 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
- WMBOCUXXNSOQHM-FLIBITNWSA-N (Z)-3-butylidenephthalide Chemical compound C1=CC=C2C(=C/CCC)/OC(=O)C2=C1 WMBOCUXXNSOQHM-FLIBITNWSA-N 0.000 title claims description 113
- WMBOCUXXNSOQHM-UHFFFAOYSA-N n-butylidenephthalide Natural products C1=CC=C2C(=CCCC)OC(=O)C2=C1 WMBOCUXXNSOQHM-UHFFFAOYSA-N 0.000 title claims description 112
- 210000004027 cell Anatomy 0.000 claims description 54
- 208000005207 oral submucous fibrosis Diseases 0.000 claims description 40
- 239000008194 pharmaceutical composition Substances 0.000 claims description 33
- 230000007705 epithelial mesenchymal transition Effects 0.000 claims description 26
- 210000001519 tissue Anatomy 0.000 claims description 25
- 239000004480 active ingredient Substances 0.000 claims description 20
- 210000000651 myofibroblast Anatomy 0.000 claims description 20
- 210000004876 tela submucosa Anatomy 0.000 claims description 17
- 230000008602 contraction Effects 0.000 claims description 13
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 claims description 12
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 claims description 12
- 210000002744 extracellular matrix Anatomy 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- 238000002347 injection Methods 0.000 claims description 11
- 239000007924 injection Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 230000004913 activation Effects 0.000 claims description 6
- 239000011248 coating agent Substances 0.000 claims description 6
- 230000004069 differentiation Effects 0.000 claims description 6
- 229940100688 oral solution Drugs 0.000 claims description 5
- 206010031023 Oral submucosal fibrosis Diseases 0.000 description 32
- 239000003814 drug Substances 0.000 description 25
- 108090000623 proteins and genes Proteins 0.000 description 21
- 230000014509 gene expression Effects 0.000 description 20
- 239000000499 gel Substances 0.000 description 18
- 238000000034 method Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 238000011529 RT qPCR Methods 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 210000002950 fibroblast Anatomy 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- -1 oral solution Substances 0.000 description 8
- 101150008656 COL1A1 gene Proteins 0.000 description 7
- 102000008186 Collagen Human genes 0.000 description 7
- 108010035532 Collagen Proteins 0.000 description 7
- 241000237858 Gastropoda Species 0.000 description 7
- 229920001436 collagen Polymers 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 206010016654 Fibrosis Diseases 0.000 description 6
- 230000012292 cell migration Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 230000004761 fibrosis Effects 0.000 description 6
- 108020004635 Complementary DNA Proteins 0.000 description 5
- 101150056859 S100a4 gene Proteins 0.000 description 5
- 101150074545 Zeb1 gene Proteins 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 5
- 238000010804 cDNA synthesis Methods 0.000 description 5
- 239000002299 complementary DNA Substances 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000004417 polycarbonate Substances 0.000 description 5
- 229920000515 polycarbonate Polymers 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- HJJPJSXJAXAIPN-UHFFFAOYSA-N arecoline Chemical compound COC(=O)C1=CCCN(C)C1 HJJPJSXJAXAIPN-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000785626 Homo sapiens Zinc finger E-box-binding homeobox 1 Proteins 0.000 description 3
- 208000003445 Mouth Neoplasms Diseases 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 210000005178 buccal mucosa Anatomy 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002430 laser surgery Methods 0.000 description 3
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000010232 migration assay Methods 0.000 description 3
- 210000004400 mucous membrane Anatomy 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- HYOAGWAIGJXNQH-UHFFFAOYSA-N 1-bromo-1-chloropropane Chemical compound CCC(Cl)Br HYOAGWAIGJXNQH-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- FFYPMLJYZAEMQB-UHFFFAOYSA-N diethyl pyrocarbonate Chemical compound CCOC(=O)OC(=O)OCC FFYPMLJYZAEMQB-UHFFFAOYSA-N 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 210000002396 uvula Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- IOAOAKDONABGPZ-UHFFFAOYSA-N 2-amino-2-ethylpropane-1,3-diol Chemical class CCC(N)(CO)CO IOAOAKDONABGPZ-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 235000006226 Areca catechu Nutrition 0.000 description 1
- 244000080767 Areca catechu Species 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- HWBUGWQMVYGLBC-UHFFFAOYSA-N C(CCC)=C1C(C(C(=O)O)=CC=C1)C(=O)O Chemical compound C(CCC)=C1C(C(C(=O)O)=CC=C1)C(=O)O HWBUGWQMVYGLBC-UHFFFAOYSA-N 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 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
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010061324 Oral fungal infection Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000006994 Precancerous Conditions Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 1
- 229920002472 Starch Polymers 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
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 102100026457 Zinc finger E-box-binding homeobox 1 Human genes 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 125000000637 arginyl group Chemical class N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 159000000009 barium salts Chemical class 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 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
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012459 cleaning agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001868 cobalt Chemical class 0.000 description 1
- 239000000512 collagen gel Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000431 effect on proliferation Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 125000000487 histidyl group Chemical class [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 235000021268 hot food Nutrition 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 230000003165 hydrotropic effect Effects 0.000 description 1
- 239000003230 hygroscopic agent Substances 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 108010004788 integrin alphavbeta6 Proteins 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000004784 molecular pathogenesis Effects 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 201000002740 oral squamous cell carcinoma Diseases 0.000 description 1
- 210000003300 oropharynx Anatomy 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 210000003254 palate Anatomy 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 235000019613 sensory perceptions of taste Nutrition 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 210000001584 soft palate Anatomy 0.000 description 1
- 235000021259 spicy food Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000035923 taste sensation Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 150000003608 titanium Chemical class 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 150000003681 vanadium Chemical class 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000016776 visual perception Effects 0.000 description 1
- 230000010388 wound contraction Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- 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
- A61K9/08—Solutions
-
- 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
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Description
A.細胞培養
正常な口腔頬粘膜から得られた2つの群の頬粘膜線維芽細胞(以下、「BMF−1」および「BMF−2」と略記する、または「BMF」と総称する)および、線維性口腔頬粘膜から得られた線維性頬粘膜線維芽細胞の2つの群(以下、「fBMF−1」および「fBMF−2」と略記する、または「fBMF」と総称する)に、それぞれ以下の手順を施した。細胞を24ウェルプレートに2×104細胞/ウェルの濃度で播種し、80%コンフルエントまで細胞を培養し、次いで異なる濃度(0、12.5、25、50、100、または200μg/mL)のブチリデンフタリド(BP)で細胞を48時間、処理した。
(製造例A)で得られた各群の細胞をトリプシンで懸濁した後、以下の操作を行った。(i)遠心分離(1000rpm、5分間)を行い、上清を除去し、(ii)上清を1mLのTRIzol試薬(Invitrogen Life Technologiesから購入)と均一に混合し、得られた混合物を室温で5分間保持し、(iii)工程(ii)の生成物を100μLのBCP(ブロモクロロプロパン)と混合し、次いで均等に振盪し、室温で5分間保持し、(iv)工程(iii)の生成物を遠心分離(エッペンドルフ遠心分離機、F45−30−11ローター、4℃、12000rpm、15分間)し、次に上部液体を新しいエッペンドルフに移動させ、イソプロパノールと均一に混合し、得られた混合物を室温で5分間保持し、(v)工程(iv)の生成物を遠心分離(エッペンドルフ遠心分離機、F45−30−11ローター、4℃、12000rpm、10分間)し、上清を除去しエッペンドルフの底に沈殿したRNAを500μLの75%エタノールで洗浄し、(vi)エタノール層を除去するために遠心分離(室温、12000rpm、5分間)を行い、RNA沈殿物を乾燥させるためにエッペンドルフをフュームフードに入れ、(vii)RNA沈殿物を20μLのジエチルピロカーボネート(DEPC)処理水で溶解し、そして、得られた混合物の吸光度値を波長260nmで測定し、RNA濃度を算出した。
(製造例A)で得られた各群の細胞に対して、以下の操作を行った。(i)24ウェルプレート中の上清を除去し、次いで各ウェルに500μLの3−(4,5−ジメチルチアゾール−2−イル)−2,5−ジフェニルテトラゾリウムブロマイド(略称:MTT)緩衝液を添加し(MTTの最終濃度は0.5mg/mLである)、(ii)37℃、5%CO2のインキュベーターに3時間静置し、(iii)上清を除去し、次いで各ウェルにそれぞれ1000μLのイソプロパノールを添加し、プレートをシェーカーに置き10分間振とうし、(iv)各ウェルから溶液200μLを96ウェルプレートに移し、分光光度計を用いて波長570nmにおける吸光度値を測定し、各群の細胞の相対生存率(%)を算出した。結果を図1に示す。
A.上皮間葉移行(EMT)におけるマーカー遺伝子の発現
上皮間葉系移行(EMT)の過程で、細胞内のTwist遺伝子、Snail遺伝子、ZEB1遺伝子の発現が増加することが知られており、これらの遺伝子はEMTのマーカー遺伝子として知られている。本実験では、ブチリデンフタリド(BP)が口腔粘膜下組織細胞におけるTwist遺伝子、Snail遺伝子、およびZEB1遺伝子の発現に影響を与えるかどうかを調べるために、定量的リアルタイムポリメラーゼ連鎖反応(Q−PCR)を行った。
この実験では、トランスウェル細胞遊走アッセイシステム(Transwell(登録商標)システム、Corning社、英国、から購入)および孔径8μmのポリカーボネート膜(Corning社、英国、から購入)を用いて、ブチリデンフタリド(BP)が、口腔粘膜下組織細胞のはいながら侵攻する能力を阻害するかどうかをさらに調べた。
組織の線維化の過程において、組織細胞が分化して筋線維芽細胞となり、α−SMA遺伝子、Col1a1遺伝子、およびS100A4遺伝子が筋線維芽細胞のマーカー遺伝子であることが知られている。したがって、この実験では、ブチリデンフタリド(BP)が口腔粘膜下組織細胞におけるα−SMA遺伝子、Col1a1遺伝子およびS100A4遺伝子の発現を阻害するかどうかを調べるために定量的リアルタイムポリメラーゼ連鎖反応(Q−PCR)を行った。
(製造例A)で得られたBMF−1、BMF−2、fBMF−1、fBMF−2を2mg/mLコラーゲン溶液(Sigma-Aldrichより購入)0.5mLにそれぞれ溶解し、得られた混合物を24穴プレートに移した。次に、24ウェルプレートを37℃、5%CO2のインキュベーターに2時間入れ、コラーゲンゲルを凝固させた。このようにして得られたゲルは、それぞれ「BMFs群」および「fBMFs群」ゲルと呼ばれた。その後、凝固したゲルを培養プレートから外し、異なる濃度(0、25または50μg/mL)のブチリデンフタリド(BP)を含有する0.5mLの培地を添加して48時間ゲルとインキュベートした。各群のゲルの収縮を観察し、撮影した。最後に、各「fBMFs群」の相対ゲル面積(%)を画像解析ソフトウェアImageJ(National Institutes of Health、米国)を用いて、ブチリデンフタリド(BP)で処理されていない「BMFs群」の結果を基礎にして計算した。結果を図5Aおよび5Bに示す。図5Aは、各群の細胞によって誘発されたゲル収縮を示し、図5Bは、各群の相対ゲル面積(%)を示す。
Claims (7)
- 有効量の有効成分および薬学的に許容される担体を含み、前記有効成分が、ブチリデンフタリド(BP)、ブチリデンフタリドの薬学的に許容される塩、およびそれらの組み合わせからなる群から選択される、口腔粘膜下線維症(OSF)の予防および/または治療用の医薬組成物。
- 経口粘膜下組織細胞の上皮−間葉移行(EMT)を阻害する、請求項1に記載の医薬組成物。
- 口腔粘膜下組織細胞の這いながら侵攻する能力を阻害する、請求項1または2に記載の医薬組成物。
- 経口粘膜下組織細胞が筋線維芽細胞に分化することを阻害する、請求項1に記載の医薬組成物。
- 筋線維芽細胞の活性化を阻害する、請求項1に記載の医薬組成物。
- 経口粘膜下組織における細胞外マトリックスの収縮を阻害する、請求項1〜5のいずれか1項に記載の医薬組成物。
- 注射剤、錠剤、経口液剤、または塗布剤である、請求項1〜6のいずれか1項に記載の医薬組成物。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2016/070376 WO2017117774A1 (zh) | 2016-01-07 | 2016-01-07 | 亚丁基苯酞的应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019501921A JP2019501921A (ja) | 2019-01-24 |
JP6559357B2 true JP6559357B2 (ja) | 2019-08-14 |
Family
ID=59273354
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018534811A Active JP6559357B2 (ja) | 2016-01-07 | 2016-01-07 | ブチリデンフタリドの使用 |
Country Status (4)
Country | Link |
---|---|
US (1) | US10441566B2 (ja) |
EP (1) | EP3400937B1 (ja) |
JP (1) | JP6559357B2 (ja) |
WO (1) | WO2017117774A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111196794A (zh) * | 2020-01-17 | 2020-05-26 | 韩城市宏达花椒香料有限公司 | 食品添加剂丁叉苯酞的合成方法及其在调味方面的应用 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5161239B2 (ja) * | 2007-01-19 | 2013-03-13 | チェン、フェイ | フタリド化合物のダイマーの抗腫瘍作用 |
TWI486165B (zh) | 2011-02-15 | 2015-06-01 | Univ China Medical | 用於抑制血管狹窄之醫藥組合物及萃取物與該等之應用 |
TWI472519B (zh) * | 2011-12-20 | 2015-02-11 | Nat Univ Dong Hwa | 含正-亞丁基苯酞之醫藥組成物用於治療肝損傷及改善肝功能 |
CN104042606B (zh) | 2013-03-12 | 2017-05-24 | 国钦生物科技股份有限公司 | 苯酞化合物的应用 |
-
2016
- 2016-01-07 JP JP2018534811A patent/JP6559357B2/ja active Active
- 2016-01-07 WO PCT/CN2016/070376 patent/WO2017117774A1/zh active Application Filing
- 2016-01-07 EP EP16882919.0A patent/EP3400937B1/en active Active
- 2016-01-07 US US16/068,257 patent/US10441566B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
EP3400937B1 (en) | 2020-09-02 |
US20190008826A1 (en) | 2019-01-10 |
US10441566B2 (en) | 2019-10-15 |
EP3400937A1 (en) | 2018-11-14 |
WO2017117774A1 (zh) | 2017-07-13 |
JP2019501921A (ja) | 2019-01-24 |
EP3400937A4 (en) | 2019-08-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11357792B2 (en) | Method of administration and treatment | |
Huang et al. | Downregulation of microRNA‐155 stimulates sevoflurane‐mediated cardioprotection against myocardial ischemia/reperfusion injury by binding to SIRT1 in mice | |
RU2009144142A (ru) | Лечение возрастной дегенерации желтого пятна с применением ингибиторов фактора d комплемента | |
Hombrebueno et al. | Intravitreal injection of normal saline induces retinal degeneration in the C57BL/6J mouse | |
US20200360386A1 (en) | Inhibitors of HSP90, PI3-Kinase, Proteasome, HDAC, and P97 Pathways for Selective Removal of Senescent Cells in the Treatment of Age Related Conditions | |
TW201038544A (en) | Anti-neurodegenerative diseases agents | |
JP2020500938A (ja) | 黄斑変性症の新しい治療法 | |
Ramadass et al. | Type I collagen and its daughter peptides for targeting mucosal healing in ulcerative colitis: A new treatment strategy | |
Acosta et al. | Treatment of corneal ulcers with platelet rich plasma | |
RU2733432C1 (ru) | Лечение вирусного конъюнктивита с применением ранпирназы и/или амфиназы | |
US11622964B2 (en) | Method for destroying cellular mechanical homeostasis and promoting regeneration and repair of tissues and organs, and use thereof | |
JP6559357B2 (ja) | ブチリデンフタリドの使用 | |
WO2006079243A1 (fr) | Emploi du flavonol et des glycosides de type flavonol dans la stimulation de la croissance des cellules épithéliales rénales tubulaires pour sécréter le facteur de croissance osseuse | |
TWI587858B (zh) | 亞丁基苯酞之應用 | |
WO2020201444A1 (en) | Repurposing small molecules for senescence-related diseases and disorders | |
WO2020009248A1 (ja) | 眼組織の線維化抑制用組成物 | |
EP3116495A1 (en) | Piperazine phenothiazine derivatives for treating spasticity | |
CN107625781B (zh) | miRNA抑制子在制备防治心肌梗死药物中的应用 | |
Hui et al. | Compound Tongluo Decoction promotes generation and homing of endothelial progenitor cells after cerebral infarction in rats by activating Shh signaling | |
JP7002756B2 (ja) | 局所と局部の麻酔と鎮痛 | |
TWI838163B (zh) | 預防及/或改善口腔黏膜下纖維化之組成物及其用途 | |
CN107050025A (zh) | 樟柳碱在制备预防或治疗肾纤维化的药物中的应用 | |
KR102340457B1 (ko) | 암의 치료를 위한 신규한 조성물 | |
JP2019531296A (ja) | 眼疾患の処置方法 | |
WO2023182468A1 (ja) | 創傷治療用組成物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180831 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180831 |
|
RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20180831 |
|
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: 20190702 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20190716 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6559357 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 |