JP2019182836A - 糖尿病性腎症の予防薬及び/又は治療薬 - Google Patents
糖尿病性腎症の予防薬及び/又は治療薬 Download PDFInfo
- Publication number
- JP2019182836A JP2019182836A JP2019040111A JP2019040111A JP2019182836A JP 2019182836 A JP2019182836 A JP 2019182836A JP 2019040111 A JP2019040111 A JP 2019040111A JP 2019040111 A JP2019040111 A JP 2019040111A JP 2019182836 A JP2019182836 A JP 2019182836A
- Authority
- JP
- Japan
- Prior art keywords
- palovarotene
- diabetic nephropathy
- drug
- diabetes
- rarγ
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000007342 Diabetic Nephropathies Diseases 0.000 title claims abstract description 51
- 208000033679 diabetic kidney disease Diseases 0.000 title claims abstract description 51
- 230000000069 prophylactic effect Effects 0.000 title claims abstract description 20
- 229940126585 therapeutic drug Drugs 0.000 title claims abstract description 9
- 229940043274 prophylactic drug Drugs 0.000 title claims abstract description 7
- 239000000556 agonist Substances 0.000 claims abstract description 54
- 239000003814 drug Substances 0.000 claims abstract description 54
- 102100033912 Retinoic acid receptor gamma Human genes 0.000 claims abstract description 50
- 108091008760 retinoic acid receptors γ Proteins 0.000 claims abstract description 50
- 230000014509 gene expression Effects 0.000 claims abstract description 32
- 108010042086 Collagen Type IV Proteins 0.000 claims abstract description 28
- 102000004266 Collagen Type IV Human genes 0.000 claims abstract description 28
- 229940079593 drug Drugs 0.000 claims abstract description 28
- 239000004480 active ingredient Substances 0.000 claims abstract description 25
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 25
- 230000004761 fibrosis Effects 0.000 claims abstract description 23
- 206010016654 Fibrosis Diseases 0.000 claims abstract description 22
- 210000003584 mesangial cell Anatomy 0.000 claims abstract description 21
- 206010058116 Nephrogenic anaemia Diseases 0.000 claims abstract description 18
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 102100024505 Bone morphogenetic protein 4 Human genes 0.000 claims abstract 2
- 101000762379 Homo sapiens Bone morphogenetic protein 4 Proteins 0.000 claims abstract 2
- YTFHCXIPDIHOIA-DHZHZOJOSA-N Palovarotene Chemical compound C1=CC=NN1CC=1C=C2C(C)(C)CCC(C)(C)C2=CC=1\C=C\C1=CC=C(C(O)=O)C=C1 YTFHCXIPDIHOIA-DHZHZOJOSA-N 0.000 claims description 67
- 229950000473 palovarotene Drugs 0.000 claims description 66
- 150000002148 esters Chemical class 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- VCQGNUWOMLYNNG-UHFFFAOYSA-N 4-[7-(1-adamantyl)-6-hydroxynaphthalen-2-yl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=C(C=C(O)C(=C2)C34CC5CC(CC(C5)C3)C4)C2=C1 VCQGNUWOMLYNNG-UHFFFAOYSA-N 0.000 claims description 15
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 13
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 9
- 239000005711 Benzoic acid Substances 0.000 claims description 6
- 235000010233 benzoic acid Nutrition 0.000 claims description 6
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 5
- 238000007911 parenteral administration Methods 0.000 claims description 3
- 210000002536 stromal cell Anatomy 0.000 claims description 3
- 210000005239 tubule Anatomy 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 49
- 108010049955 Bone Morphogenetic Protein 4 Proteins 0.000 description 40
- 102000008137 Bone Morphogenetic Protein 4 Human genes 0.000 description 40
- 102100025744 Mothers against decapentaplegic homolog 1 Human genes 0.000 description 32
- 101700032040 SMAD1 Proteins 0.000 description 32
- 108010005094 Advanced Glycation End Products Proteins 0.000 description 26
- 241000699670 Mus sp. Species 0.000 description 21
- 101000934638 Homo sapiens Bone morphogenetic protein receptor type-1A Proteins 0.000 description 20
- 102100025423 Bone morphogenetic protein receptor type-1A Human genes 0.000 description 19
- 230000000694 effects Effects 0.000 description 19
- 230000037361 pathway Effects 0.000 description 19
- GPTFURBXHJWNHR-UHFFFAOYSA-N protopine Chemical compound C1=C2C(=O)CC3=CC=C4OCOC4=C3CN(C)CCC2=CC2=C1OCO2 GPTFURBXHJWNHR-UHFFFAOYSA-N 0.000 description 19
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 18
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 18
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 18
- 241000699666 Mus <mouse, genus> Species 0.000 description 16
- 206010046406 Ureteric obstruction Diseases 0.000 description 14
- 230000002401 inhibitory effect Effects 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- 230000003449 preventive effect Effects 0.000 description 14
- -1 pyrazol-1-ylmethyl Chemical group 0.000 description 13
- 238000000502 dialysis Methods 0.000 description 12
- 230000026731 phosphorylation Effects 0.000 description 12
- 238000006366 phosphorylation reaction Methods 0.000 description 12
- 238000011282 treatment Methods 0.000 description 12
- 102100025751 Mothers against decapentaplegic homolog 2 Human genes 0.000 description 11
- 101710143123 Mothers against decapentaplegic homolog 2 Proteins 0.000 description 11
- 230000009471 action Effects 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 239000003112 inhibitor Substances 0.000 description 11
- 230000003902 lesion Effects 0.000 description 11
- LDGIHZJOIQSHPB-UHFFFAOYSA-N CD437 Chemical compound C1C(C2)CC(C3)CC2CC13C1=CC(C2=CC3=CC=C(C=C3C=C2)C(=O)O)=CC=C1O LDGIHZJOIQSHPB-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 10
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 10
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 9
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 9
- 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 9
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 9
- 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 9
- 239000008103 glucose Substances 0.000 description 9
- 229960001052 streptozocin Drugs 0.000 description 9
- 208000037999 tubulointerstitial fibrosis Diseases 0.000 description 9
- 102000003951 Erythropoietin Human genes 0.000 description 8
- 108090000394 Erythropoietin Proteins 0.000 description 8
- 229940105423 erythropoietin Drugs 0.000 description 8
- 210000002744 extracellular matrix Anatomy 0.000 description 8
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 230000007423 decrease Effects 0.000 description 7
- 231100000673 dose–response relationship Toxicity 0.000 description 7
- 238000011156 evaluation Methods 0.000 description 7
- 210000002950 fibroblast Anatomy 0.000 description 7
- 230000001434 glomerular Effects 0.000 description 7
- 210000003734 kidney Anatomy 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 235000000346 sugar Nutrition 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 230000000638 stimulation Effects 0.000 description 6
- 230000001629 suppression Effects 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- 102000003702 retinoic acid receptors Human genes 0.000 description 5
- 108090000064 retinoic acid receptors Proteins 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- VYLJAYXZTOTZRR-BTPDVQIOSA-N CC(C)(O)[C@H]1CC[C@@]2(C)[C@H]1CC[C@]1(C)[C@@H]2CC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3[C@@H](O)[C@H](O)[C@@]12C Chemical compound CC(C)(O)[C@H]1CC[C@@]2(C)[C@H]1CC[C@]1(C)[C@@H]2CC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3[C@@H](O)[C@H](O)[C@@]12C VYLJAYXZTOTZRR-BTPDVQIOSA-N 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 4
- 108010035532 Collagen Proteins 0.000 description 4
- 102100023195 Nephrin Human genes 0.000 description 4
- 238000002123 RNA extraction Methods 0.000 description 4
- 208000001647 Renal Insufficiency Diseases 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 4
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920001436 collagen Polymers 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- VYLJAYXZTOTZRR-UHFFFAOYSA-N hopane-6alpha,7beta,22-triol Natural products C12CCC3C4(C)CCCC(C)(C)C4C(O)C(O)C3(C)C1(C)CCC1C2(C)CCC1C(C)(O)C VYLJAYXZTOTZRR-UHFFFAOYSA-N 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 201000006370 kidney failure Diseases 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 108010027531 nephrin Proteins 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 238000013424 sirius red staining Methods 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 108010051696 Growth Hormone Proteins 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 206010023421 Kidney fibrosis Diseases 0.000 description 3
- 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 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- 102100038803 Somatotropin Human genes 0.000 description 3
- 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 3
- 230000032683 aging Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000000122 growth hormone Substances 0.000 description 3
- 201000001421 hyperglycemia Diseases 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 235000019426 modified starch Nutrition 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 210000000626 ureter Anatomy 0.000 description 3
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- FRDAATYAJDYRNW-UHFFFAOYSA-N 3-methylpentanol-3 Natural products CCC(C)(O)CC FRDAATYAJDYRNW-UHFFFAOYSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 208000037157 Azotemia Diseases 0.000 description 2
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 2
- 241000725101 Clea Species 0.000 description 2
- 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 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- 206010054805 Macroangiopathy Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 102100025725 Mothers against decapentaplegic homolog 4 Human genes 0.000 description 2
- 101710143112 Mothers against decapentaplegic homolog 4 Proteins 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 102000013275 Somatomedins Human genes 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 235000011132 calcium sulphate Nutrition 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 2
- 210000003855 cell nucleus Anatomy 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229940094517 chondroitin 4-sulfate Drugs 0.000 description 2
- KXKPYJOVDUMHGS-OSRGNVMNSA-N chondroitin sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 KXKPYJOVDUMHGS-OSRGNVMNSA-N 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 2
- XHBVYDAKJHETMP-UHFFFAOYSA-N dorsomorphin Chemical compound C=1C=C(C2=CN3N=CC(=C3N=C2)C=2C=CN=CC=2)C=CC=1OCCN1CCCCC1 XHBVYDAKJHETMP-UHFFFAOYSA-N 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 231100000853 glomerular lesion Toxicity 0.000 description 2
- 210000001282 glomerular podocyte Anatomy 0.000 description 2
- 230000002641 glycemic effect Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 235000009200 high fat diet Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000008011 inorganic excipient Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Chemical class 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 206010062198 microangiopathy Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000009456 molecular mechanism Effects 0.000 description 2
- 102000045246 noggin Human genes 0.000 description 2
- 108700007229 noggin Proteins 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000008012 organic excipient Substances 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 210000000557 podocyte Anatomy 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 201000001474 proteinuria Diseases 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 150000003509 tertiary alcohols Chemical class 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 239000013638 trimer Substances 0.000 description 2
- 208000009852 uremia Diseases 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- ICGCSXAZTJXZAG-UHFFFAOYSA-N 3-methyl-1-benzofuran-5-carboxylic acid Chemical compound C1=C(C(O)=O)C=C2C(C)=COC2=C1 ICGCSXAZTJXZAG-UHFFFAOYSA-N 0.000 description 1
- CDOVNWNANFFLFJ-UHFFFAOYSA-N 4-[6-[4-(1-piperazinyl)phenyl]-3-pyrazolo[1,5-a]pyrimidinyl]quinoline Chemical compound C1CNCCN1C1=CC=C(C2=CN3N=CC(=C3N=C2)C=2C3=CC=CC=C3N=CC=2)C=C1 CDOVNWNANFFLFJ-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 102000000584 Calmodulin Human genes 0.000 description 1
- 108010041952 Calmodulin Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 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
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 102000002664 Core Binding Factor Alpha 2 Subunit Human genes 0.000 description 1
- 108010043471 Core Binding Factor Alpha 2 Subunit Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 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-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
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- JMIFGARJSWXZSH-UHFFFAOYSA-N DMH1 Chemical compound C1=CC(OC(C)C)=CC=C1C1=CN2N=CC(C=3C4=CC=CC=C4N=CC=3)=C2N=C1 JMIFGARJSWXZSH-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010017711 Gangrene Diseases 0.000 description 1
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 1
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 1
- 102100038367 Gremlin-1 Human genes 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101001032872 Homo sapiens Gremlin-1 Proteins 0.000 description 1
- 101001059713 Homo sapiens Inner nuclear membrane protein Man1 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010020710 Hyperphagia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102100028799 Inner nuclear membrane protein Man1 Human genes 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Chemical compound CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 101710091439 Major capsid protein 1 Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010027525 Microalbuminuria Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 102100025748 Mothers against decapentaplegic homolog 3 Human genes 0.000 description 1
- 101710143111 Mothers against decapentaplegic homolog 3 Proteins 0.000 description 1
- 102100030590 Mothers against decapentaplegic homolog 6 Human genes 0.000 description 1
- 101710143114 Mothers against decapentaplegic homolog 6 Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 102000001759 Notch1 Receptor Human genes 0.000 description 1
- 108010029755 Notch1 Receptor Proteins 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000012124 Opti-MEM Substances 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000001280 Prediabetic State Diseases 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102000005622 Receptor for Advanced Glycation End Products Human genes 0.000 description 1
- 108010045108 Receptor for Advanced Glycation End Products Proteins 0.000 description 1
- 229940096885 Retinoic acid receptor agonist Drugs 0.000 description 1
- 102100023606 Retinoic acid receptor alpha Human genes 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 108091005735 TGF-beta receptors Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000016715 Transforming Growth Factor beta Receptors Human genes 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 101100068489 Vicia faba AGPC gene Proteins 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 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
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000002604 chemokine receptor CCR2 antagonist Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 230000037319 collagen production Effects 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 230000009850 completed effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000009207 exercise therapy Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 208000004104 gestational diabetes Diseases 0.000 description 1
- 230000024924 glomerular filtration Effects 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 230000036732 histological change Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 210000004692 intercellular junction Anatomy 0.000 description 1
- 210000001596 intra-abdominal fat Anatomy 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 235000020845 low-calorie diet Nutrition 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000000885 nephron Anatomy 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 230000030648 nucleus localization Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000020830 overeating Nutrition 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 208000037920 primary disease Diseases 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 210000005084 renal tissue Anatomy 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 108091008726 retinoic acid receptors α Proteins 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 230000000580 secretagogue effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 125000005624 silicic acid group Chemical class 0.000 description 1
- NGHMEZWZOZEZOH-UHFFFAOYSA-N silicic acid;hydrate Chemical compound O.O[Si](O)(O)O NGHMEZWZOZEZOH-UHFFFAOYSA-N 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- MUTNCGKQJGXKEM-UHFFFAOYSA-N tamibarotene Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1NC(=O)C1=CC=C(C(O)=O)C=C1 MUTNCGKQJGXKEM-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000008719 thickening Effects 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
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000023750 transforming growth factor beta production Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000003442 weekly effect Effects 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Urology & Nephrology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
また、近年、尿細管間質線維化の病巣を構築する線維芽細胞(少なくともその一部)がエリスロポエチン(EPO)産生細胞に由来しており、線維芽細胞へと形質転換する際にEPO産生能を喪失することから、間質線維化の進行と腎性貧血の進展に共通するメカニズムが想定されている14。この仮説によれば、間質線維化の予防および/または治療薬は、腎性貧血の有効な予防および/または治療薬となり得ると考えられる。
(1)RARγアゴニストを有効成分として含む、糖尿病性腎症の予防薬及び/又は治療薬。
(2)RARγアゴニストが、Palovarotene、3-Fluoro-4-(2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydronaphthalen-2-yl)acetamido)benzoic acid、4-[7-(1-Adamantyl)-6-hydroxynaphthalen-2-yl]benzoic acid、それらのエステル及びそれらの塩からなる群より選択される少なくとも1種の化合物である(1)記載の予防薬及び/又は治療薬。
(3)糖尿病性腎症が2型糖尿病由来である(1)記載の予防薬及び/又は治療薬。
(4)RARγアゴニストを有効成分として含む、腎性貧血の予防薬及び/又は治療薬。
(5)RARγアゴニストを有効成分として含む、メサンギウム細胞におけるIV型コラーゲンの発現を抑制する薬剤。
(6)RARγアゴニストが、Palovarotene、4-[7-(1-Adamantyl)-6-hydroxynaphthalen-2-yl]benzoic acid、それらのエステル及びそれらの塩からなる群より選択される少なくとも1種の化合物である(5)記載の薬剤。
(7)RARγアゴニストを有効成分として含む、メサンギウム細胞におけるBMP4の発現を抑制する薬剤。
(8)RARγアゴニストが、Palovarotene、3-Fluoro-4-(2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydronaphthalen-2-yl)acetamido)benzoic acid、それらのエステル及びそれらの塩からなる群より選択される少なくとも1種の化合物である(7)記載の薬剤。
(9)RARγアゴニストを有効成分として含む、腎尿細管間質における線維化を抑制する薬剤。
(10)RARγアゴニストが、Palovarotene、又はPalovaroteneのエステル及びそれらの塩からなる群より選択される少なくとも1種の化合物である(9)記載の薬剤。
(11)尿細管間質細胞におけるpSmad2/3の発現を抑制する(9)記載の薬剤。
(12)腎尿細管間質における線維化が糖尿病性腎症由来である(9)記載の薬剤。
(13)投与形態が経口投与又は非経口投与である、(1)〜(12)のいずれかに記載の薬剤。
本発明は、RARγアゴニストを有効成分として含む、糖尿病性腎症の予防薬及び/又は治療薬を提供する。
近年、尿細管間質線維化の病巣を構築する線維芽細胞(少なくともその一部)がエリスロポエチン(EPO)産生細胞に由来しており、線維芽細胞へと形質転換する際にEPO産生能を喪失することから、間質線維化の進行と腎性貧血の進展に共通するメカニズムが想定されている14。この仮説によれば、間質線維化の予防および/または治療薬は、腎性貧血の有効な予防および/または治療薬となり得ると考えられる。よって、本発明は、RARγアゴニストを有効成分として含む、腎性貧血の予防薬及び/又は治療薬も提供する。
本発明のさらに別の態様としては、RARγアゴニストを対象に投与することを特徴とする腎性貧血の予防及び/又は治療方法や、腎性貧血の予防薬及び/又は治療薬として使用するためのRARγアゴニストや、RARγアゴニストの腎性貧血の予防薬及び/又は治療薬の調製における使用を挙げることができる。
<マウスメサンギウム細胞に対するPalovaroteneの作用の検討>
(方法)
4週齢の野生型C57BL/6JマウスからDavies Mらの方法(Kidney Int. 1994;45(2):320-7)36に準じて糸球体を単離、初期培養を行い、マウスメサンギウム細胞株を確立した。細胞刺激に用いるためのAGEはDoi Tらの方法(Proc, Nalt. Acad. Sci. U.S.A. 1992; 89:2873-2877)37に準じて作製した。
マウスメサンギウム培養細胞をコンフルエンスまで増殖させ、Opti-MEM(Invitrogen)にて血清飢餓を行い、(1)無刺激条件、(2)AGE 300μg/mL、(3)AGE 300μg/mL + Palovarotene 0.5μM および(4)1μMを添加し、24時間後にAGPC法によるRNA抽出を行った。そのRNAを用いてRT-quantitative PCRを行い、サイクル比較法(ΔΔCt法)にてmRNA発現レベルを評価した。評価対象遺伝子は、TGF-β1、BMP4、及びCol4α1とした。
結果を図2に示す。
RARアゴニストがTGF-βシグナル伝達を抑制するという知見に基づき、まず、PalovaroteneがAGE刺激によるTGF-βの発現を抑制するか否かを検討したところ、図2A に示すように、AGE刺激により発現促進されたTGF-βの発現が強く抑制された。
次いで、AGE刺激によりメサンギウム細胞のBMP4の発現が増加するとの知見に基づき、PalovaroteneのBMP4発現に対する作用を検討したところ、図2Bに示すように、Palovaroteneは、AGE刺激により増加したBMP4発現を用量依存的に抑制し、1 μMの濃度でほぼ完全に抑制することが明らかになった。
さらに、メサンギウム領域の拡大の原因因子であるCol4α1(IV型コラーゲン)の発現に対するPalovaroteneの作用を検討したところ、AGE刺激により増加したCol4α1(IV型コラーゲン)の産生を、0.5 μMの濃度においても、完全に抑制することが判明した(図2C)。
以上の結果より、Palovaroteneは、BMP4の発現の抑制を介して、BMP4/ALK3を介したIV型コラーゲンの発現を抑制できる可能性が示唆された。
そこで、この可能性を検討するために、糖尿病モデルマウスを用いたPalovaroteneの評価を実施した。
<STZ誘発糖尿病マウスに対するPalovaroteneの作用の検討>
(方法)
12〜15週齢のICRマウス(日本クレア社より購入)に1回あたり50mg/kgのストレプトゾトシン(Wako)を5日連続腹腔内投与(I.P.)を行い、糖尿病を惹起させた。ストレプトゾトシン投与4週間後から、高脂肪食HFD60(オリエンタル酵母工業)に切り替えるとともに、Palovaroteneを60μg/kgで週2回の腹腔内投与を開始し、その12週間後に解剖、組織学的評価を実施した。結果を図3に示す。
図3に示すように、ストレプトゾトシンを投与した糖尿病マウス(DM)では、コントロールマウス(Ctrl)に比べ、糸球体メサンギウム領域の拡大(PAS染色)、Smad1の活性化(pSmad1)、Smad2/3の活性化(pSmad2/3)、およびIV型コラーゲン(Col4)の発現増加が観察された。さらに、糸球体ポドサイトの細胞間接合分子ネフリンの発現領域の低下(Nephrin)およびポドサイト細胞核に発現するWT1の減少(WT1)が観察された。以上の結果は、ストレプトゾトシンを投与した糖尿病マウスは、ヒトの糖尿病性腎症の病理組織学的変化をよく反映した優れたモデルマウスであることを示す。
そして、この糖尿病マウスにPalovaroteneを投与した(DM+Palo)場合には、糖尿病マウス(DM)に比べ、糸球体メサンギウム領域の拡大の抑制(PAS染色)、Smad1の活性化の抑制(pSmad1)、およびIV型コラーゲン発現の低下(Col4)が観察された。さらに、ネフリンの発現領域の低下抑制(Nephrin)およびポドサイト細胞核に発現するWT1の減少抑制(WT1)が観察された。
また、糖尿病マウスにPalovaroteneを投与した(DM+Palo)場合には、糖尿病マウス(DM)に比べ、Smad2/3のリン酸化が強く抑制されることが判明した。Smad2/3の活性化は糖尿病により誘発される尿細管間質病変を進展させる重要な因子である。Smad2/3のリン酸化を抑制する結果に基づいて、Palovaroteneは尿細管間質線維化を抑制することが示めされた。これを根拠に、Palovaroteneの糖尿病性腎症に対する予防又は治療能力は、糸球体ではSmad1のリン酸化を抑制し糸球体硬化病変を抑え、間質ではSmad2/3のリン酸化を抑制し間質線維化を抑えることを示す。
<腎臓尿細管間質線維化モデルとしての一側尿管結紮(UUO)マウスに対するPalovaroteneの効果>
(方法)
一側尿管結紮(UUO:unilateral ureter obstruction)モデルは尿管結紮状態で7日間飼育し腎臓間質線維化を惹起さるモデルである。すなわち、片側背部切開により腎臓を腹膜外に露出させ、縫合糸にて1mm間隔で2〜3ヶ所の尿管結紮を行なうと、尿管結紮により腎血流および糸球体ろ過率が低下する。また尿細管間質にマクロファージが浸潤し、尿細管上皮細胞のアポトーシスが起こり、間質に線維芽細胞及び細胞外基質タンパクの増加が進行することにより、間質の線維化は惹起される。このモデルは、短期間で線維化を惹起し、毒物を使用しないため尿毒症を合併しない再現性の高い間質線維化モデルである。
10〜12週齢のICRマウス(日本クレアより購入)を用いて、UUOモデルを作成した。Control群は、尿管結紮を行わなかったマウスである。UUO群は、尿管結紮状態で7日間飼育し腎臓間質線維化を惹起させたマウスである。Palovarotene群は、UUO処置1日後からPalovarotene 1mg/kgを6日間連続で腹腔内投与したマウスである。各群のマウスについて、UUO処置7日後に解剖し、シリウスレッド染色にて腎臓の組織学的評価を実施した。各群の典型的な組織染色の結果(各群2切片)を図4に示す。
図4に示すように、Control群のマウスの腎臓では、尿細管間質の線維化は全く観察されなかった。尿管結紮後7日間経過したUUOマウスの腎臓では、尿細管間質がシリウスレッドにより非常に強く染色されたことから、尿細管間質の顕著な線維化が明らかになった。そして、UUOマウスに6日間Palovaroteneを投与した(UUO+Palo)ところ、尿細管間質のシリウスレッドによる染色される程度が、UUOマウスの腎臓組織に比べ、明らかに軽度であったことから、Palovaroteneは、尿細管間質の線維化を顕著に抑制することが判明した。
尿細管間質線維化の病巣を構築する線維芽細胞がEPO産生細胞に由来しており、線維芽細胞へと形質転換する際にEPO産生能を喪失するという仮説14によれば、Palovaroteneは尿細管間質線維化の予防および/または治療薬としてのみならず、腎性貧血の有効な予防および/または治療薬となり得ると考えられる。
<マウスメサンギウム細胞に対する4種類のRARγアゴニストの作用の比較>
(方法)
実施例1の方法に従って、4種類のRARγアゴニスト(Palovarotene、O-Desmethyl Adapalene、BMS189961、CD1530)のTGF-β1、BMP4、およびCol4α1発現抑制作用の比較を行った。
「AGE 300 μg/ml +Palovarotene 0.5μM」の値を100%とした時の相対値で示した。
まず、RARγアゴニストのTGF-β1発現抑制作用を検討したところ、表3に示すように、Palovaroteneは用量依存的な抑制作用を示した。CD1530も用量依存的な抑制作用を示したが、その作用はPalovaroteneに比べて弱かった。O-Desmethyl Adapalene及びBMS189961は、Palovaroteneに比べて、抑制活性が弱かった。
次いで、BMP4発現の抑制作用について、検討したところ、表3に示すようにPalovaroteneは用量依存的な抑制作用を示した。しかし、他の3種類の化合物は抑制作用を示さなかった。
さらに、Col4α1(IV型コラーゲン)発現の抑制作用について検討したところ、表3に示すように、Palovaroteneは用量依存的な抑制作用を示した。CD1530も用量依存的な抑制作用を示したが、その作用はPalovaroteneに比べて弱かった。一方、O-Desmethyl Adapaleneは用量依存的なCol4α1(IV型コラーゲン)の発現促進作用を示した。また、CD1530の抑制作用はPalovaroteneより弱かった。
[引用文献]
1.Doi T, Vlassara H, Kirstein M, Yamada Y, et al. Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation endproducts is mediated via platelet derived growth factor. Proc Natl Acad Sci USA 1992; 89:2873-2877.
2.Abe H, Matsubara T, Iehara N, et al. Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end product (AGE) stimulation. J Biol Chem 2004; 279:14201-14206.
3.Matsubara T, Abe H, Arai H, et al. Expression of Smad1 is directly associated with glomerulosclerosis in diabetic nephropathy. Lab Invest 2006; 86:357-68.
4.Mima A, Matsubara T, Arai H, et al. Angiotensin II-dependent Src and Smad1 signaling pathway is crucial for the development of diabetic nephropathy. Lab Invest 2006; 86:927-939.
5.Ohashi S, Abe H, Takahashi T, et al. Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy. J Biol Chem 2004; 279:19816-23.
6.Takahashi T, Abe H, Arai H, et al. Activation of STAT3/Smad1 is a key signaling pathway for progression to glomerulosclerosis in experimental glomerulonephritis. J Biol Chem 2005; 280:7100-7106.
7.Tominaga T, Abe H, Ueda O, et al. Activation of BMP4 signaling leads to glomerulosclerosis that mimics diabetic nephropathy. J Biol Chem 2011; 286:20109-20116.
8.Kishi S, Abe H, Akiyama H, et al. Sox9 protein induces a chondrogenic phenotype of mesangial cells and contributes to advanced diabetic nephropathy. J Biol Chem 2011; 286:32162-32169.
9.Abe H, Tominaga T, Matsubara T, et al. Scleraxis modulates bone morphogenetic protein 4 (BMP4)-Smad1-smooth muscle α-actin (SMA) signal transduction in diabetic nephropathy. J Biol Chem 2012; 287:20430-42.
10.Matsubara T, Araki M, Abe H, et al. Bone morphogenetic protein 4 and Smad1 mediate extracellular matrix production in the development of diabetic nephropathy. Diabetes 2015, 64(8):2978-90.
11.Tominaga T, Abe H, Ueda O, et al. Activation of BMP4 signaling leads to glomerulosclerosis that mimics diabetic nephropathy. J Biol Chem 2011; 286:20109-20116.
12.Pendaries V, Verrcchia F, Michel S, et al. Retinoic acid receptors interfere with the TGF-β/Smad signaling pathway in a ligand-specific manner. Oncogene 2003; 22:8212-8220.
13.Khalil H, Kanisicak O, Prasad V, et al. Fibroblas-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. The journal of Clinical Investigation 2017; 127(10):3770-3783.
14.岡田浩一 腎臓疾患と線維化 日本内科学会雑誌2015、104巻8号、1658-1664。
15.渡邊乃梨子、草場哲郎 糖尿病性腎症 京都府立医科大学雑誌2017、126巻10号、685-695。
16.阿部秀斉、土井俊夫 糖尿病性腎症の発症・進展の分子病態 日本内科学会雑誌2008、97巻4号、122-128。
17.澁谷浩司 TGF-β細胞内シグナル伝達の分子機構 化学と生物 35巻7号、477-482。
18.Sun SY et al. The synthetic retinoid CD437 selectively induces apoptosis in human lung cancer cells while sparing normal human lung epithelial cells. Cancer Research 2002; 62(8): 2430-2436.
19.Shimono K, Tung W, Macolino C, et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-[gamma] agonists. Nature medicine 2011; 17:454-460.
20.Zhang Y, Liu J, Tian XY, et al. Inhibition of bone morphogenic protein 4 restores endothelial function in db/db diabetic. Arteriosclerosis, Thrombosis, and Vascular Biology 2014; 34:152-159.
21.Maciel TT, Melo RS, Schor N, et al. Gremlin promotes vascular smooth muscle cell proliferation and migration. J Mol Cell Cardiol 2008; 44:370-9.
22.Yu PB, Hong CC, Sachidanandan C, et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nature Chemical Biology 2008; 4(1): 33-41.
23.Yu PB, Deng DY, Lai CS, et al. BMP type I receptor inhibition reduces heterotopic ossification. Nature Medicine 2008; 14:1363-1369.
24.Xu RH, Lechleider RJ, Shih HM, et al. Functional Analysis of Human Smad1: Role of the Amino-Terminal Domain. Biochemical and Biophysical Research Communications 1999; 258(2): 366-373.
25.Pimanda JE, Donaldson IJ, Bruijn MFTR, et al. The SCL transcriptional network and BMP signaling pathway interact to regulate RUNX1 activity. Proceedings of the National Academy of Sciences of the United States of America 2007; 104(3): 840-845.
26.Novinec M, Lenarcic B, Turk B. Cysteine cathepsin activity regulation by glycosaminoglycans. Biomed Research Intnational 2014; doi: 10.1155/2014/309718.
27.Neely MD, Litt MJ, Tidball AM, et al. DMH1, a highly selective small molecule BMP inhibitor promotes neurogenesis of hiPSCs: Comparison of PAX6 and SOX1 expression during neural induction. ACS Chemical Neuroscience 2012; 3(6):482-491.
28.Wawersik S, Evola C, Whitman M, et al. Conditional BMP inhibition in Xenopus reveals stage-specific roles for BMPs in neural and neural crest induction. Developmental Biology 2005; 277(2):425-442.
29.Bourgeois B, Gilquin B, Tellier-Lebegue C, et al. Inhibition of TGF-βsignaling at the nuclear envelope: Characterization of interactions between MAN1, Smad2 and Smad3, and PPM1A. Science Signaling 2013; 6(280): ra49.
30.Li W, Wei W, Zhu S, et al. Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell 2009; 4(1):16-19.
31.Rena G, Bain J, Elliott M, et al. D4476, a cell permeant inhibitor of CK1, suppresses the site‐specific phosphorylation and nuclear exclusion of FOXO1a. EMBO report 2004; 5(1): 60-65
32.Sawyer JS, Andersonhttps://pubs.acs.org/doi/abs/10.1021/jm0205705 - jm0205705AF10 BD, Beight DB, et al. Synthesis and activity of new Aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-β type I receptor kinase domain. Journal of Medicinal Chemistry 2003; 46(19):3953-3956.
33.Ogawa K, Saito A, Matsui H, et al. Activin-Nodal signaling is involved in propagation of mouse embryonic stem cell. Journal of Cell Science 2007; 120: 55-65.
34.Grygielko ET, Martin WM, Tweed C, et al. Inhibition of gene markers of fibrosis with a novel inhibitor of transforming growth factor-βtype I receptor kinase in puromycin induced nephritis. The journal of pharmacology and Experimental Therapeutics 2005; 313(3): 943-951.
35.Kapoun AM, Gaspar NJ, Wang Y, et al. Transforming growth factor-βreceptor type 1 (TGFRI) kinase activity but not p38 activation is required for TGF RI-induced myofibroblast differentiation and profibrotic gene expression. Molecular Pharmacology 2006; 70(2): 518-531.
36.Davies M. The mesangial cell: A tissue culture view. Kidney International 1994; 45(2):320-327.
37.Doi T, Vlassara H, Kirstein M, et al. Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor. Proc. Nalt Acad Sci. USA. 1992; 89:2873-2877.
[特許文献1]国際公開第2014/073209号パンフレット
[特許文献2]再表2007/037188号公報
[特許文献3]アメリカ公開第20160120843号公報
[特許文献4]国際公開第2014/188716号パンフレット
[特許文献5]国際公開第2002/028810号パンフレット
[特許文献6]国際公開第2008/057930号パンフレット
[特許文献7]アメリカ公開第20140363402号公報
[特許文献8]特開第2013−536855号公報
Claims (13)
- RARγアゴニストを有効成分として含む、糖尿病性腎症の予防薬及び/又は治療薬。
- RARγアゴニストが、Palovarotene、3-Fluoro-4-(2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydronaphthalen-2-yl)acetamido)benzoic acid、4-[7-(1-Adamantyl)-6-hydroxynaphthalen-2-yl]benzoic acid、それらのエステル及びそれらの塩からなる群より選択される少なくとも1種の化合物である請求項1記載の予防薬及び/又は治療薬。
- 糖尿病性腎症が2型糖尿病由来である請求項1記載の予防薬及び/又は治療薬。
- RARγアゴニストを有効成分として含む、腎性貧血の予防薬及び/又は治療薬。
- RARγアゴニストを有効成分として含む、メサンギウム細胞におけるIV型コラーゲンの発現を抑制する薬剤。
- RARγアゴニストが、Palovarotene、4-[7-(1-Adamantyl)-6-hydroxynaphthalen-2-yl]benzoic acid、それらのエステル及びそれらの塩からなる群より選択される少なくとも1種の化合物である請求項5記載の薬剤。
- RARγアゴニストを有効成分として含む、メサンギウム細胞におけるBMP4の発現を抑制する薬剤。
- RARγアゴニストが、Palovarotene、3-Fluoro-4-(2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydronaphthalen-2-yl)acetamido)benzoic acid、それらのエステル及びそれらの塩からなる群より選択される少なくとも1種の化合物である請求項7記載の薬剤。
- RARγアゴニストを有効成分として含む、腎尿細管間質における線維化を抑制する薬剤。
- RARγアゴニストが、Palovarotene、又はPalovaroteneのエステル及びそれらの塩からなる群より選択される少なくとも1種の化合物である請求項9記載の薬剤。
- 尿細管間質細胞におけるpSmad2/3の発現を抑制する請求項9記載の薬剤。
- 腎尿細管間質における線維化が糖尿病性腎症由来である請求項9記載の薬剤。
- 投与形態が経口投与又は非経口投与である、請求項1〜12のいずれかに記載の薬剤。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2023191490A JP2024003130A (ja) | 2018-04-02 | 2023-11-09 | 糖尿病性腎症の予防薬及び/又は治療薬 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2018071111 | 2018-04-02 | ||
JP2018071111 | 2018-04-02 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023191490A Division JP2024003130A (ja) | 2018-04-02 | 2023-11-09 | 糖尿病性腎症の予防薬及び/又は治療薬 |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2019182836A true JP2019182836A (ja) | 2019-10-24 |
Family
ID=68095932
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019040111A Pending JP2019182836A (ja) | 2018-04-02 | 2019-03-06 | 糖尿病性腎症の予防薬及び/又は治療薬 |
JP2023191490A Pending JP2024003130A (ja) | 2018-04-02 | 2023-11-09 | 糖尿病性腎症の予防薬及び/又は治療薬 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023191490A Pending JP2024003130A (ja) | 2018-04-02 | 2023-11-09 | 糖尿病性腎症の予防薬及び/又は治療薬 |
Country Status (5)
Country | Link |
---|---|
US (1) | US10828279B2 (ja) |
JP (2) | JP2019182836A (ja) |
KR (2) | KR20190115400A (ja) |
CA (1) | CA3019069A1 (ja) |
TW (1) | TWI769325B (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2021058274A (ja) * | 2019-10-03 | 2021-04-15 | 株式会社三共 | 遊技機 |
JP2021058273A (ja) * | 2019-10-03 | 2021-04-15 | 株式会社三共 | 遊技機 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2004611A1 (en) * | 2006-03-31 | 2008-12-24 | F. Hoffmann-La Roche AG | Process for preparing retinoid compounds |
NZ607547A (en) * | 2010-09-01 | 2015-06-26 | Univ Jefferson | Composition and method for muscle repair and regeneration |
US8772273B2 (en) * | 2011-10-04 | 2014-07-08 | Quretino Therapeutics, Inc. | Formulations and uses of retinoic acid receptor selective agonists |
-
2018
- 2018-09-27 CA CA3019069A patent/CA3019069A1/en active Pending
- 2018-09-28 TW TW107134300A patent/TWI769325B/zh active
- 2018-09-30 KR KR1020180116682A patent/KR20190115400A/ko active Application Filing
-
2019
- 2019-03-06 JP JP2019040111A patent/JP2019182836A/ja active Pending
- 2019-04-02 US US16/372,571 patent/US10828279B2/en active Active
-
2023
- 2023-11-09 JP JP2023191490A patent/JP2024003130A/ja active Pending
-
2024
- 2024-01-15 KR KR1020240006231A patent/KR20240013820A/ko active Application Filing
Non-Patent Citations (2)
Title |
---|
2017年度生命科学系学会合同年次大会(CONBIO2017), JPN6022042491, 2017, pages 2 - 1011, ISSN: 0004960662 * |
日本内科学会雑誌, vol. 104, no. 8, JPN6022042493, 2015, pages 1658 - 1664, ISSN: 0004960663 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2021058274A (ja) * | 2019-10-03 | 2021-04-15 | 株式会社三共 | 遊技機 |
JP2021058273A (ja) * | 2019-10-03 | 2021-04-15 | 株式会社三共 | 遊技機 |
Also Published As
Publication number | Publication date |
---|---|
JP2024003130A (ja) | 2024-01-11 |
CA3019069A1 (en) | 2019-10-02 |
TWI769325B (zh) | 2022-07-01 |
US20190314339A1 (en) | 2019-10-17 |
KR20240013820A (ko) | 2024-01-30 |
TW201941771A (zh) | 2019-11-01 |
US10828279B2 (en) | 2020-11-10 |
KR20190115400A (ko) | 2019-10-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2024003130A (ja) | 糖尿病性腎症の予防薬及び/又は治療薬 | |
JP2020521734A (ja) | 老化細胞除去化合物 | |
EP1545560B1 (de) | Zusammensetzungen zur hemmung der proteinkinase c alpha zur behandlung von diabetes mellitus | |
CN109843378B (zh) | 用于治疗肺血管疾病的组合物和方法 | |
US20130123248A1 (en) | Pharmacological modulation of positive ampa receptor modulator effects on neurotrophin expression | |
Shi et al. | Angiotensin II as a morphogenic cytokine stimulating fibrogenesis of human tenon's capsule fibroblasts | |
RU2591210C2 (ru) | Соединения и способы лечения боли и других расстройств | |
Hall et al. | Cardiac natriuretic peptide deficiency sensitizes the heart to stress-induced ventricular arrhythmias via impaired CREB signalling | |
JPWO2004093910A1 (ja) | PPARδアゴニストによる脳神経変性疾患治療剤 | |
US20120046333A1 (en) | Methods and Compositions of PI-3 Kinase Inhibitors for Treating Fibrosis | |
US20220257716A1 (en) | Methods and compositions for the treatment of secretory disorders | |
IL293895A (en) | Combined treatment of liver diseases using integrin inhibitors | |
WO2006022281A1 (ja) | コラーゲンまたはエラスチン代謝異常疾患の予防剤および治療剤 | |
WO2014065370A1 (ja) | 肺高血圧症治療剤 | |
JP5044775B2 (ja) | 糖尿病性腎症の治療用医薬組成物 | |
KR102142559B1 (ko) | Dpp4 억제제를 유효성분으로 포함하는 심근섬유증의 예방 또는 치료용 조성물 | |
WO2007089774A2 (en) | Compositions and methods for treating cognitive disorders | |
US10576151B2 (en) | Ciclopirox for use in modulation of glucose homeostasis | |
KR20030087051A (ko) | 아릴에텐술폰아미드 유도체의 신규한 용도 | |
JP6352411B2 (ja) | Dpp−iv阻害剤を含有する腎疾患予防または治療用組成物 | |
Taguchi et al. | Therapeutic Strategies Targeting RAGE Prevent Kidney Injury and Renal Fibrosis in Systemic Lupus Erythematosus: FR-PO1060 | |
IL295452A (en) | Use of cyclosporine analogs to treat leprosy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20211018 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20221012 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221212 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230111 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230308 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230510 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20230809 |