WO2019186171A1 - Treatment of sarcopenic diseases - Google Patents
Treatment of sarcopenic diseases Download PDFInfo
- Publication number
- WO2019186171A1 WO2019186171A1 PCT/GB2019/050892 GB2019050892W WO2019186171A1 WO 2019186171 A1 WO2019186171 A1 WO 2019186171A1 GB 2019050892 W GB2019050892 W GB 2019050892W WO 2019186171 A1 WO2019186171 A1 WO 2019186171A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- inhibitor
- hsd11
- sarcopenia
- subject
- sarcopenic
- Prior art date
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 103
- 201000010099 disease Diseases 0.000 title claims abstract description 60
- 238000011282 treatment Methods 0.000 title claims abstract description 50
- 239000003112 inhibitor Substances 0.000 claims abstract description 84
- 208000001076 sarcopenia Diseases 0.000 claims abstract description 83
- 102100036506 11-beta-hydroxysteroid dehydrogenase 1 Human genes 0.000 claims abstract description 66
- 101000928753 Homo sapiens 11-beta-hydroxysteroid dehydrogenase 1 Proteins 0.000 claims abstract description 66
- 238000000034 method Methods 0.000 claims abstract description 60
- 208000035475 disorder Diseases 0.000 claims abstract description 43
- 230000002265 prevention Effects 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 239000003937 drug carrier Substances 0.000 claims abstract description 10
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 104
- 229960000890 hydrocortisone Drugs 0.000 claims description 52
- 210000003205 muscle Anatomy 0.000 claims description 30
- 241000282414 Homo sapiens Species 0.000 claims description 24
- 108090000623 proteins and genes Proteins 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 101000926939 Homo sapiens Glucocorticoid receptor Proteins 0.000 claims description 15
- 230000032683 aging Effects 0.000 claims description 15
- 230000004220 muscle function Effects 0.000 claims description 13
- 229940124639 Selective inhibitor Drugs 0.000 claims description 11
- 239000012472 biological sample Substances 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 208000014674 injury Diseases 0.000 claims description 10
- CLHMYBJIOZXCEX-UHFFFAOYSA-N 4-[[2-methyl-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]propanoyl]amino]adamantane-1-carboxamide Chemical compound C1C(C2)(C(N)=O)CC3CC2CC1C3NC(=O)C(C)(C)N(CC1)CCN1C1=CC=C(C(F)(F)F)C=N1 CLHMYBJIOZXCEX-UHFFFAOYSA-N 0.000 claims description 9
- 241001465754 Metazoa Species 0.000 claims description 9
- 102000004169 proteins and genes Human genes 0.000 claims description 9
- NCDZABJPWMBMIQ-INIZCTEOSA-N 2-[(3s)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]piperidin-3-yl]acetic acid Chemical compound CCCSC1=NC(N2C[C@H](CC(O)=O)CCC2)=CC=C1C(=O)NC1CCCCC1 NCDZABJPWMBMIQ-INIZCTEOSA-N 0.000 claims description 8
- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 claims description 8
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 claims description 8
- 230000001225 therapeutic effect Effects 0.000 claims description 8
- PTIFVLOBVCIMKL-UHFFFAOYSA-N 2-[3-[1-(4-chlorophenyl)cyclopropyl]-[1,2,4]triazolo[4,3-a]pyridin-8-yl]propan-2-ol Chemical compound N=1N=C2C(C(C)(O)C)=CC=CN2C=1C1(C=2C=CC(Cl)=CC=2)CC1 PTIFVLOBVCIMKL-UHFFFAOYSA-N 0.000 claims description 7
- -1 ABT305 Chemical compound 0.000 claims description 7
- 206010028289 Muscle atrophy Diseases 0.000 claims description 7
- 229960000516 bezafibrate Drugs 0.000 claims description 7
- 229960000530 carbenoxolone Drugs 0.000 claims description 7
- 229960000616 diflunisal Drugs 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 201000000585 muscular atrophy Diseases 0.000 claims description 7
- BDQCDIWFPIDPQU-NDEPHWFRSA-N n-methyl-5-[4-[1-[(1r)-3-oxospiro[2-benzofuran-1,3'-pyrrolidine]-1'-carbonyl]cyclopropyl]phenyl]pyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC=C1C1=CC=C(C2(CC2)C(=O)N2C[C@@]3(CC2)C2=CC=CC=C2C(=O)O3)C=C1 BDQCDIWFPIDPQU-NDEPHWFRSA-N 0.000 claims description 7
- 210000002381 plasma Anatomy 0.000 claims description 7
- 239000000523 sample Substances 0.000 claims description 7
- 238000012360 testing method Methods 0.000 claims description 7
- 208000008589 Obesity Diseases 0.000 claims description 6
- 208000027418 Wounds and injury Diseases 0.000 claims description 6
- 210000004369 blood Anatomy 0.000 claims description 6
- 239000008280 blood Substances 0.000 claims description 6
- 230000006378 damage Effects 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 235000020824 obesity Nutrition 0.000 claims description 6
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 5
- 230000003247 decreasing effect Effects 0.000 claims description 5
- 230000002255 enzymatic effect Effects 0.000 claims description 5
- 230000006718 epigenetic regulation Effects 0.000 claims description 5
- 230000004481 post-translational protein modification Effects 0.000 claims description 5
- 238000012216 screening Methods 0.000 claims description 5
- 210000002700 urine Anatomy 0.000 claims description 5
- 230000001172 regenerating effect Effects 0.000 claims description 4
- 230000011664 signaling Effects 0.000 claims description 4
- 208000036119 Frailty Diseases 0.000 claims description 2
- 206010003549 asthenia Diseases 0.000 claims description 2
- OBZHEBDUNPOCJG-SZTGPWMUSA-N carbenoxolone Chemical compound C([C@H]1C2=CC(=O)[C@@H]34)[C@](C)(C(O)=O)CC[C@@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@H]1[C@@]3(C)CC[C@@H](OC(=O)CCC(O)=O)C1(C)C OBZHEBDUNPOCJG-SZTGPWMUSA-N 0.000 claims 3
- 239000000203 mixture Substances 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 17
- 229930003316 Vitamin D Natural products 0.000 description 14
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 14
- 238000009472 formulation Methods 0.000 description 14
- 235000019166 vitamin D Nutrition 0.000 description 14
- 239000011710 vitamin D Substances 0.000 description 14
- 150000003710 vitamin D derivatives Chemical class 0.000 description 14
- 229940046008 vitamin d Drugs 0.000 description 14
- 230000005764 inhibitory process Effects 0.000 description 10
- 102100033417 Glucocorticoid receptor Human genes 0.000 description 9
- 239000003862 glucocorticoid Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000007935 oral tablet Substances 0.000 description 9
- 229940096978 oral tablet Drugs 0.000 description 8
- 108090000874 11-beta-hydroxysteroid dehydrogenases Proteins 0.000 description 7
- 102000004277 11-beta-hydroxysteroid dehydrogenases Human genes 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 230000011987 methylation Effects 0.000 description 7
- 238000007069 methylation reaction Methods 0.000 description 7
- 239000002243 precursor Substances 0.000 description 7
- 210000001057 smooth muscle myoblast Anatomy 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 230000008995 epigenetic change Effects 0.000 description 6
- 239000000849 selective androgen receptor modulator Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 6
- 102100039939 Growth/differentiation factor 8 Human genes 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 101100351033 Mus musculus Pax7 gene Proteins 0.000 description 5
- 108010056852 Myostatin Proteins 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 238000003745 diagnosis Methods 0.000 description 5
- 235000021196 dietary intervention Nutrition 0.000 description 5
- 230000004069 differentiation Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000008733 trauma Effects 0.000 description 4
- BQENDLAVTKRQMS-SBBGFIFASA-L Carbenoxolone sodium Chemical compound [Na+].[Na+].C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C([O-])=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](OC(=O)CCC([O-])=O)C1(C)C BQENDLAVTKRQMS-SBBGFIFASA-L 0.000 description 3
- 101150065958 NR3C1 gene Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 3
- 229960003105 metformin Drugs 0.000 description 3
- 229960003248 mifepristone Drugs 0.000 description 3
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 description 3
- 210000004940 nucleus Anatomy 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 210000002027 skeletal muscle Anatomy 0.000 description 3
- 239000013589 supplement Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229940037128 systemic glucocorticoids Drugs 0.000 description 3
- PBXJLTZMKLFZGS-ZANVPECISA-N (5s)-5-methyl-2-[[(1s)-1-(2-methylphenyl)ethyl]amino]-5-(trifluoromethyl)-1,3-thiazol-4-one Chemical compound N([C@@H](C)C=1C(=CC=CC=1)C)C1=NC(=O)[C@@](C)(C(F)(F)F)S1 PBXJLTZMKLFZGS-ZANVPECISA-N 0.000 description 2
- WZFZJEPHYDDFCT-UHFFFAOYSA-N 3-chloro-2-methyl-n-[4-[2-(3-oxomorpholin-4-yl)ethyl]-1,3-thiazol-2-yl]benzenesulfonamide Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)NC1=NC(CCN2C(COCC2)=O)=CS1 WZFZJEPHYDDFCT-UHFFFAOYSA-N 0.000 description 2
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 2
- 102000005606 Activins Human genes 0.000 description 2
- 108010059616 Activins Proteins 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 101710088194 Dehydrogenase Proteins 0.000 description 2
- 102000003676 Glucocorticoid Receptors Human genes 0.000 description 2
- 108090000079 Glucocorticoid Receptors Proteins 0.000 description 2
- 206010020100 Hip fracture Diseases 0.000 description 2
- 108010044467 Isoenzymes Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 244000269722 Thea sinensis Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000488 activin Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000003124 biologic agent Substances 0.000 description 2
- 239000013060 biological fluid Substances 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 239000013043 chemical agent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000011284 combination treatment Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 230000002542 deteriorative effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000009547 dual-energy X-ray absorptiometry Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000001973 epigenetic effect Effects 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 230000005021 gait Effects 0.000 description 2
- 235000009569 green tea Nutrition 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 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 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 201000000083 maturity-onset diabetes of the young type 1 Diseases 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000001964 muscle biopsy Methods 0.000 description 2
- 210000003098 myoblast Anatomy 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000002250 progressing effect Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical compound O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 description 1
- JNGVJMBLXIUVRD-SFHVURJKSA-N (2s)-3-(4-cyanophenoxy)-n-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)OC1=CC=C(C#N)C=C1 JNGVJMBLXIUVRD-SFHVURJKSA-N 0.000 description 1
- MMZFGTAMARVHAF-UHFFFAOYSA-N (3-hydroxy-3-pyrimidin-2-yl-8-azabicyclo[3.2.1]octan-8-yl)-[5-(1h-pyrazol-4-yl)thiophen-3-yl]methanone Chemical compound C1C(O)(C=2N=CC=CN=2)CC2CCC1N2C(=O)C(C=1)=CSC=1C=1C=NNC=1 MMZFGTAMARVHAF-UHFFFAOYSA-N 0.000 description 1
- ODRPEKCTTLECBX-HNNXBMFYSA-N (3s)-1-(3-chloro-2-methylphenyl)sulfonyl-n-cyclohexylpiperidine-3-carboxamide Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)N1C[C@@H](C(=O)NC2CCCCC2)CCC1 ODRPEKCTTLECBX-HNNXBMFYSA-N 0.000 description 1
- KNHNFKZUNFPPQE-MADCSZMMSA-N (5s)-2-{[(1s)-1-(2-fluorophenyl)ethyl]amino}-5-methyl-5-(trifluoromethyl)-1,3-thiazol-4(5h)-one Chemical compound N([C@@H](C)C=1C(=CC=CC=1)F)C1=NC(=O)[C@@](C)(C(F)(F)F)S1 KNHNFKZUNFPPQE-MADCSZMMSA-N 0.000 description 1
- GHCOGKQPGMIPPT-UHFFFAOYSA-N 1-oxo-n-phenyl-1,3-thiazol-2-amine Chemical class O=S1C=CN=C1NC1=CC=CC=C1 GHCOGKQPGMIPPT-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical class C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- YDPRNGAPPNPYQQ-UHFFFAOYSA-N 3-chloro-2-methyl-n-[4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1,3-thiazol-2-yl]benzenesulfonamide Chemical compound C1CN(C)CCN1C(=O)CC1=CSC(NS(=O)(=O)C=2C(=C(Cl)C=CC=2)C)=N1 YDPRNGAPPNPYQQ-UHFFFAOYSA-N 0.000 description 1
- BUEXHNPQNIWNFB-UHFFFAOYSA-N 4-[[2-methyl-2-[[4-(trifluoromethyl)phenyl]methoxy]propanoyl]amino]adamantane-1-carboxamide Chemical compound C1C(C2)(C(N)=O)CC3CC2CC1C3NC(=O)C(C)(C)OCC1=CC=C(C(F)(F)F)C=C1 BUEXHNPQNIWNFB-UHFFFAOYSA-N 0.000 description 1
- 102000018918 Activin Receptors Human genes 0.000 description 1
- 108010052946 Activin Receptors Proteins 0.000 description 1
- 102000014777 Adipokines Human genes 0.000 description 1
- 108010078606 Adipokines Proteins 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- 239000012110 Alexa Fluor 594 Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- ZAZOPXOKXNYGDE-ZDUSSCGKSA-N CC(C)(c1ccccc1F)NC(S[C@]1(C)C(F)(F)F)=NC1=O Chemical compound CC(C)(c1ccccc1F)NC(S[C@]1(C)C(F)(F)F)=NC1=O ZAZOPXOKXNYGDE-ZDUSSCGKSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- 108010002154 Cortisone Reductase Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 230000007067 DNA methylation Effects 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- WMBWREPUVVBILR-UHFFFAOYSA-N GCG Natural products C=1C(O)=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
- 102000000393 Ghrelin Receptors Human genes 0.000 description 1
- 108010016122 Ghrelin Receptors 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
- 244000303040 Glycyrrhiza glabra Species 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000018127 Idiopathic intracranial hypertension Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 1
- 208000007117 Oral Ulcer Diseases 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 208000010067 Pituitary ACTH Hypersecretion Diseases 0.000 description 1
- 208000020627 Pituitary-dependent Cushing syndrome Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- CKBZJTAMRPPVSR-UHFFFAOYSA-N adamantane-1-carboxamide Chemical compound C1C(C2)CC3CC2CC1(C(=O)N)C3 CKBZJTAMRPPVSR-UHFFFAOYSA-N 0.000 description 1
- 239000000478 adipokine Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- VQPFSIRUEPQQPP-MXBOTTGLSA-N anamorelin Chemical compound C([C@@]1(C(=O)N(C)N(C)C)CN(CCC1)C(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)C(C)(C)N)C1=CC=CC=C1 VQPFSIRUEPQQPP-MXBOTTGLSA-N 0.000 description 1
- 229950005896 anamorelin Drugs 0.000 description 1
- 108010052640 anamorelin Proteins 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 102000016966 beta-2 Adrenergic Receptors Human genes 0.000 description 1
- 108010014499 beta-2 Adrenergic Receptors Proteins 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
- 229940043052 bezafibrate oral tablet Drugs 0.000 description 1
- 229950006326 bimagrumab Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000001369 bisulfite sequencing Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 230000001925 catabolic effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 235000019646 color tone Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000018823 dietary intake Nutrition 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
- 229940031453 diflunisal oral tablet Drugs 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 229940030275 epigallocatechin gallate Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009920 food preservation Methods 0.000 description 1
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 1
- 229960002848 formoterol Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 235000008085 high protein diet Nutrition 0.000 description 1
- 238000011540 hip replacement Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 238000003365 immunocytochemistry Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000037230 mobility Effects 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 230000037257 muscle growth Effects 0.000 description 1
- 210000001665 muscle stem cell Anatomy 0.000 description 1
- 230000001114 myogenic effect Effects 0.000 description 1
- 210000001087 myotubule Anatomy 0.000 description 1
- 210000000715 neuromuscular junction Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 238000013116 obese mouse model Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 239000012663 orally bioavailable inhibitor Substances 0.000 description 1
- 229940044205 orally bioavailable inhibitor Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 230000036314 physical performance Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000006041 probiotic Substances 0.000 description 1
- 230000000529 probiotic effect Effects 0.000 description 1
- 235000018291 probiotics Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 208000001381 pseudotumor cerebri Diseases 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 210000003314 quadriceps muscle Anatomy 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 230000025175 skeletal muscle hypertrophy Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/603—Salicylic acid; Derivatives thereof having further aromatic rings, e.g. diflunisal
-
- 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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- 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
-
- 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
- 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
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
Definitions
- This invention relates generally to the treatment (or prevention or amelioration) of sarcopenia and related diseases and disorders. More particularly, the invention relates to the treatment of sarcopenia associated with ageing, obesity and sarcopenia secondary to disease, injury, trauma or medication; to pharmaceutical compositions useful in the treatment of such conditions, and also to methods for identifying patients who are likely candidates for treatment. Related methods of screening and diagnosis are also disclosed. Background
- Sarcopenia (loss of muscle mass and strength) affects between 5-13% of 60-70 year olds and 11-50% of over 80 year olds. It is a major public health issue, with the number of sarcopenic patients likely to dramatically increase in the next 30 years. It has been estimated that overall prevalence rate in the elderly will rise in Europe from 11.1 %-20.2% in 2016 to 12.9%-22.3% in 2045. Sarcopenia is a strong predictor of low quality of life, mobility impairment, falls, fractures and all-cause mortality. It is the second most common cause of disability in humans. Sarcopenia is also an independent risk factor for other serious health conditions, such as cardiovascular disease.
- EWGSOP European working group on sarcopenia in older people
- diagnostic criteria which include muscle mass (appendicular lean mass divided by height squared, men:£7.23kg/m 2 , womans 5.67kg/m 2 ) and muscle function (gait speed ⁇ 0.8 m/s; or grip strength, men: ⁇ 30kg, women ⁇ 20kg).
- Sarcopenia was classified in the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) in 2016 under code M62.84.
- Sarcopenia is currently treated by use of resistance exercise and nutritional interventions, such as high protein diet and vitamin D. These interventions to some extent rescue satellite cell proliferative capacity and reserve numbers, but the quality of evidence for efficacy is low. Testosterone treatment has been shown to increase muscle size and power but it also induces undesirable side effects.
- SARM Selective androgen receptor modulators
- Androgens and SARMs are thought to increase muscle mass without improvements in muscle strength or function and have no effect on regenerative capacity (i.e. satellite cells). Accordingly, these constitute at best a symptomatic, not disease-modifying, treatment.
- Myostatin inhibition is a secreted protein that normally inhibits muscle growth. Myostatin-null animals and humans show skeletal muscle hypertrophy. Myostatin inhibitors, and inhibitors of its cognate receptor activin, have been developed. Most have shown at best only modest efficacy or a lack of long-term efficacy, and require regular injections, which has negative implications for compliance.
- the present inventors have undertaken research which has enabled them to propose a novel approach to the treatment (including prevention or amelioration) of sarcopenia and sarcopenic diseases, based on a new understanding of the mechanisms involved in these diseases.
- the present inventors have identified the significance of the observation that the decrease in proliferative capacity of muscle associated with ageing and other‘insults’ is mediated in part by cortisol.
- Cortisol is an active glucocorticoid that is convertible from the inert cortisone by action of an enzyme, cortisone reductase (also known as HSD11 B1 or I ⁇ b-HSDI).
- cortisone reductase also known as HSD11 B1 or I ⁇ b-HSDI
- the present invention provides an inhibitor of HSD11 B1 for use in the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder.
- the present invention alternatively provides a method for the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder, which method comprises administration to a human or non-human animal in need thereof of a therapeutically effective amount of an inhibitor of HSD11 B1.
- each aspect of the present invention is to be understood as applying to either a human or non-human animal.
- the subject to be treated is a human patient.
- Sarcopenia primarily relates to degenerative loss of skeletal muscle mass, quality and strength associated with ageing.
- the above“sarcopenic” symptoms are also seen in other, non-age related, conditions.
- the terms“sarcopenic disease” or“sarcopenic disorder” should be understood as encompassing these.
- the invention encompasses sarcopenia associated with ageing, obesity and sarcopenia secondary to disease, injury, trauma or medication.
- glucocorticoid glucocorticoid
- sarcopenia steroid-induced, in particular glucocorticoid (GC)-induced sarcopenia, which can be seen, for example, in individuals who (for whatever reason) are subject to, often high, exposure to endogenous or exogenous glucocorticoids. In particular, this may include exposure to higher than normal levels of cortisol.
- GC glucocorticoid
- “Sarcopenic disease” also encompasses secondary sarcopenia, for example that consequent upon surgery, such as that suffered by people that are immobilised after a bone fracture, especially after hip fracture or hip replacement surgery. This is particularly prevalent in elderly patients with hip fractures, but is not restricted to this group.
- HSD11 B1 inhibition as a therapeutic strategy to treat the loss of muscle strength and regenerative capacity, including muscle wasting, associated with age (sarcopenia), injury, disease, trauma or medication (e.g. sarcopenic obesity or glucocorticoid- induced sarcopenia).
- the present invention thus provides an inhibitor of HSD11 B1 , or a pharmaceutical formulation thereof in association with a pharmaceutically acceptable carrier therefor, for use in the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder in a subject in need thereof.
- a method for the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder comprises administration to a subject in need thereof of a therapeutically effective amount of an inhibitor of HSD11 B1.
- the invention also provides the use of an inhibitor of HSD11 B1 , or a pharmaceutical formulation thereof in association with a pharmaceutically acceptable carrier therefor, in the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder in a subject in need thereof.
- the invention provides the use of an inhibitor of HSD11 B1 in the preparation of a medicament for the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder in a subject in need thereof.
- HSD11 B1 inhibitors Suitable HSD11 B1 inhibitors and pharmaceutical formulations for use in accordance with the invention are described further below.
- Another aspect of the invention provides an inhibitor, method or use according to any aspect of the invention, comprised in a therapeutic strategy to treat the loss of muscle strength or muscle regenerative capacity, optionally muscle wasting, associated with age (sarcopenia), injury, disease, trauma, or medication.
- sarcopenia sarcopenic obesity or glucocorticoid-induced sarcopenia.
- the invention provides an inhibitor, method or use according to any aspect of the invention wherein the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder comprises inhibiting HSD11 B1 signalling, and decreasing cortisol in the subject.
- Decreasing cortisol suitably means decreasing the level of cortisol in the blood or plasma of the subject.
- the subject in need may be identified in a test for sarcopenia and/or a sarcopenic disease or disorder.
- the subject in need may be identified by measuring the level of cortisol in a biological sample taken from the subject and/or by analysing the DNA sequence, epigenetic regulation, transcript or protein levels, enzymatic activity or post-translational modification of their HSD11B1 and/or NR3C1 genes.
- a subject in need of treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder is one having an elevated cortisol level, compared to levels in a control population or a predetermined standard.
- the elevated level may be, for example, in blood, plasma or urine.
- the elevated level in humans may be a cortisol level of equal to or greater than 6ng/ml of sample body fluid.
- HSD11 B1 inhibition is a promising therapeutic strategy for sarcopenia and sarcopenic conditions as described herein that offers advantages over the existing therapies by avoiding at least some of the problems associated with the existing therapies mentioned above.
- glucocorticoid system in particular, is modulated at an epigenetic level as a result of life environment.
- prenatal stress and/or adverse early life experience has been shown to cause increased methylation of exon 1 F (in humans) or GR17 (in rats) of the NR3C1 gene in many different scenarios.
- Epigenetic marks are a result of the interaction of genetic predisposition and environmental influences and, as such, they are more informative for multifactorial diseases than stratification signature using genotype alone.
- the present invention further provides method of identifying a human or non human animal suitable for or in need of the treatment, prevention or amelioration or sarcopenia or a sarcopenic disease or disorder by use or administration of an inhibitor of HSD11 B1 , which method of identifying comprises diagnosing epigenetic changes to a gene selected from HSD11B1 and NR3C1, and genes that interact with HSD11B1 and NR3C1
- Such epigenetic changes may for example comprise increased methylation or increased phosphorylation of the NR3C1 gene over levels in a control population.
- Suitable techniques for measuring epigenetic changes are well known, and include bisulphate sequencing of candidate genes from patient DNA that enables determination of the methylation status of NR3C1 (as described by Meissner, Alexander, et al. in Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis, Nucleic acids resea rch 33.18 (2005): 5868-5877). Additionally, analysing publically-deposited methylation data from control samples (non-diseased) will allow comparison of the relative extent of gene methylation in patient versus control populations.
- Mifepristone is a non-specific NR3C1 inhibitor: in a small experimental clinical study of mifepristone to treat anxiety and cognitive decline in individuals over 60 years of age, mifepristone showed an improvement in memory, executive function and worry severity only for those individuals with baseline cortisol >6ng/ml.
- NR3C1 phosphorylation may also be a marker of subjects exposed to high cortisol and so likely responsive to HSD11 B1 inhibition. Therefore, we propose that patients that may benefit from HSD11 B1 inhibition are identifiable by their exhibiting high baseline cortisol.
- the invention also provides a method of identifying a human or non-human animal suitable for or in need of the treatment, prevention or amelioration or sarcopenia or a sarcopenic disease or disorder by use or administration of an inhibitor of HSD11 B1 , which method of identifying comprises:
- step (b) comparing the level determined in step (a) with a baseline of cortisol in a control population of animals which do not have sarcopenia or a sarcopenic disease or disorder;
- step (c) selecting for animals in which the baseline level determined in step (a) is greater than that seen in step (b).
- Determining the level of cortisol in step (a) and/or step (b) can be carried out in blood, plasma, urine or other biological fluids using any suitable method, and such methods are well known, such as immunoassay and chromatographic methods (LC-MS/MS), as described by Gatti, Rosalba, et al. in Cortisol assays and diagnostic laboratory procedures in human biological fluids, Clinical biochemistry 42.12 (2009): 1205-1217. Further methods are mentioned hereinbelow and are discussed by El-Farhan, Nadia, D. Aled Rees, and Carol Evans in Measuring cortisol in serum, urine and saliva-are our assays good enough?, Annals of clinical biochemistry 54.3 (2017): 308-322.
- LC-MS/MS immunoassay and chromatographic methods
- the invention also provides a method of diagnosing sarcopenia or a sarcopenic disease or disorder comprising the steps of:
- the above method of diagnosing sarcopenia or a sarcopenic disease or disorder may, if desired, additionally comprise the step of diagnosing epigenetic changes to a gene selected from HSD11B1 and NR3C1, and/or genes that interact with HSD11B1 and NR3C1.
- Such epigenetic changes may, for example, comprise increased methylation or increased phosphorylation of the NR3C1 gene compared to the level of methylation or increased phosphorylation (respectively) in a control population or predetermined standard. Combining both approaches is likely to improve the accuracy of diagnosis.
- the one or more control samples may be isolated from a subject with or without sarcopenia or a sarcopenic disease or disorder. Accordingly, comparison with such control samples may provide an indication of the subject having sarcopenia, or deteriorating towards the state of sarcopenia or a sarcopenic disease or disorder.
- a control sample may be from the same subject, taken at an earlier time point.
- a reference level may be determined based on previous analyses carried out on the same subject.
- the invention provides a method of determining the progression of sarcopenia or sarcopenic disease or disorder in a subject comprising the steps:
- step (c) comparing the level of cortisol determined in step (b) with a cortisol level determined from a sample taken from the same subject at an earlier time.
- This method may then be used to determine the effectiveness, over time, of the use of a particular inhibitor in a method for treatment (including amelioration or prophylaxis) of sarcopenia or sarcopenic disease or disorder in a particular patient.
- control samples may enable the determination of a standard (reference level), against which the test sample(s) (from the subject or patient) can be compared.
- a level of cortisol below a pre-determined reference level may indicate the subject does not have sarcopenia or a sarcopenic disease or disorder, while a level of cortisol above a different predetermined reference level may indicate the subject does have sarcopenia or a sarcopenic disease or disorder.
- a suitable reference level may be about 6ng/ml cortisol, such that subjects having at least this concentration of cortisol, may have sarcopenia or a sarcopenic disease or disorder, or may be deteriorating towards the state of sarcopenia or a sarcopenic disease or disorder.
- the biological sample used in any aspect of the present invention may be any suitable sample for isolating from the body of a subject, such as a blood sample (e.g. plasma or serum) or tissue biopsy (in particular a muscle biopsy), or urine.
- a blood sample e.g. plasma or serum
- tissue biopsy in particular a muscle biopsy
- the method may comprise a further step of administering an HSD11 B1 inhibitor to the subject, wherein the subject has been diagnosed as having sarcopenia or a sarcopenic disease or disorder or as being at risk of developing such a condition, or diagnosed as having or progressing towards sarcopenia or a sarcopenic disease or disorder.
- the method may comprise a further step of applying a dietary intervention for maintaining or increasing muscle function and/or mass wherein the subject has been diagnosed as having sarcopenia or a sarcopenic disease or disorder or being at risk of developing such a condition, or diagnosed as having or progressing towards sarcopenia or a sarcopenic disease or disorder.
- the dietary intervention is for maintaining or increasing muscle mass.
- Example dietary interventions include high protein and/or carbohydrate diets.
- the dietary intervention may be or include the use or administration of vitamin D, as described further below in relation to combination treatments.
- the above-described method steps may also be used to provide a method of diagnosing loss of muscle function and/or mass with age.
- HSD11B1 polymorphisms in HSD11B1 are associated with raised physiological cortisol levels and are also associated with varying susceptibility to glucocorticoids.
- HSD11 B1 inhibition may be identified from detecting one or more polymorphic variations in the HSD11B1 and/or NR3C1 genes.
- patients may be identifiable from detecting a fragment of such variations or such genes, or the proteins encoded thereby, for example by detecting an amino acid sequence that has at least 60% identity to the wild type; preferably about 70% or 80% or 90-100% identity.
- HSD11 B1 inhibitors for use in the invention or in the methods of treatment of the invention include any chemical or biological agent that is known or can be identified as such, or a chemical or biological agent that down-regulates cortisol or a precursor thereof, or that inactivates or reduces activation of the glucocorticoid receptor (NR3C1) or precursor or activator thereof.
- the inhibitor is a selective inhibitor of HSD11 B1 , and especially preferred are those with high potency.
- Suitable HSD11 B1 inhibitors include: 11b-HDS1 inhibitors developed for the treatment of type 2 diabetes mellitus.
- 11b-HDS1 inhibitors developed for the treatment of type 2 diabetes mellitus.
- salicylate downregulates I ⁇ b-HSDI expression in adipose tissue in obese mice and hence may explain why aspirin improves glycemic control in type 2 diabetes.
- Newer compounds such as adamantyltriazoles, arylsulfonamidothiazoles, anilinothiazolones, BVT2733, INCB- 13739, MK-0916 and MK-0736, are currently under investigation, and the preliminary findings from both experimental and human studies show a favourable effect on glucose and lipid metabolism, weight reduction and adipokine levels.
- Butylated hydroxyanisole is a widely used antioxidant for food preservation, and is a selective inhibitor of HSD11 B2, of the natural products, 18a-glycyrrhizic acid from the root of glycyrrhiza glabra, and also curcumin and derivatives have been identified as HSD11 B1 inhibitors.
- Green tea is a complex mixture of various phenolics with contents varying with production and processing.
- Potent and selective inhibitors of the HSD11 B1 enzyme also include those known as AZD4017, ABT384, ABT305, INCB-13739, BVT.3498, BVT 116429, CRx-401 , bezafibrate; CRx-401 , diflunisal; BMS-823778; UE2343; and carbenoxolone, respectively:
- AZD4017 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]piperidin-3-yl]acetic acid.
- AZD4017 is a selective, orally bioavailable inhibitor of the enzyme 11-b- hydroxysteroid dehydrogenase type 1 , with potential protective activity.
- AZD4017 has been used in clinical trials for a number of indications: Idiopathic Intracranial Hypertension (400 mg oral tablet twice daily for 12 weeks); Obesity (oral suspensions 1200 mg once daily for 10 days); Diabetes Mellitus Type 2 (1st trial: oral suspension, ascending multiple doses starting at 75 mg once daily; 2nd trial: 400 mg oral tablet twice daily for 35 days); Iatrogenic Cushing's Disease (400 mg twice daily for 7 days with 20 mg prednisolone); Raised Intraocular Pressure (Europe: 200 mg oral tablet once daily for 28 days; USA: 2 x 200 mg oral tablets twice daily for 28 days).
- ABT384 is a potent, selective inhibitor of 11-b-hydroxysteroid dehydrogenase type 1. ABT384 has been used in clinical trials for adults with mild to moderate Alzheimer’s disease with subjects receiving 10 mg or 50 mg of ABT384 once daily for 12 weeks.
- INCB-13739 is an orally available small molecule inhibitor of 11-b- hydroxysteroid dehydrogenase type 1. INCB-13739 has been used in clinical trials for adults with Type 2 Diabetes, with a maximum dose of 200 mg per day (either as one dose, combined with metformin or 100 mg twice daily, alone).
- BVT3498 3-chloro-2-methyl-N-[4-[2-(3-oxomorpholin-4-yl)ethyl]-1 ,3-thiazol-2- yljbenzenesulphonamide (BVT 3498).
- BVT3498 is a highly selective inhibitor of the enzyme 11-b-hydroxysteroid dehydrogenase type 1.
- BVT.3498 has been used in clinical trials for adults with Type 2 Diabetes, completing phase I trials in 2002 and entering phase II trials. The trials were stopped in 2005.
- BVT 116429 is a selective inhibitor of the enzyme I I-b-hydroxysteroid dehydrogenase type 1. Studies have been performed on diabetic mice using up to 30 mg/kg once daily for 10 days.
- CRx-401 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid
- CRx-401 diflunisal
- CRx-401 is a novel insulin sensitizer designed to provide anti-diabetic activity. It consists of a low dose of diflunisal in conjunction with a modified-release therapeutic dose of bezafibrate. It has been used in clinical trials for patients with Type II Diabetes taking metformin. Patients were given CRx-401 consisting of 400 mg bezafibrate sustained-release and 250 mg diflunisal once daily.
- BMS-823778 is an orally available potent and selective inhibitor of 11-b- hydroxysteroid-dehydrogenase 1. It has been used in clinical trails for the conditions of: Atherosclerotic Cardiovascular Disease (2 mg - 15 g orally once daily for 1 year); Hypertension (2 mg - 15 mg orally once daily for 12 weeks); Dyslipidemia (2 mg - 20 mg orally once daily for 28 days); and Diabetes Mellitus Type 2 (2 mg - 20 mg orally once daily for 28 days, with metformin).
- UE2343 (3-hydroxy-3-pyrimidin-2-yl-8-azabicyclo[3.2.1 ]octan-8-yl)-[5-(1 H-pyrazol-4-yl)thiophen-3- yl]methanone (UE2343).
- UE2343 is a potent, orally bioavailable, brain-penetrant 11-b- hydroxysteroid-dehydrogenase 1 inhibitor.
- Clinical trials have evaluated the safety, tolerability of efficacy of XanamemTM (comprising UE2343) in subjects with mild dementia due to Alzheimer’s Disease. In the trial, oral XanamemTM 10 mg capsules were given once daily.
- Carbenoxolone is a hemisuccinate derivative of glycyrrhetinic acid and is frequently used in the treatment of peptic ulcers and the topical treatment of mouth ulcers. It is also a non- selective I I-b-hydroxysteroid-dehydrogenase 1 inhibitor that also inhibits 11-b- hydroxysteroid-dehydrogenase 2. It has also been used in clinical trials for Type 2 diabetes, with a dosage of 100 mg three times per day.
- inhibitors include derivatives thereof well-known for use in the pharmaceutical art. Accordingly, wherever such inhibitors are mentioned herein are also encompassed their pharmaceutically acceptable salts or solvates and hydrates.
- pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Also encompassed are salts that are not pharmaceutically acceptable when they are used as precursors to the free inhibitors or to their pharmaceutically acceptable salts or in other synthetic manipulations.
- the inhibitors for use according to this invention include any metabolites thereof that are therapeutically active.
- the inhibitors for use according to this invention include any prodrugs thereof. Prodrugs are compounds that are converted to therapeutically active compounds as they are being administered to a patient or after they have been administered to a patient.
- the inhibitors for use according to this invention are selective inhibitors of the I ⁇ b-HSDI (or HSD11 B1) enzyme.
- I ⁇ b-HSDI or HSD11 B1 enzyme.
- glucocorticoid concentrations are modulated by two enzymes of I ⁇ b-HSD (namely, IIb-HSDI and I ⁇ -HSD2), which have differing cofactor requirements and substrate affinities, and in vitro studies have shown that llb-HSDI is capable of acting as both a reductase and a dehydrogenase.
- selectivity for the type 1 isoenzyme, 11b-HDSl is preferred.
- the invention provides a method of screening for an agent capable of inhibiting HSD11 B1 levels in a patient in need thereof comprising the steps of:
- step (c) comparing the level of cortisol or precursor thereof determined in step (b) with a cortisol or precursor level in a control population of cells which has not been contacted with the candidate inhibitor.
- the method is an in vitro method.
- the candidate inhibitor is optionally comprised in a library of candidate inhibitors.
- the invention provides an inhibitor for decreasing cortisol levels or levels of a cortisol precursor in a patient, wherein the inhibitor has been identified by the method of screening of the invention.
- level of cortisol refers to the amount of cortisol that is found in a sample, e.g. of serum or plasma. The amount of may be determined directly or indirectly. Direct methods of determining cortisol include chromatographic methods, radioimmunoassay, enzyme- linked immunoassays and non-isotopic immunoassays. Liquid chromatography based mass spectrometry (LC-MS/MS) are commonly used to measure serum and plasma cortisol levels from multiple time points with high sensitivity. The effect of the candidate inhibitor on cortisol levels may be assessed as a function of time, by carrying out repeated measurements over a particular time-course.
- LC-MS/MS Liquid chromatography based mass spectrometry
- the present invention also provides for the case when the HSD11 B1 inhibitor is used, administered or formulated together with vitamin D.
- the vitamin D may be administered by oral, parental, sub-lingual, sub-cutaneous, transdermal or intra-nasal administration. It may be administered as an oral vitamin D supplement or a probiotic supplement.
- the vitamin D may, for example, be in the form of a nutritional composition or supplement, or a diet product.
- the patient may have previously been determined to be vitamin D deficient.
- the invention provides a method of maintaining or increasing muscle function and/or mass and/or preventing or reducing muscle wasting in a patient in need thereof, particularly an ageing or elderly patient, comprising administering to the patient the inhibitor and vitamin D.
- the vitamin D maintains or increases muscle mass; alternatively, the vitamin D substantially prevents or reduces a reduction in muscle mass.
- the invention provides for the use or method according to the invention of a combined preparation of an inhibitor and vitamin D, wherein the inhibitor and vitamin D are for simultaneous, combined, sequential or separate administration to a patient.
- HSD11 B1 inhibitor instead of or as well as combining an inhibitor with vitamin D, other combinations comprising an HSD11 B1 inhibitor are within the scope of this invention, such as a diet product, as mentioned above in relation to patient identification/diagnosis, and/or an exercise regime may be combined with the inhibitor to maintain or increase muscle function and/or mass.
- a diet product as mentioned above in relation to patient identification/diagnosis, and/or an exercise regime may be combined with the inhibitor to maintain or increase muscle function and/or mass.
- one or more other pharmacologically active agent(s) may be combined with an inhibitor, including selective androgen receptor modulators (SARMs), such as ostarine or myostatin blockers (e.g. myostatin antibodies, activin receptor antibodies and activin receptor-Fc), such as LY2495655 or Bimagrumab, or beta2 receptor agonists such as formoterol, or ghrelin receptor agonists such as anamorelin, or anabolic catabolic transforming agents (ACTA), such as MT-102, or other compounds mentioned hereinabove.
- SARMs selective androgen receptor modulators
- ostarine or myostatin blockers e.g. myostatin antibodies, activin receptor antibodies and activin receptor-Fc
- beta2 receptor agonists such as formoterol
- ghrelin receptor agonists such as anamorelin
- anabolic catabolic transforming agents (ACTA) such as MT-102, or other compounds mentioned herein
- the inhibitors may be administered at any suitable pharmacological dose, it being understood that the exact amounts will depend upon the nature of the inhibitor.
- suitable doses may comprise a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
- the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 300 milligrams, especially from about 1 mg to about 100mg
- the total daily dose will generally be in the range of from about 7 milligrams to about 350 milligrams.
- such doses may comprise in the range of from about 50 to 500 mg per day, such as about 240mg or about 100mg per day. This dosage regimen may be adjusted to provide the optimal therapeutic response.
- Another aspect of the present invention provides a use or method as described herein, wherein the inhibitor is comprised in a pharmaceutical composition or formulation together with a pharmaceutically acceptable carrier therefor.
- compositions such as those described above.
- the inhibitors can be brought into intimate physical admixture with a pharmaceutical carrier according to conventional pharmaceutical formulating techniques.
- the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
- the active inhibitors can also be administered as intranasal formulations, such as, for example, liquid drops or spray.
- any of the usual pharmaceutical excipients may be employed, such as, for example, diluents of a solid or liquid nature, flavouring agents, preservatives, colouring agents, and the like.
- Oral liquid preparations may be in the form of, for example, suspensions, elixirs and solutions. Such liquid preparations may comprise sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavouring.
- Oral solid preparations are preferred over oral liquid preparations and are preferably in the form of, for example, powders, hard and soft capsules and tablets.
- the carrier may include one or more of: starches, sugars, microcrystalline cellulose, solid or liquid diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
- the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
- a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
- tablets and capsules represent the most advantageous oral dosage unit form.
- tablets may be coated by standard aqueous or non-aqueous techniques.
- tablets may be coated with shellac, sugar or both.
- Such compositions and preparations will preferably contain at least 0.1 % of active inhibitor.
- the percentage of active inhibitor in these compositions may, of course, be varied and may conveniently be between about 2% to about 60% by weight of the unit dose.
- the amount of active inhibitor in such therapeutically useful compositions is such that an effective dosage will be obtained.
- Various other materials may be present to act as coatings or to modify the physical form of the dosage unit.
- the pharmaceutical forms include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- Solutions or suspensions of these active inhibitors can be prepared in water for injections, optionally suitably mixed with a surfactant such as hydroxypropylcellulose.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils.
- the carrier can be a solvent or dispersion medium containing, for example, water, an alcohol (e.g. ethanol), a polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycols), suitable mixtures thereof, and vegetable oils, and combinations thereof.
- the form must be sterile and must be fluid to enable administration via a syringe.
- the formulation must be stable under the conditions of manufacture and storage, according to regulatory requirements. Under ordinary conditions of storage and use, these preparations optionally comprise a preservative or antimicrobial agent to prevent the growth of microorganisms.
- the present invention further provides a pharmaceutical formulation comprising an inhibitor of HSD11 B1 and a pharmaceutically acceptable carrier therefor, for use in the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder.
- the present invention alternatively provides a method for the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder, which method comprises administration to a human or non-human animal in need thereof of a therapeutically effective amount of a pharmaceutical formulation comprising an inhibitor of HSD11 B1 and a pharmaceutically acceptable carrier therefor.
- the invention provides a means to address loss of muscle function and mass that occurs with age.
- Age-related loss of muscle function and mass occurs inevitably in all individuals, however its progression depends on a range of genetic and environmental factors, such as physical activity and nutritional intake.
- sarcopenia as referred to in the present invention is defined as occurring at the point at which the age-related loss of muscle mass and function becomes debilitating and impacts on quality of life (Sayer, A. A. et al. (2013) Age Ageing 42: 145- 150).
- the present invention encompasses “sarcopenic” symptoms such as degenerative loss of skeletal muscle mass, quality and strength as seen in other non-age related conditions; and, in relation to the present invention, the terms “sarcopenic disease” or“sarcopenic disorder” are to be understood in a broad sense as encompassing such conditions.
- the inhibitor for use according to the invention provides in a patient an increased effect of: (a) maintaining or increasing muscle function and/or mass in an ageing subject; (b) preventing or reducing muscle wasting in an ageing subject; and/or (c) treating sarcopenia, sarcopenic disease or a sarcopenic disorder, compared to patient’s baseline.
- the invention is particularly applicable to ageing subjects, for example, a human subject over the age of 30, or of an age in the range of from 30 to 100 years old.
- the muscle referred to herein is skeletal muscle.
- references herein to treatment include curative and prophylactic treatment; it also includes arresting progression in the severity of a disease or disorder (i.e. amelioration by varying degrees and prevention are both encompassed).
- the treatment of mammals, particularly humans, is preferred.
- both human and veterinary treatments are within the scope of the invention.
- the age of the animal would be scaled from the human situation using the average lifespan for calibration.
- the inhibitors, compositions, uses and methods according to the invention may provide for the maintenance of or increase in muscle function and/or mass in an ageing subject.
- muscle function refers to the ability of a muscle to perform in a manner that does not negatively impact on the life of a subject, and encompasses parameters of muscle strength, muscle contraction, muscle endurance and/or muscle elasticity.
- Suitable tests for assessing muscle function include grip strength assessment using a dynamometer; one repeat maximum on leg press, chest press or leg extension; gait speed; 6 min walk test; time up and go; short physical performance battery; Fried frailty criteria; and stair climbing time assessments.
- Muscle mass (which may equate with muscle volume, muscle thickness or myofibre/muscle fiber size) may be measured by dual-energy X-ray absorptiometry (DXA) or bio-impedance tests.
- DXA dual-energy X-ray absorptiometry
- MRI may be used for assessing muscle volume and ultra-sound may be used for assessing muscle thickness and pennation angle.
- the inhibitors, compositions, uses and methods of the invention provide for the maintenance of or increase in muscle mass in an ageing subject in accordance with the aforementioned tests and measurements.
- muscle mass increases by at least 1 %, such as 1-2.5%, 1-5%, 1-10% or 1-20%, relative to either baseline or just prior to the start of treatment with an inhibitor according to the invention.
- Figure 1A is a graph showing the results of Pax7 + cell number experiments described below in Example 1 ; and Figure 1 B is a graph showing the results of the Fusion Index calculated on the basis of the experiments described below in Example 1.
- HCS Hertfordshire Cohort Study
- ALM appendicular lean mass
- fat mass was assessed by dual-energy x- ray absorptiometry (DXA) (Hologic Discovery, software version 12.5) for all participants.
- DXA dual-energy x- ray absorptiometry
- Isometric grip strength (kg) was measured three times in each hand using a Jamar handheld hydraulic dynamometer (Promedics, UK) and the highest value of six measures was used for analysis. Customary walking speed was measured over a three-metre course.
- Percutaneous muscle biopsies of the vastus lateralis were conducted, biopsies were digested with collagenase and muscle satellite cells isolated and stored. Myogenic purity of sorted cell cultures was measured using immunocytochemistry with CD56 as a marker.
- cells were grown in differentiation media (DM EM containing 2% HS and 1 % P/S). Cultures derived from 3 sarcopenic donors (defined in Cruz Jenioft (2019) Age and Ageing, Volume 48, Issue 1, Pages 16-31) and two aged matched controls (one repeated as a technical replicate) were assessed for differentiation potential and renewal capacity.
- An AxioCam MRm digital camera (Zeiss) was used to capture grey-scale images, whilst Axiovision software was used to assign colour tones corresponding to the emission wavelength of the secondary antibody. To ensure all counts were comparable, cells from the same experiment were photographed at identical exposures. Cells on raw unadjusted images were counted using the ‘Count’ feature of ImageJ. To calculate the fusion index, the number of nuclei incorporated into the myotubes (containing 2+ nuclei) was counted and the ratio of this number to the total number of nuclei was determined.
- FIG. 1A Pax7+ Cells are reduced in Sarcopenic patient-derived myoblasts and Pax7+ Cells in Sarcopenic patients are normalized by ABT384.
- Figure 1 B illustrates that the percentage of cells fused to form differentiated myotubes (Fusion Index) is not affected by the treatment.
- Example Formulations and Treatments for Sarcopenia in Insulin Sensitive Patients A number of example formulations are provided below along with suggested dosage regimes. It will be understood that these are for illustrative purposes and these would be optimized during further experimentation, which may include clinical trials. For simplicity, the formulations do not stipulate any non-active components (such as pharmaceutically acceptable carriers or excipients etc.)
- Formulation 2E Diflunisal - Oral Tablet for the Treatment of Sarcopenia
- Formulation 2F BMS-823778 - Oral Inhaled Solution for the Treatment of Sarcopenia
- HSD11 B1 inhibitors could also be employed in place of those outlined above.
- the therapeutically effective doses will of course depend on the activity and format of the chosen inhibitor.
- Organism Homo sapiens (Human) from http://www.uniprot.org/uniprot/P288451:
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to an inhibitor of HSD11B1, or a pharmaceutical formulation thereof in association with a pharmaceutically acceptable carrier therefor, for use in the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder in a subject in need thereof. The invention also relates to methods and uses of an inhibitor of HSD11B1.
Description
Treatment of Sarcopenic Diseases
This invention relates generally to the treatment (or prevention or amelioration) of sarcopenia and related diseases and disorders. More particularly, the invention relates to the treatment of sarcopenia associated with ageing, obesity and sarcopenia secondary to disease, injury, trauma or medication; to pharmaceutical compositions useful in the treatment of such conditions, and also to methods for identifying patients who are likely candidates for treatment. Related methods of screening and diagnosis are also disclosed. Background
Sarcopenia (loss of muscle mass and strength) affects between 5-13% of 60-70 year olds and 11-50% of over 80 year olds. It is a major public health issue, with the number of sarcopenic patients likely to dramatically increase in the next 30 years. It has been estimated that overall prevalence rate in the elderly will rise in Europe from 11.1 %-20.2% in 2016 to 12.9%-22.3% in 2045. Sarcopenia is a strong predictor of low quality of life, mobility impairment, falls, fractures and all-cause mortality. It is the second most common cause of disability in humans. Sarcopenia is also an independent risk factor for other serious health conditions, such as cardiovascular disease. The European working group on sarcopenia in older people (EWGSOP) defined diagnostic criteria, which include muscle mass (appendicular lean mass divided by height squared, men:£7.23kg/m2, womans 5.67kg/m2) and muscle function (gait speed <0.8 m/s; or grip strength, men: <30kg, women <20kg). Sarcopenia was classified in the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) in 2016 under code M62.84.
The underlying mechanism of muscle loss and function in sarcopenia is not fully understood, but studies to date have suggested that reduced muscle stem cell (satellite cell) numbers; impaired satellite cell proliferative function; loss through senescence; and ability to remain quiescent may each contribute to the loss of muscle mass and function and neuromuscular junction degeneration. Epigenetic changes in satellite cells may underlie their changed phenotype in injury-induced sarcopenia and age-related sarcopenia. Manipulation of satellite cell state and maintenance of the quiescent state is possibly a promising therapeutic strategy for sarcopenia.
Sarcopenia is currently treated by use of resistance exercise and nutritional interventions, such as high protein diet and vitamin D. These interventions to some extent rescue satellite cell proliferative capacity and reserve numbers, but the quality of evidence for efficacy is low.
Testosterone treatment has been shown to increase muscle size and power but it also induces undesirable side effects.
Selective androgen receptor modulators (SARM) have been trialled for sarcopenia and show some efficacy, but SARMs have a limiting side-effect profile and potential for abuse. Androgens and SARMs are thought to increase muscle mass without improvements in muscle strength or function and have no effect on regenerative capacity (i.e. satellite cells). Accordingly, these constitute at best a symptomatic, not disease-modifying, treatment.
Another therapeutic approach to sarcopenia is myostatin inhibition. Myostatin is a secreted protein that normally inhibits muscle growth. Myostatin-null animals and humans show skeletal muscle hypertrophy. Myostatin inhibitors, and inhibitors of its cognate receptor activin, have been developed. Most have shown at best only modest efficacy or a lack of long-term efficacy, and require regular injections, which has negative implications for compliance.
We have appreciated that there remains, therefore, an urgent need for an improved treatment for sarcopenia and sarcopenic diseases, and other diseases involving muscle wasting. Demographic changes are likely to increase the need for effective and safe treatments for these diseases, particularly in an ageing population.
The present inventors have undertaken research which has enabled them to propose a novel approach to the treatment (including prevention or amelioration) of sarcopenia and sarcopenic diseases, based on a new understanding of the mechanisms involved in these diseases. In particular, the present inventors have identified the significance of the observation that the decrease in proliferative capacity of muscle associated with ageing and other‘insults’ is mediated in part by cortisol.
Cortisol is an active glucocorticoid that is convertible from the inert cortisone by action of an enzyme, cortisone reductase (also known as HSD11 B1 or I ΐ b-HSDI).
General description of the invention
HSD11 B1 inhibition and sarcopenic conditions
Accordingly, in a broad aspect, the present invention provides an inhibitor of HSD11 B1 for use in the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder.
The present invention alternatively provides a method for the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder, which method comprises administration to a human or non-human animal in need thereof of a therapeutically effective amount of an inhibitor of HSD11 B1.
Each aspect of the present invention is to be understood as applying to either a human or non-human animal. In a preferred aspect, the subject to be treated is a human patient.
Sarcopenia primarily relates to degenerative loss of skeletal muscle mass, quality and strength associated with ageing. However, the above“sarcopenic” symptoms are also seen in other, non-age related, conditions. Accordingly, in the description of present invention, the terms“sarcopenic disease” or“sarcopenic disorder” (which are often used interchangeably) should be understood as encompassing these. In particular, the invention encompasses sarcopenia associated with ageing, obesity and sarcopenia secondary to disease, injury, trauma or medication. This includes steroid-induced, in particular glucocorticoid (GC)-induced sarcopenia, which can be seen, for example, in individuals who (for whatever reason) are subject to, often high, exposure to endogenous or exogenous glucocorticoids. In particular, this may include exposure to higher than normal levels of cortisol. “Sarcopenic disease” also encompasses secondary sarcopenia, for example that consequent upon surgery, such as that suffered by people that are immobilised after a bone fracture, especially after hip fracture or hip replacement surgery. This is particularly prevalent in elderly patients with hip fractures, but is not restricted to this group.
In one aspect of the invention, we propose HSD11 B1 inhibition as a therapeutic strategy to treat the loss of muscle strength and regenerative capacity, including muscle wasting, associated with age (sarcopenia), injury, disease, trauma or medication (e.g. sarcopenic obesity or glucocorticoid- induced sarcopenia).
The present invention thus provides an inhibitor of HSD11 B1 , or a pharmaceutical formulation thereof in association with a pharmaceutically acceptable carrier therefor, for use in the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder in a subject in need thereof.
There is also provided a method for the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder, which method comprises administration to a subject in need thereof of a therapeutically effective amount of an inhibitor of HSD11 B1.
The invention also provides the use of an inhibitor of HSD11 B1 , or a pharmaceutical formulation thereof in association with a pharmaceutically acceptable carrier therefor, in the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder in a subject in need thereof.
Alternatively, the invention provides the use of an inhibitor of HSD11 B1 in the preparation of a medicament for the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder in a subject in need thereof.
Suitable HSD11 B1 inhibitors and pharmaceutical formulations for use in accordance with the invention are described further below.
Another aspect of the invention provides an inhibitor, method or use according to any aspect of the invention, comprised in a therapeutic strategy to treat the loss of muscle strength or muscle regenerative capacity, optionally muscle wasting, associated with age (sarcopenia), injury, disease, trauma, or medication. This includes, for example, sarcopenic obesity or glucocorticoid-induced sarcopenia.
In a further aspect, the invention provides an inhibitor, method or use according to any aspect of the invention wherein the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder comprises inhibiting HSD11 B1 signalling, and decreasing cortisol in the subject. Decreasing cortisol suitably means decreasing the level of cortisol in the blood or plasma of the subject.
According to an aspect of the invention, the subject in need may be identified in a test for sarcopenia and/or a sarcopenic disease or disorder. In a preferred aspect, the subject in need may be identified by measuring the level of cortisol in a biological sample taken from the subject and/or by analysing the DNA sequence, epigenetic regulation, transcript or protein levels, enzymatic activity or post-translational modification of their HSD11B1 and/or NR3C1 genes.
In a preferred aspect of the invention, a subject in need of treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder is one having an elevated cortisol level, compared to levels in a control population or a predetermined standard. The elevated level may be, for example, in blood, plasma or urine. In one aspect, the elevated level (in humans) may be a cortisol level of equal to or greater than 6ng/ml of sample body fluid.
HSD11 B1 inhibition is a promising therapeutic strategy for sarcopenia and sarcopenic conditions as described herein that offers advantages over the existing therapies by avoiding at least some of the problems associated with the existing therapies mentioned above.
Patient identification/diagnosis
Individual risk for sarcopenia in old age is variable and seems to be determined in significant part by adverse early life environmental exposures. The glucocorticoid system, in particular, is modulated at an epigenetic level as a result of life environment. In particular, prenatal stress and/or adverse early life experience has been shown to cause increased methylation of exon 1 F (in humans) or GR17 (in rats) of the NR3C1 gene in many different scenarios. Epigenetic marks are a result of the interaction of genetic predisposition and environmental influences and, as such, they are more informative for multifactorial diseases than stratification signature using genotype alone.
Accordingly, the present invention further provides method of identifying a human or non human animal suitable for or in need of the treatment, prevention or amelioration or sarcopenia or a sarcopenic disease or disorder by use or administration of an inhibitor of HSD11 B1 , which method of identifying comprises diagnosing epigenetic changes to a gene selected from HSD11B1 and NR3C1, and genes that interact with HSD11B1 and NR3C1
Such epigenetic changes may for example comprise increased methylation or increased phosphorylation of the NR3C1 gene over levels in a control population. Suitable techniques for measuring epigenetic changes are well known, and include bisulphate sequencing of candidate genes from patient DNA that enables determination of the methylation status of NR3C1 (as described by Meissner, Alexander, et al. in Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis, Nucleic acids resea rch 33.18 (2005): 5868-5877). Additionally, analysing publically-deposited methylation data from control samples (non-diseased) will allow comparison of the relative extent of gene methylation in patient versus control populations.
Consistent with the idea that earlier exposure to endogenous or exogenous cortisol would predispose patients to respond positively to blockage of cortisol biosynthesis, are findings relating to glucocorticoid receptor (NR3C1) inhibition. Mifepristone is a non-specific NR3C1 inhibitor: in a small experimental clinical study of mifepristone to treat anxiety and cognitive decline in individuals over 60 years of age, mifepristone showed an improvement
in memory, executive function and worry severity only for those individuals with baseline cortisol >6ng/ml.
NR3C1 phosphorylation may also be a marker of subjects exposed to high cortisol and so likely responsive to HSD11 B1 inhibition. Therefore, we propose that patients that may benefit from HSD11 B1 inhibition are identifiable by their exhibiting high baseline cortisol.
In a further aspect, therefore, the invention also provides a method of identifying a human or non-human animal suitable for or in need of the treatment, prevention or amelioration or sarcopenia or a sarcopenic disease or disorder by use or administration of an inhibitor of HSD11 B1 , which method of identifying comprises:
(a) determining the baseline level of cortisol in the animal, such as the human patient;
(b) comparing the level determined in step (a) with a baseline of cortisol in a control population of animals which do not have sarcopenia or a sarcopenic disease or disorder; and
(c) selecting for animals in which the baseline level determined in step (a) is greater than that seen in step (b).
Determining the level of cortisol in step (a) and/or step (b) can be carried out in blood, plasma, urine or other biological fluids using any suitable method, and such methods are well known, such as immunoassay and chromatographic methods (LC-MS/MS), as described by Gatti, Rosalba, et al. in Cortisol assays and diagnostic laboratory procedures in human biological fluids, Clinical biochemistry 42.12 (2009): 1205-1217. Further methods are mentioned hereinbelow and are discussed by El-Farhan, Nadia, D. Aled Rees, and Carol Evans in Measuring cortisol in serum, urine and saliva-are our assays good enough?, Annals of clinical biochemistry 54.3 (2017): 308-322.
In another aspect, the invention also provides a method of diagnosing sarcopenia or a sarcopenic disease or disorder comprising the steps of:
(a) providing a biological sample isolated from a subject;
(b) determining the level of cortisol in the biological sample; and
(c) comparing the level of cortisol determined in step (b) with a cortisol level determined from one or more control samples or reference levels.
To aid in accuracy of diagnosis, the above method of diagnosing sarcopenia or a sarcopenic disease or disorder may, if desired, additionally comprise the step of diagnosing epigenetic changes to a gene selected from HSD11B1 and NR3C1, and/or genes that interact with HSD11B1 and NR3C1. Such epigenetic changes may, for example, comprise increased methylation or increased phosphorylation of the NR3C1 gene compared to the level of methylation or increased phosphorylation (respectively) in a control population or predetermined standard. Combining both approaches is likely to improve the accuracy of diagnosis.
The one or more control samples may be isolated from a subject with or without sarcopenia or a sarcopenic disease or disorder. Accordingly, comparison with such control samples may provide an indication of the subject having sarcopenia, or deteriorating towards the state of sarcopenia or a sarcopenic disease or disorder.
A control sample may be from the same subject, taken at an earlier time point. Similarly, a reference level may be determined based on previous analyses carried out on the same subject.
Accordingly in another aspect, the invention provides a method of determining the progression of sarcopenia or sarcopenic disease or disorder in a subject comprising the steps:
(a) providing a biological sample isolated from a subject;
(b) determining the level of cortisol in the biological sample; and
(c) comparing the level of cortisol determined in step (b) with a cortisol level determined from a sample taken from the same subject at an earlier time.
This method may then be used to determine the effectiveness, over time, of the use of a particular inhibitor in a method for treatment (including amelioration or prophylaxis) of sarcopenia or sarcopenic disease or disorder in a particular patient.
Use of control samples may enable the determination of a standard (reference level), against which the test sample(s) (from the subject or patient) can be compared.
Therefore, alternatively or additionally, a level of cortisol below a pre-determined reference level may indicate the subject does not have sarcopenia or a sarcopenic disease or disorder, while a level of cortisol above a different predetermined reference level may indicate the subject does have sarcopenia or a sarcopenic disease or disorder. We
propose that a suitable reference level may be about 6ng/ml cortisol, such that subjects having at least this concentration of cortisol, may have sarcopenia or a sarcopenic disease or disorder, or may be deteriorating towards the state of sarcopenia or a sarcopenic disease or disorder.
The biological sample used in any aspect of the present invention may be any suitable sample for isolating from the body of a subject, such as a blood sample (e.g. plasma or serum) or tissue biopsy (in particular a muscle biopsy), or urine.
In one aspect, the method may comprise a further step of administering an HSD11 B1 inhibitor to the subject, wherein the subject has been diagnosed as having sarcopenia or a sarcopenic disease or disorder or as being at risk of developing such a condition, or diagnosed as having or progressing towards sarcopenia or a sarcopenic disease or disorder.
In another aspect, the method may comprise a further step of applying a dietary intervention for maintaining or increasing muscle function and/or mass wherein the subject has been diagnosed as having sarcopenia or a sarcopenic disease or disorder or being at risk of developing such a condition, or diagnosed as having or progressing towards sarcopenia or a sarcopenic disease or disorder. Preferably, the dietary intervention is for maintaining or increasing muscle mass. Example dietary interventions include high protein and/or carbohydrate diets. Alternatively or as well, the dietary intervention may be or include the use or administration of vitamin D, as described further below in relation to combination treatments.
The above-described method steps may also be used to provide a method of diagnosing loss of muscle function and/or mass with age.
There is also provided according to the invention methods for detecting individuals having a history of high exposure to endogenous or exogenous glucocorticoids, through salivary or blood measurements of cortisol and/or the DNA sequence, epigenetic regulation, transcript or protein levels, enzymatic activity or post-translational modification of the HSD11B1 and NR3C1 genes. These individuals are likely to have a heightened response to HSD11 B1 inhibition.
We have appreciated that polymorphisms in HSD11B1 are associated with raised physiological cortisol levels and are also associated with varying susceptibility to glucocorticoids. We propose, therefore, that patients who may benefit from HSD11 B1
inhibition may be identified from detecting one or more polymorphic variations in the HSD11B1 and/or NR3C1 genes.
In some cases, patients may be identifiable from detecting a fragment of such variations or such genes, or the proteins encoded thereby, for example by detecting an amino acid sequence that has at least 60% identity to the wild type; preferably about 70% or 80% or 90-100% identity.
Candidate drugs (HSD11 B1 inhibitors)
HSD11 B1 inhibitors for use in the invention or in the methods of treatment of the invention include any chemical or biological agent that is known or can be identified as such, or a chemical or biological agent that down-regulates cortisol or a precursor thereof, or that inactivates or reduces activation of the glucocorticoid receptor (NR3C1) or precursor or activator thereof. Preferably, the inhibitor is a selective inhibitor of HSD11 B1 , and especially preferred are those with high potency.
Suitable HSD11 B1 inhibitors include: 11b-HDS1 inhibitors developed for the treatment of type 2 diabetes mellitus. For example, salicylate downregulates I ΐ b-HSDI expression in adipose tissue in obese mice and hence may explain why aspirin improves glycemic control in type 2 diabetes.
Natural products and older agents such as thiazolidinediones and fibrates seem to exert an inhibitory effect on 11 b-HSDI , ameliorating the cardiometabolic profile. Newer compounds, such as adamantyltriazoles, arylsulfonamidothiazoles, anilinothiazolones, BVT2733, INCB- 13739, MK-0916 and MK-0736, are currently under investigation, and the preliminary findings from both experimental and human studies show a favourable effect on glucose and lipid metabolism, weight reduction and adipokine levels. Butylated hydroxyanisole (BHA) is a widely used antioxidant for food preservation, and is a selective inhibitor of HSD11 B2, of the natural products, 18a-glycyrrhizic acid from the root of glycyrrhiza glabra, and also curcumin and derivatives have been identified as HSD11 B1 inhibitors.
Epigallocatechin gallate from green tea can also potently inhibit this enzyme, green tea is a complex mixture of various phenolics with contents varying with production and processing.
Potent and selective inhibitors of the HSD11 B1 enzyme also include those known as AZD4017, ABT384, ABT305, INCB-13739, BVT.3498, BVT 116429, CRx-401 , bezafibrate; CRx-401 , diflunisal; BMS-823778; UE2343; and carbenoxolone, respectively:
2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]piperidin-3-yl]acetic acid (AZD4017). AZD4017 is a selective, orally bioavailable inhibitor of the enzyme 11-b- hydroxysteroid dehydrogenase type 1 , with potential protective activity. AZD4017 has been used in clinical trials for a number of indications: Idiopathic Intracranial Hypertension (400 mg oral tablet twice daily for 12 weeks); Obesity (oral suspensions 1200 mg once daily for 10 days); Diabetes Mellitus Type 2 (1st trial: oral suspension, ascending multiple doses starting at 75 mg once daily; 2nd trial: 400 mg oral tablet twice daily for 35 days); Iatrogenic Cushing's Disease (400 mg twice daily for 7 days with 20 mg prednisolone); Raised Intraocular Pressure (Europe: 200 mg oral tablet once daily for 28 days; USA: 2 x 200 mg oral tablets twice daily for 28 days).
4-[[2-methyl-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-l]propanoyl]amino]adamantane- 1-carboxamide (ABT-384). ABT384 is a potent, selective inhibitor of 11-b-hydroxysteroid dehydrogenase type 1. ABT384 has been used in clinical trials for adults with mild to
moderate Alzheimer’s disease with subjects receiving 10 mg or 50 mg of ABT384 once daily for 12 weeks.
4-[[2-methyl-2-[[4-(trifluoromethyl)phenyl]methoxy]propanoyl]amino]adamantane-1- carboxamide (ABT-305)
(3S)-1-[(3-Chloro-2-methylphenyl)sulphonyl]-N-cyclohexyl-3-piperidinecarboxamide
(INCB-13739). INCB-13739 is an orally available small molecule inhibitor of 11-b- hydroxysteroid dehydrogenase type 1. INCB-13739 has been used in clinical trials for adults with Type 2 Diabetes, with a maximum dose of 200 mg per day (either as one dose, combined with metformin or 100 mg twice daily, alone).
3-chloro-2-methyl-N-[4-[2-(3-oxomorpholin-4-yl)ethyl]-1 ,3-thiazol-2- yljbenzenesulphonamide (BVT 3498). BVT3498 is a highly selective inhibitor of the enzyme 11-b-hydroxysteroid dehydrogenase type 1. BVT.3498 has been used in clinical trials for
adults with Type 2 Diabetes, completing phase I trials in 2002 and entering phase II trials. The trials were stopped in 2005.
(5S)-2-[[(1S)-1-(2-fluorophenyl)ethyl]amino]-5-methyl-5-(trifluoromethyl)-1 ,3-thiazol-4-one (BVT 116429) and its methyl analogue, (5S)-2-[[(1S)-1-(2-methylphenyl)ethyl]amino]-5- methyl-5-(trifluoromethyl)-1 ,3-thiazol-4-one. BVT 116429 is a selective inhibitor of the enzyme I I-b-hydroxysteroid dehydrogenase type 1. Studies have been performed on diabetic mice using up to 30 mg/kg once daily for 10 days.
2-(4-{2-[(4-chlorobenzoyl)amino]ethyl}phenoxy)-2-methylpropanoic acid (CRx-401 , bezafibrate)
2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid (CRx-401 , diflunisal). CRx-401 is a novel insulin sensitizer designed to provide anti-diabetic activity. It consists of a low dose of diflunisal in conjunction with a modified-release therapeutic dose of bezafibrate. It has been
used in clinical trials for patients with Type II Diabetes taking metformin. Patients were given CRx-401 consisting of 400 mg bezafibrate sustained-release and 250 mg diflunisal once daily.
2-[3-[1-(4-chlorophenyl)cyclopropyl]-[1 ,2,4]triazolo[4,3-a]pyridin-8-yl]propan-2-ol
(BMS-823778). BMS-823778 is an orally available potent and selective inhibitor of 11-b- hydroxysteroid-dehydrogenase 1. It has been used in clinical trails for the conditions of: Atherosclerotic Cardiovascular Disease (2 mg - 15 g orally once daily for 1 year); Hypertension (2 mg - 15 mg orally once daily for 12 weeks); Dyslipidemia (2 mg - 20 mg orally once daily for 28 days); and Diabetes Mellitus Type 2 (2 mg - 20 mg orally once daily for 28 days, with metformin).
(3-hydroxy-3-pyrimidin-2-yl-8-azabicyclo[3.2.1 ]octan-8-yl)-[5-(1 H-pyrazol-4-yl)thiophen-3- yl]methanone (UE2343). UE2343 is a potent, orally bioavailable, brain-penetrant 11-b- hydroxysteroid-dehydrogenase 1 inhibitor. Clinical trials have evaluated the safety, tolerability of efficacy of Xanamem™ (comprising UE2343) in subjects with mild dementia due to Alzheimer’s Disease. In the trial, oral Xanamem™ 10 mg capsules were given once daily.
^)-3-[(3-carboxypropanoyl)oxy]-11-oxoolean-12-en-30-oic acid (carbenoxolone). Carbenoxolone is a hemisuccinate derivative of glycyrrhetinic acid and is frequently used in the treatment of peptic ulcers and the topical treatment of mouth ulcers. It is also a non- selective I I-b-hydroxysteroid-dehydrogenase 1 inhibitor that also inhibits 11-b- hydroxysteroid-dehydrogenase 2. It has also been used in clinical trials for Type 2 diabetes, with a dosage of 100 mg three times per day.
Derivatives of inhibitors
Included in the scope of the above-described inhibitors are derivatives thereof well-known for use in the pharmaceutical art. Accordingly, wherever such inhibitors are mentioned herein are also encompassed their pharmaceutically acceptable salts or solvates and hydrates. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Also encompassed are salts that are not pharmaceutically acceptable when they are used as precursors to the free inhibitors or to their pharmaceutically acceptable salts or in other synthetic manipulations.
The inhibitors for use according to this invention include any metabolites thereof that are therapeutically active. The inhibitors for use according to this invention include any prodrugs thereof. Prodrugs are compounds that are converted to therapeutically active compounds as they are being administered to a patient or after they have been administered to a patient.
Preferably, the inhibitors for use according to this invention are selective inhibitors of the I ΐ b-HSDI (or HSD11 B1) enzyme. This is because glucocorticoid concentrations are modulated by two enzymes of I ΐ b-HSD (namely, IIb-HSDI and I ^-HSD2), which have differing cofactor requirements and substrate affinities, and in vitro studies have shown that
llb-HSDI is capable of acting as both a reductase and a dehydrogenase. Hence, selectivity for the type 1 isoenzyme, 11b-HDSl, is preferred.
Screening for inhibitors
In another aspect, the invention provides a method of screening for an agent capable of inhibiting HSD11 B1 levels in a patient in need thereof comprising the steps of:
(a) contacting a population of cells with a candidate inhibitor;
(b) determining the level of cortisol or a precursor thereof in the population of cells; and
(c) comparing the level of cortisol or precursor thereof determined in step (b) with a cortisol or precursor level in a control population of cells which has not been contacted with the candidate inhibitor.
Preferably, the method is an in vitro method.
The candidate inhibitor is optionally comprised in a library of candidate inhibitors.
In another aspect, the invention provides an inhibitor for decreasing cortisol levels or levels of a cortisol precursor in a patient, wherein the inhibitor has been identified by the method of screening of the invention.
The term "level of cortisol" refers to the amount of cortisol that is found in a sample, e.g. of serum or plasma. The amount of may be determined directly or indirectly. Direct methods of determining cortisol include chromatographic methods, radioimmunoassay, enzyme- linked immunoassays and non-isotopic immunoassays. Liquid chromatography based mass spectrometry (LC-MS/MS) are commonly used to measure serum and plasma cortisol levels from multiple time points with high sensitivity. The effect of the candidate inhibitor on cortisol levels may be assessed as a function of time, by carrying out repeated measurements over a particular time-course.
Combination with Vitamin D
The present invention also provides for the case when the HSD11 B1 inhibitor is used, administered or formulated together with vitamin D. By together with is not meant to imply only an intimate admixture of the two active ingredients, but also encompassed is separate, simultaneous or sequential administration.
The vitamin D may be administered by oral, parental, sub-lingual, sub-cutaneous, transdermal or intra-nasal administration. It may be administered as an oral vitamin D supplement or a probiotic supplement. The vitamin D may, for example, be in the form of a nutritional composition or supplement, or a diet product.
The patient may have previously been determined to be vitamin D deficient.
In another aspect, the invention provides a method of maintaining or increasing muscle function and/or mass and/or preventing or reducing muscle wasting in a patient in need thereof, particularly an ageing or elderly patient, comprising administering to the patient the inhibitor and vitamin D. Preferably, the vitamin D maintains or increases muscle mass; alternatively, the vitamin D substantially prevents or reduces a reduction in muscle mass.
In another aspect, the invention provides for the use or method according to the invention of a combined preparation of an inhibitor and vitamin D, wherein the inhibitor and vitamin D are for simultaneous, combined, sequential or separate administration to a patient.
Other combination treatments
Instead of or as well as combining an inhibitor with vitamin D, other combinations comprising an HSD11 B1 inhibitor are within the scope of this invention, such as a diet product, as mentioned above in relation to patient identification/diagnosis, and/or an exercise regime may be combined with the inhibitor to maintain or increase muscle function and/or mass.
Furthermore, one or more other pharmacologically active agent(s) may be combined with an inhibitor, including selective androgen receptor modulators (SARMs), such as ostarine or myostatin blockers (e.g. myostatin antibodies, activin receptor antibodies and activin receptor-Fc), such as LY2495655 or Bimagrumab, or beta2 receptor agonists such as formoterol, or ghrelin receptor agonists such as anamorelin, or anabolic catabolic transforming agents (ACTA), such as MT-102, or other compounds mentioned hereinabove.
Pharmaceutical formulations/dosage
For use according to the present invention, the inhibitors may be administered at any suitable pharmacological dose, it being understood that the exact amounts will depend upon the nature of the inhibitor. For example, suitable doses may comprise a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight,
preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 300 milligrams, especially from about 1 mg to about 100mg In the case of a 70 kg adult human, the total daily dose will generally be in the range of from about 7 milligrams to about 350 milligrams. Typically, such doses may comprise in the range of from about 50 to 500 mg per day, such as about 240mg or about 100mg per day. This dosage regimen may be adjusted to provide the optimal therapeutic response.
Another aspect of the present invention provides a use or method as described herein, wherein the inhibitor is comprised in a pharmaceutical composition or formulation together with a pharmaceutically acceptable carrier therefor.
Optionally, other therapeutic ingredients may be included in the pharmaceutical composition, such as those described above.
The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the inhibitor or other active ingredient(s) present. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. Solid oral dosage forms, such as tablets or capsules or the like, are preferred.
In practical use, the inhibitors can be brought into intimate physical admixture with a pharmaceutical carrier according to conventional pharmaceutical formulating techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). The active inhibitors can also be administered as intranasal formulations, such as, for example, liquid drops or spray.
In preparing the compositions for oral dosage form, any of the usual pharmaceutical excipients may be employed, such as, for example, diluents of a solid or liquid nature, flavouring agents, preservatives, colouring agents, and the like. Oral liquid preparations may be in the form of, for example, suspensions, elixirs and solutions. Such liquid preparations may comprise sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavouring. Oral solid preparations are preferred over oral liquid preparations and are preferably in the form of, for example, powders, hard and soft
capsules and tablets. When in solid form, the carrier may include one or more of: starches, sugars, microcrystalline cellulose, solid or liquid diluents, granulating agents, lubricants, binders, disintegrating agents and the like. The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. For example, tablets may be coated with shellac, sugar or both. Such compositions and preparations will preferably contain at least 0.1 % of active inhibitor. The percentage of active inhibitor in these compositions may, of course, be varied and may conveniently be between about 2% to about 60% by weight of the unit dose. The amount of active inhibitor in such therapeutically useful compositions is such that an effective dosage will be obtained.
Various other materials may be present to act as coatings or to modify the physical form of the dosage unit.
For parenteral administration, the pharmaceutical forms include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Solutions or suspensions of these active inhibitors can be prepared in water for injections, optionally suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Accordingly, the carrier can be a solvent or dispersion medium containing, for example, water, an alcohol (e.g. ethanol), a polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycols), suitable mixtures thereof, and vegetable oils, and combinations thereof. In all cases, the form must be sterile and must be fluid to enable administration via a syringe. The formulation must be stable under the conditions of manufacture and storage, according to regulatory requirements. Under ordinary conditions of storage and use, these preparations optionally comprise a preservative or antimicrobial agent to prevent the growth of microorganisms.
Accordingly, the present invention further provides a pharmaceutical formulation comprising an inhibitor of HSD11 B1 and a pharmaceutically acceptable carrier therefor, for
use in the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder.
The present invention alternatively provides a method for the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder, which method comprises administration to a human or non-human animal in need thereof of a therapeutically effective amount of a pharmaceutical formulation comprising an inhibitor of HSD11 B1 and a pharmaceutically acceptable carrier therefor.
Pharmacological indications
The invention provides a means to address loss of muscle function and mass that occurs with age. Age-related loss of muscle function and mass occurs inevitably in all individuals, however its progression depends on a range of genetic and environmental factors, such as physical activity and nutritional intake.
The specific condition of sarcopenia as referred to in the present invention is defined as occurring at the point at which the age-related loss of muscle mass and function becomes debilitating and impacts on quality of life (Sayer, A. A. et al. (2013) Age Ageing 42: 145- 150). However, as noted above, the present invention encompasses “sarcopenic” symptoms such as degenerative loss of skeletal muscle mass, quality and strength as seen in other non-age related conditions; and, in relation to the present invention, the terms “sarcopenic disease” or“sarcopenic disorder” are to be understood in a broad sense as encompassing such conditions.
Preferably, the inhibitor for use according to the invention provides in a patient an increased effect of: (a) maintaining or increasing muscle function and/or mass in an ageing subject; (b) preventing or reducing muscle wasting in an ageing subject; and/or (c) treating sarcopenia, sarcopenic disease or a sarcopenic disorder, compared to patient’s baseline.
The invention is particularly applicable to ageing subjects, for example, a human subject over the age of 30, or of an age in the range of from 30 to 100 years old.
Preferably, the muscle referred to herein is skeletal muscle.
It is to be appreciated that all references herein to treatment include curative and prophylactic treatment; it also includes arresting progression in the severity of a disease or disorder (i.e. amelioration by varying degrees and prevention are both encompassed).
The treatment of mammals, particularly humans, is preferred. However, both human and veterinary treatments are within the scope of the invention. For veterinary applications, the age of the animal would be scaled from the human situation using the average lifespan for calibration.
The inhibitors, compositions, uses and methods according to the invention may provide for the maintenance of or increase in muscle function and/or mass in an ageing subject.
The term "muscle function" refers to the ability of a muscle to perform in a manner that does not negatively impact on the life of a subject, and encompasses parameters of muscle strength, muscle contraction, muscle endurance and/or muscle elasticity.
Suitable tests for assessing muscle function include grip strength assessment using a dynamometer; one repeat maximum on leg press, chest press or leg extension; gait speed; 6 min walk test; time up and go; short physical performance battery; Fried frailty criteria; and stair climbing time assessments. Muscle mass (which may equate with muscle volume, muscle thickness or myofibre/muscle fiber size) may be measured by dual-energy X-ray absorptiometry (DXA) or bio-impedance tests. Similarly, MRI may be used for assessing muscle volume and ultra-sound may be used for assessing muscle thickness and pennation angle.
Preferably, the inhibitors, compositions, uses and methods of the invention provide for the maintenance of or increase in muscle mass in an ageing subject in accordance with the aforementioned tests and measurements.
The term "maintains" refers to a particular parameter, such as muscle function and/or mass, remaining substantially unchanged over a period of time (e.g. over 1 or more years, preferably in the range of from 5 to 50 or more years). Preferably, muscle mass increases by at least 1 %, such as 1-2.5%, 1-5%, 1-10% or 1-20%, relative to either baseline or just prior to the start of treatment with an inhibitor according to the invention.
Detailed Description of the Invention
Embodiments of the invention are described below, by way of example only, with reference to the accompanying figures in which:
Figure 1A is a graph showing the results of Pax7 + cell number experiments described below in Example 1 ; and
Figure 1 B is a graph showing the results of the Fusion Index calculated on the basis of the experiments described below in Example 1.
Example 1
Assessing the inhibition of HSD11 B1 for use as a treatment of sarcopenia
Primary human myoblasts were isolated from the UK Hertfordshire Cohort Study (HCS) extension study which recruited a total of 168 men and women. Body composition (total lean mass, appendicular lean mass [ALM], and fat mass) was assessed by dual-energy x- ray absorptiometry (DXA) (Hologic Discovery, software version 12.5) for all participants.
Isometric grip strength (kg) was measured three times in each hand using a Jamar handheld hydraulic dynamometer (Promedics, UK) and the highest value of six measures was used for analysis. Customary walking speed was measured over a three-metre course. Percutaneous muscle biopsies of the vastus lateralis were conducted, biopsies were digested with collagenase and muscle satellite cells isolated and stored. Myogenic purity of sorted cell cultures was measured using immunocytochemistry with CD56 as a marker. For differentiation studies, cells were grown in differentiation media (DM EM containing 2% HS and 1 % P/S). Cultures derived from 3 sarcopenic donors (defined in Cruz Jenioft (2019) Age and Ageing, Volume 48, Issue 1, Pages 16-31) and two aged matched controls (one repeated as a technical replicate) were assessed for differentiation potential and renewal capacity.
For analysis of differentiation potential and renewal capacity, cells were analysed for both MYHC and Pax 7 expression at differentiation day 2, day 6 and day 10. Briefly, cells were fixed in 3.7% PFA for 10 minutes at room temperature. Following a PBS wash, cells were then permeabilised (0.3% Triton X-100, 1% BSA in PBS) for 7 min at RT. Cells were then washed in PBST and blocked (5% goat serum, 1 % BSA in PBS) for 1 hr at RT. Cells were next washed and incubated with the Primary antibodys overnight at 40°C with agitation (MYHC: (MF20) DSHB, Pax 7: abeam). Cells were then washed and incubated with secondary antibody (GAM IgG Alexa Fluor 488, abeam, GAR IgG Alexa Fluor 594 abeam). To visualise nuclei, cells were incubated in DAPI 1 ug/ml. Cells were imaged using the Axio observer D1 microscope (Zeiss), using appropriate fluorescent filters (Green - 38 GFP ex 450-490, em 500-550, Red - 45 TR ex 550-580, Em 593-668, Blue - 49 Dapi ex 335-383, em 420-470). For ICC counting purposes, a 20x objective was used. Five images of randomly selected non-overlapping fields were captured for each well. An AxioCam MRm digital camera (Zeiss) was used to capture grey-scale images, whilst Axiovision software
was used to assign colour tones corresponding to the emission wavelength of the secondary antibody. To ensure all counts were comparable, cells from the same experiment were photographed at identical exposures. Cells on raw unadjusted images were counted using the ‘Count’ feature of ImageJ. To calculate the fusion index, the number of nuclei incorporated into the myotubes (containing 2+ nuclei) was counted and the ratio of this number to the total number of nuclei was determined.
As illustrated in Figures 1A, Pax7+ Cells are reduced in Sarcopenic patient-derived myoblasts and Pax7+ Cells in Sarcopenic patients are normalized by ABT384. Figure 1 B illustrates that the percentage of cells fused to form differentiated myotubes (Fusion Index) is not affected by the treatment.
The experiments therefore provide strong evidence that an inhibitor of HSD11 B1 would be effective for use as a therapeutic for sarcopenia or a sarcopenic disease.
Example 2
Example Formulations and Treatments for Sarcopenia in Insulin Sensitive Patients A number of example formulations are provided below along with suggested dosage regimes. It will be understood that these are for illustrative purposes and these would be optimized during further experimentation, which may include clinical trials. For simplicity, the formulations do not stipulate any non-active components (such as pharmaceutically acceptable carriers or excipients etc.)
Formulation 2A - AZD4017 - Oral Tablet for the Treatment of Sarcopenia
Formulation 2E - Diflunisal - Oral Tablet for the Treatment of Sarcopenia
Formulation 2F - BMS-823778 - Oral Inhaled Solution for the Treatment of Sarcopenia
Formulation 2G - UE2343 - Oral Tablet for the Treatment of Sarcopenia
Formulation 2H - Carbenoxolone - Oral Tablet for the Treatment of Sarcopenia
The skilled addressee will of course understand that alternative HSD11 B1 inhibitors could also be employed in place of those outlined above. The therapeutically effective doses will of course depend on the activity and format of the chosen inhibitor.
The forgoing embodiments are not intended to limit the scope of the protection afforded by the claims, but rather to describe examples of how the invention may be put into practice.
Sequences
Gene sequence for the gene encoding the protein, _corticosteroid 11 -beta-dehydrogenase isozyme 1 , namely: HSD11 B1 (SEQ ID No. 1):
Organism: Homo sapiens (Human) from http://www.uniprot.org/uniprot/P288451:
Claims
1. An inhibitor of HSD11 B1 , or a pharmaceutical formulation thereof in association with a pharmaceutically acceptable carrier therefor, for use in the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder in a subject in need thereof.
2. The inhibitor according to claim 1 , wherein the HSD11 B1 inhibitor is a selective inhibitor of HSD11 B1.
3. The inhibitor according to either claim 1 or 2, wherein the HSD11 B1 inhibitor is selected from one or more of the following: ABT384, AZD4017, ABT305, INCB-13739, BVT.3498, BVT 116429, bezafibrate; CRx-401 , diflunisal; BMS-823778; UE2343; and carbenoxolone.
4. A method for the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder, which method comprises administration to a subject in need thereof of a therapeutically effective amount of an inhibitor of HSD11 B1.
5. The method according to claim 4, wherein the HSD11 B1 inhibitor is a selective inhibitor of HSD11 B1.
6. The method according to either claim 4 or 5, wherein the HSD11 B1 inhibitor is selected from one or more of the following: ABT384, AZD4017, ABT305, INCB-13739, BVT.3498, BVT 116429, bezafibrate; CRx-401 , diflunisal; BMS-823778; UE2343; and carbenoxolone.
7. Use of an inhibitor of HSD11 B1 , or a pharmaceutical formulation thereof in association with a pharmaceutically acceptable carrier therefor, in the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder in a subject in need thereof.
8. Use of an inhibitor of HSD11 B1 in the preparation of a medicament for the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder in a subject in need thereof.
9. The use according to either claim 7 or 8, wherein the HSD11 B1 inhibitor is a selective inhibitor of HSD11 B1.
10. The use according to any one of claims 7 to 9, wherein the HSD11 B1 inhibitor is selected from one or more of the following: ABT384, AZD4017, ABT305, INCB-13739,
BVT.3498, BVT 116429, bezafibrate; CRx-401 , diflunisal; BMS-823778; UE2343; and carbenoxolone.
11. An inhibitor, method or use according to any preceding claim, comprised in a therapeutic strategy to treat the loss of muscle strength or muscle regenerative capacity, optionally muscle wasting, associated with age (sarcopenia), injury or disease (e.g. sarcopenic obesity).
12. An inhibitor, method or use according to any preceding claim wherein the treatment, prevention or amelioration of sarcopenia or a sarcopenic disease or disorder comprises one or more of: inhibiting HSD11 B1 signalling, and decreasing cortisol in the subject.
13. A method or use according to any preceding claim, wherein the subject in need is identified in a test for sarcopenia and/or a sarcopenic disease or disorder.
14. A method or use according to claim 13, wherein the subject in need is identified by measuring the level of cortisol in a biological sample taken from the subject and/or by analysing the DNA sequence, epigenetic regulation, transcript or protein levels, enzymatic activity or post-translational modification of their HSD11B1 and/or NR3C1 genes.
15. A method of identifying a human or non-human animal suitable for or in need of the treatment, prevention or amelioration or sarcopenia or a sarcopenic disease or disorder by use or administration of an inhibitor of HSD11 B1 which method of identifying comprises (a) determining the baseline level of cortisol in the animal, such as the human patient; (b) comparing the level determined in step (a) with a baseline of cortisol in a control population of animals which do not have sarcopenia or a sarcopenic disease or disorder; and (c) selecting for animals in which the baseline level determined in step (a) is greater than that seen in step (b).
16. A method of diagnosing sarcopenia or a sarcopenic disease or disorder comprising the steps of: (a) providing a biological sample isolated from a subject; (b) determining the level of cortisol in the biological sample; and (c) comparing the level of cortisol determined in step (b) with a cortisol level determined from one or more control samples or reference levels.
17. A method according to any of claims wherein the level of cortisol is determined in a sample of the subject’s in blood, plasma or urine.
18. A method of screening for an agent capable of inhibiting HSD11 B1 signalling levels in a subject comprising the steps:
(a) contacting a population of cells with a candidate agent;
(b) determining the level of an agent selected from: cortisol and/or the DNA sequence, epigenetic regulation, transcript or protein levels, enzymatic activity or post-translational modification of the HSD11B1 and NR3C1 genes in the population of cells; and (c) comparing the level of agent determined in step (b) with an agent level in a control population of cells which has not been contacted with the candidate agent.
19. An agent for inhibiting HSD11 B1 signalling levels in a subject, optionally wherein the agent has been identified by the method of claim 18.
20. The agent of claim 19 for use in:
(a) maintaining or increasing muscle function and/or mass in an ageing subject;
(b) substantially preventing or reducing muscle wasting in an ageing subject; and/or
(c) treating sarcopenia or frailty.
21. A method of diagnosing sarcopenia or a sarcopenic disease or disorder, which method comprises the steps of:
(a) providing a biological sample isolated from a subject;
(b) determining the level of an agent selected from: cortisol and/or the DNA sequence, epigenetic regulation, transcript or protein levels, enzymatic activity or post-translational modification of the HSD11B1 and NR3C1 genes in the biological sample; and
(c) comparing the level of the agent determined in step (b) with an agent level determined from one or more control samples or reference levels.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1805100.3 | 2018-03-28 | ||
GBGB1805100.3A GB201805100D0 (en) | 2018-03-28 | 2018-03-28 | Treatment of sarcopenic diseases |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2019186171A1 true WO2019186171A1 (en) | 2019-10-03 |
Family
ID=62068297
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2019/050892 WO2019186171A1 (en) | 2018-03-28 | 2019-03-28 | Treatment of sarcopenic diseases |
Country Status (2)
Country | Link |
---|---|
GB (1) | GB201805100D0 (en) |
WO (1) | WO2019186171A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020128529A1 (en) * | 2018-12-21 | 2020-06-25 | Benevolentai Bio Limited | Compositions and uses thereof |
CN113488163A (en) * | 2021-07-07 | 2021-10-08 | 四川大学华西医院 | Hypomyosis identification method, device, equipment and medium based on machine vision |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004027047A2 (en) * | 2002-09-18 | 2004-04-01 | Hanauske-Abel Hartmut M | INHIBITORS OF 11β-HYDROXYSTEROID DEHYDROGENASE AND USES THEREFOR |
WO2010125348A1 (en) * | 2009-04-29 | 2010-11-04 | Myotec Therapeutics Limited | Prevention and treatment of sarcopenia |
US20110275584A1 (en) * | 2003-09-22 | 2011-11-10 | Onepharm Research And Development Gmbh | Prevention and treatment of inflammation-induced and/or immune-mediated bone loss |
WO2017208211A1 (en) * | 2016-06-03 | 2017-12-07 | The Regents Of The University Of California | Identification of drugs that increase muscle mass |
-
2018
- 2018-03-28 GB GBGB1805100.3A patent/GB201805100D0/en not_active Ceased
-
2019
- 2019-03-28 WO PCT/GB2019/050892 patent/WO2019186171A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004027047A2 (en) * | 2002-09-18 | 2004-04-01 | Hanauske-Abel Hartmut M | INHIBITORS OF 11β-HYDROXYSTEROID DEHYDROGENASE AND USES THEREFOR |
US20110275584A1 (en) * | 2003-09-22 | 2011-11-10 | Onepharm Research And Development Gmbh | Prevention and treatment of inflammation-induced and/or immune-mediated bone loss |
WO2010125348A1 (en) * | 2009-04-29 | 2010-11-04 | Myotec Therapeutics Limited | Prevention and treatment of sarcopenia |
WO2017208211A1 (en) * | 2016-06-03 | 2017-12-07 | The Regents Of The University Of California | Identification of drugs that increase muscle mass |
Non-Patent Citations (6)
Title |
---|
CRUZ JENTOFT, AGE AND AGEING, vol. 48, no. 1, 2019, pages 16 - 31 |
EL-FARHAN; NADIA, D; ALED REES; CAROL EVANS: "Measuring cortisol in serum, urine and saliva-are our assays good enough?", ANNALS OF CLINICAL BIOCHEMISTRY, vol. 54.3, 2017, pages 308 - 322 |
GATTI; ROSALBA ET AL.: "Cortisol assays and diagnostic laboratory procedures in human biological fluids", CLINICAL BIOCHEMISTRY, vol. 42.12, 2009, pages 1205 - 1217, XP026351676 |
GERARD J. MAREK ET AL: "Efficacy and safety evaluation of HSD-1 inhibitor ABT-384 in Alzheimer's disease", ALZHEIMER'S & DEMENTIA: THE JOURNAL OF THE ALZHEIMER'SASSOCIATION, vol. 10, no. 5, 1 October 2014 (2014-10-01), US, pages S364 - S373, XP055598497, ISSN: 1552-5260, DOI: 10.1016/j.jalz.2013.09.010 * |
MEISSNER, ALEXANDER ET AL.: "Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis", NUCLEIC ACIDS RESEARCH, vol. 33.18, 2005, pages 5868 - 5877, XP002661907, DOI: doi:10.1093/nar/gki901 |
SAYER, A.A. ET AL., AGE AGEING, vol. 42, 2013, pages 145 - 150 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020128529A1 (en) * | 2018-12-21 | 2020-06-25 | Benevolentai Bio Limited | Compositions and uses thereof |
CN113488163A (en) * | 2021-07-07 | 2021-10-08 | 四川大学华西医院 | Hypomyosis identification method, device, equipment and medium based on machine vision |
Also Published As
Publication number | Publication date |
---|---|
GB201805100D0 (en) | 2018-05-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10398680B2 (en) | Methods of treating muscular dystrophy | |
US10537553B2 (en) | Methods of treating muscular dystrophy | |
EP2015777B1 (en) | Use of organic compounds | |
EP2281058B1 (en) | Methods, compositions, uses, and kits useful for vitamin d deficiency and related disorders | |
DK2902035T3 (en) | METHODS FOR TREATING MUSCLE DYROPHY | |
EP3145513B1 (en) | 3-(4-((4-(morpholinomethyl-benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione for the treatment of systemic lupus erythematosus | |
JP7294756B2 (en) | Methods of predicting and stratifying the risk of sarcopenia and NAD deficiency | |
WO2019186171A1 (en) | Treatment of sarcopenic diseases | |
KR20220011652A (en) | How to Treat Sjogren's Syndrome Using Bruton's Tyrosine Kinase Inhibitors | |
US20140113972A1 (en) | Preselection of subjects for therapeutic treatment with elesclomol based on hypoxic status | |
CA3141059A1 (en) | Methods for objective assessment of memory, early detection of risk for alzheimer's disease, matching individuals with treatments, monitoring response to treatment, and new methods of use for drugs | |
EP3058371B1 (en) | Use of acamprosate to modulate erk 1-2 activation in animal models for fxs and asd and individuals diagnosed with fxs and asd | |
AU2014337504A1 (en) | Use of acamprosate to modulate ERK 1-2 activation in animal models for FXS and ASD and individuals diagnosed with FXS and ASD | |
US20110034551A1 (en) | Methods of increasing sarcosine levels for treating schizophrenia | |
WO2013148183A2 (en) | Compositions and methods for inhibiting drusen | |
Dourish et al. | Anti-obesity drugs: from animal models to clinical efficacy | |
KR101907909B1 (en) | Novel pharmaceutical composition for treating hypertension | |
WO2020128529A1 (en) | Compositions and uses thereof | |
EP1705256A1 (en) | Methods for the treatment of insulin resistance and disease states characterized by insulin resistance | |
CN117813095A (en) | VCP inhibitors for the treatment of amyotrophic lateral sclerosis | |
PATIENT | FUNDAMENTAL PHARMACOLOGICAL MECHANISMS | |
KR20130026399A (en) | Composition for promoting intracellular metabolism, and pharmaceutical preparation for preventing and/or treating saccharometabolism or lipid metabolism disease, functional food, and health food containing the composition | |
CA2843582A1 (en) | Methods for predicting risk of stroke |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 19716505 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 19716505 Country of ref document: EP Kind code of ref document: A1 |