JP6824888B2 - 筋肉の疾患および障害を治療するための方法および組成物 - Google Patents
筋肉の疾患および障害を治療するための方法および組成物 Download PDFInfo
- Publication number
- JP6824888B2 JP6824888B2 JP2017541619A JP2017541619A JP6824888B2 JP 6824888 B2 JP6824888 B2 JP 6824888B2 JP 2017541619 A JP2017541619 A JP 2017541619A JP 2017541619 A JP2017541619 A JP 2017541619A JP 6824888 B2 JP6824888 B2 JP 6824888B2
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- composition according
- muscle
- subject
- elp
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 208000021642 Muscular disease Diseases 0.000 title claims description 84
- 238000000034 method Methods 0.000 title description 63
- 239000000203 mixture Substances 0.000 title description 55
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 11
- 208000035475 disorder Diseases 0.000 title description 6
- 208000029578 Muscle disease Diseases 0.000 title 1
- 239000008194 pharmaceutical composition Substances 0.000 claims description 191
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 claims description 99
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 claims description 96
- 210000003205 muscle Anatomy 0.000 claims description 86
- 201000009623 Myopathy Diseases 0.000 claims description 83
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 81
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 43
- 150000001413 amino acids Chemical group 0.000 claims description 40
- 230000002227 vasoactive effect Effects 0.000 claims description 36
- 210000000663 muscle cell Anatomy 0.000 claims description 32
- 206010013801 Duchenne Muscular Dystrophy Diseases 0.000 claims description 30
- 108090000623 proteins and genes Proteins 0.000 claims description 29
- 230000000747 cardiac effect Effects 0.000 claims description 28
- 102000004169 proteins and genes Human genes 0.000 claims description 27
- 201000006938 muscular dystrophy Diseases 0.000 claims description 24
- 230000002861 ventricular Effects 0.000 claims description 23
- 210000002027 skeletal muscle Anatomy 0.000 claims description 22
- 230000002829 reductive effect Effects 0.000 claims description 21
- 238000011282 treatment Methods 0.000 claims description 21
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 17
- 102000008186 Collagen Human genes 0.000 claims description 16
- 108010035532 Collagen Proteins 0.000 claims description 16
- 229920001436 collagen Polymers 0.000 claims description 16
- 238000004904 shortening Methods 0.000 claims description 15
- 230000003252 repetitive effect Effects 0.000 claims description 13
- 210000002865 immune cell Anatomy 0.000 claims description 12
- 210000000107 myocyte Anatomy 0.000 claims description 12
- 201000006935 Becker muscular dystrophy Diseases 0.000 claims description 11
- 230000003111 delayed effect Effects 0.000 claims description 11
- 210000002540 macrophage Anatomy 0.000 claims description 11
- 102100038286 Vasoactive intestinal polypeptide receptor 2 Human genes 0.000 claims description 10
- 230000006378 damage Effects 0.000 claims description 10
- 238000013268 sustained release Methods 0.000 claims description 9
- 239000012730 sustained-release form Substances 0.000 claims description 9
- 101000666868 Homo sapiens Vasoactive intestinal polypeptide receptor 2 Proteins 0.000 claims description 8
- 206010048654 Muscle fibrosis Diseases 0.000 claims description 8
- 230000002107 myocardial effect Effects 0.000 claims description 8
- 102000037865 fusion proteins Human genes 0.000 claims description 7
- 108020001507 fusion proteins Proteins 0.000 claims description 7
- 210000004413 cardiac myocyte Anatomy 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 4
- 230000004118 muscle contraction Effects 0.000 claims description 4
- 230000002093 peripheral effect Effects 0.000 claims description 3
- 102100022745 Laminin subunit alpha-2 Human genes 0.000 claims description 2
- 201000006815 congenital muscular dystrophy Diseases 0.000 claims description 2
- 230000001815 facial effect Effects 0.000 claims description 2
- 210000002363 skeletal muscle cell Anatomy 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 230000003442 weekly effect Effects 0.000 claims description 2
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 claims 12
- 201000011212 X-linked dilated cardiomyopathy Diseases 0.000 claims 2
- 238000007918 intramuscular administration Methods 0.000 claims 1
- 238000001990 intravenous administration Methods 0.000 claims 1
- 210000003314 quadriceps muscle Anatomy 0.000 claims 1
- 102000055135 Vasoactive Intestinal Peptide Human genes 0.000 description 62
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 48
- 238000009472 formulation Methods 0.000 description 40
- 235000001014 amino acid Nutrition 0.000 description 35
- 229940024606 amino acid Drugs 0.000 description 33
- 230000000968 intestinal effect Effects 0.000 description 33
- 125000003275 alpha amino acid group Chemical group 0.000 description 32
- 239000003814 drug Substances 0.000 description 32
- 206010016654 Fibrosis Diseases 0.000 description 26
- 230000004761 fibrosis Effects 0.000 description 26
- 230000008602 contraction Effects 0.000 description 24
- 230000007423 decrease Effects 0.000 description 24
- 239000011780 sodium chloride Substances 0.000 description 23
- 125000000539 amino acid group Chemical group 0.000 description 21
- 235000018102 proteins Nutrition 0.000 description 21
- 229940124597 therapeutic agent Drugs 0.000 description 21
- 230000007704 transition Effects 0.000 description 20
- 108090001081 Dipeptidases Proteins 0.000 description 19
- 102000004860 Dipeptidases Human genes 0.000 description 19
- 108700027322 VIP-ELP fusion molecule PB1046 Proteins 0.000 description 18
- 230000006870 function Effects 0.000 description 18
- 229960002885 histidine Drugs 0.000 description 18
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 18
- 235000014304 histidine Nutrition 0.000 description 18
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 16
- 229930182817 methionine Natural products 0.000 description 16
- 229960004452 methionine Drugs 0.000 description 16
- 235000006109 methionine Nutrition 0.000 description 16
- 241000699670 Mus sp. Species 0.000 description 15
- 230000004217 heart function Effects 0.000 description 15
- 229920000642 polymer Polymers 0.000 description 15
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 14
- 108010069091 Dystrophin Proteins 0.000 description 14
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 14
- 206010061218 Inflammation Diseases 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 230000004054 inflammatory process Effects 0.000 description 13
- 230000002265 prevention Effects 0.000 description 13
- 229920001184 polypeptide Polymers 0.000 description 12
- 102000001039 Dystrophin Human genes 0.000 description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 11
- 241000699666 Mus <mouse, genus> Species 0.000 description 11
- 230000003213 activating effect Effects 0.000 description 11
- 238000011161 development Methods 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 230000006872 improvement Effects 0.000 description 11
- 230000009467 reduction Effects 0.000 description 11
- 208000024891 symptom Diseases 0.000 description 11
- 230000001225 therapeutic effect Effects 0.000 description 11
- 102000004127 Cytokines Human genes 0.000 description 10
- 108090000695 Cytokines Proteins 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 10
- 210000004165 myocardium Anatomy 0.000 description 10
- 239000004474 valine Substances 0.000 description 10
- 229960004295 valine Drugs 0.000 description 10
- 102100039246 Elongator complex protein 1 Human genes 0.000 description 9
- 101710167754 Elongator complex protein 1 Proteins 0.000 description 9
- 208000029549 Muscle injury Diseases 0.000 description 9
- 238000011156 evaluation Methods 0.000 description 9
- 230000004927 fusion Effects 0.000 description 9
- 230000014509 gene expression Effects 0.000 description 9
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 9
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 8
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 8
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 8
- 102100037790 VIP peptides Human genes 0.000 description 8
- -1 alkaline earth metal salts Chemical class 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 230000029087 digestion Effects 0.000 description 8
- 230000004220 muscle function Effects 0.000 description 8
- 230000000770 proinflammatory effect Effects 0.000 description 8
- 231100000241 scar Toxicity 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 7
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 7
- 102000035195 Peptidases Human genes 0.000 description 7
- 108091005804 Peptidases Proteins 0.000 description 7
- 230000037319 collagen production Effects 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 6
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 6
- 101710137655 Vasoactive intestinal polypeptide receptor 1 Proteins 0.000 description 6
- 102100038388 Vasoactive intestinal polypeptide receptor 1 Human genes 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- 238000002592 echocardiography Methods 0.000 description 6
- 230000002209 hydrophobic effect Effects 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 102100035090 Elongator complex protein 4 Human genes 0.000 description 5
- 101710167759 Elongator complex protein 4 Proteins 0.000 description 5
- 241000588724 Escherichia coli Species 0.000 description 5
- 239000004471 Glycine Substances 0.000 description 5
- 102000004889 Interleukin-6 Human genes 0.000 description 5
- 108090001005 Interleukin-6 Proteins 0.000 description 5
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 5
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 5
- 239000004472 Lysine Substances 0.000 description 5
- 201000002481 Myositis Diseases 0.000 description 5
- 102100022397 Nitric oxide synthase, brain Human genes 0.000 description 5
- 101710111444 Nitric oxide synthase, brain Proteins 0.000 description 5
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 5
- 229960003767 alanine Drugs 0.000 description 5
- 235000004279 alanine Nutrition 0.000 description 5
- 229960002449 glycine Drugs 0.000 description 5
- 230000001976 improved effect Effects 0.000 description 5
- 229940100601 interleukin-6 Drugs 0.000 description 5
- 229960003646 lysine Drugs 0.000 description 5
- 235000018977 lysine Nutrition 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 210000001087 myotubule Anatomy 0.000 description 5
- 229960004799 tryptophan Drugs 0.000 description 5
- 239000004475 Arginine Substances 0.000 description 4
- 102000004420 Creatine Kinase Human genes 0.000 description 4
- 108010042126 Creatine kinase Proteins 0.000 description 4
- 125000000998 L-alanino group Chemical group [H]N([*])[C@](C([H])([H])[H])([H])C(=O)O[H] 0.000 description 4
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 4
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 4
- 102000013009 Pyruvate Kinase Human genes 0.000 description 4
- 108020005115 Pyruvate Kinase Proteins 0.000 description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 4
- 101710128740 VIP peptides Proteins 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 238000009825 accumulation Methods 0.000 description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 4
- 229960003121 arginine Drugs 0.000 description 4
- 235000009697 arginine Nutrition 0.000 description 4
- 230000036760 body temperature Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000001934 delay Effects 0.000 description 4
- 230000008021 deposition Effects 0.000 description 4
- 239000000539 dimer Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 208000014674 injury Diseases 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000003387 muscular Effects 0.000 description 4
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 4
- 229960005190 phenylalanine Drugs 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- 235000019833 protease Nutrition 0.000 description 4
- 229960001153 serine Drugs 0.000 description 4
- 235000004400 serine Nutrition 0.000 description 4
- 210000002700 urine Anatomy 0.000 description 4
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
- 201000010046 Dilated cardiomyopathy Diseases 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 101710181812 Methionine aminopeptidase Proteins 0.000 description 3
- 206010028289 Muscle atrophy Diseases 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- 230000005856 abnormality Effects 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000001668 ameliorated effect Effects 0.000 description 3
- 229960005261 aspartic acid Drugs 0.000 description 3
- 235000003704 aspartic acid Nutrition 0.000 description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000007385 chemical modification Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 3
- 229960002433 cysteine Drugs 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 230000003205 diastolic effect Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003792 electrolyte Substances 0.000 description 3
- 235000013922 glutamic acid Nutrition 0.000 description 3
- 229960002989 glutamic acid Drugs 0.000 description 3
- 239000004220 glutamic acid Substances 0.000 description 3
- 125000000267 glycino group Chemical group [H]N([*])C([H])([H])C(=O)O[H] 0.000 description 3
- 125000001165 hydrophobic group Chemical group 0.000 description 3
- 206010020871 hypertrophic cardiomyopathy Diseases 0.000 description 3
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 210000004969 inflammatory cell Anatomy 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 244000144972 livestock Species 0.000 description 3
- 238000002595 magnetic resonance imaging Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 201000000585 muscular atrophy Diseases 0.000 description 3
- 230000002085 persistent effect Effects 0.000 description 3
- 229960002429 proline Drugs 0.000 description 3
- 235000019419 proteases Nutrition 0.000 description 3
- 239000002464 receptor antagonist Substances 0.000 description 3
- 229940044551 receptor antagonist Drugs 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 210000002435 tendon Anatomy 0.000 description 3
- 229960002898 threonine Drugs 0.000 description 3
- 235000008521 threonine Nutrition 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- 229960004441 tyrosine Drugs 0.000 description 3
- 238000002562 urinalysis Methods 0.000 description 3
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 2
- 102100029077 3-hydroxy-3-methylglutaryl-coenzyme A reductase Human genes 0.000 description 2
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 2
- 208000006029 Cardiomegaly Diseases 0.000 description 2
- 102000010958 Cortactin Human genes 0.000 description 2
- 108010037663 Cortactin Proteins 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 102000004237 Decorin Human genes 0.000 description 2
- 108090000738 Decorin Proteins 0.000 description 2
- 206010052337 Diastolic dysfunction Diseases 0.000 description 2
- 102100029921 Dipeptidyl peptidase 1 Human genes 0.000 description 2
- 101710087078 Dipeptidyl peptidase 1 Proteins 0.000 description 2
- 102100020750 Dipeptidyl peptidase 3 Human genes 0.000 description 2
- 102100036968 Dipeptidyl peptidase 8 Human genes 0.000 description 2
- 102100036969 Dipeptidyl peptidase 9 Human genes 0.000 description 2
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 2
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 101100494157 Escherichia phage Mu P gene Proteins 0.000 description 2
- 102100026060 Exosome component 10 Human genes 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 229910052688 Gadolinium Inorganic materials 0.000 description 2
- 102000006395 Globulins Human genes 0.000 description 2
- 108010044091 Globulins Proteins 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 101000988577 Homo sapiens 3-hydroxy-3-methylglutaryl-coenzyme A reductase Proteins 0.000 description 2
- 101001055976 Homo sapiens Exosome component 10 Proteins 0.000 description 2
- 101000738901 Homo sapiens PMS1 protein homolog 1 Proteins 0.000 description 2
- 101000805490 Homo sapiens VIP peptides Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102100040449 Inactive dipeptidyl peptidase 10 Human genes 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 2
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 108700021757 Minicore Myopathy with External Ophthalmoplegia Proteins 0.000 description 2
- 201000002169 Mitochondrial myopathy Diseases 0.000 description 2
- 208000007101 Muscle Cramp Diseases 0.000 description 2
- 102000008934 Muscle Proteins Human genes 0.000 description 2
- 108010074084 Muscle Proteins Proteins 0.000 description 2
- 208000010428 Muscle Weakness Diseases 0.000 description 2
- 206010028372 Muscular weakness Diseases 0.000 description 2
- 102000036675 Myoglobin Human genes 0.000 description 2
- 108010062374 Myoglobin Proteins 0.000 description 2
- 206010028629 Myoglobinuria Diseases 0.000 description 2
- 206010028851 Necrosis Diseases 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 102100037482 PMS1 protein homolog 1 Human genes 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 206010033799 Paralysis Diseases 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 108091081062 Repeated sequence (DNA) Proteins 0.000 description 2
- 208000005392 Spasm Diseases 0.000 description 2
- 102000004338 Transferrin Human genes 0.000 description 2
- 108090000901 Transferrin Proteins 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 102000011856 Utrophin Human genes 0.000 description 2
- 108010075653 Utrophin Proteins 0.000 description 2
- 101710137651 Vasoactive intestinal polypeptide receptor 2 Proteins 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 230000006793 arrhythmia Effects 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 230000009787 cardiac fibrosis Effects 0.000 description 2
- 238000013184 cardiac magnetic resonance imaging Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 201000011474 congenital myopathy Diseases 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 230000000447 dimerizing effect Effects 0.000 description 2
- 230000003292 diminished effect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 238000002565 electrocardiography Methods 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 235000004554 glutamine Nutrition 0.000 description 2
- 229960002743 glutamine Drugs 0.000 description 2
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 2
- 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 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 208000023692 inborn mitochondrial myopathy Diseases 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 230000000297 inotrophic effect Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 238000011813 knockout mouse model Methods 0.000 description 2
- 229960003136 leucine Drugs 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 238000011866 long-term treatment Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 230000037191 muscle physiology Effects 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 208000018360 neuromuscular disease Diseases 0.000 description 2
- 210000004492 nuclear pore Anatomy 0.000 description 2
- 229960001699 ofloxacin Drugs 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000012261 overproduction Methods 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 230000002688 persistence Effects 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- 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 2
- 230000008569 process Effects 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- 210000001057 smooth muscle myoblast Anatomy 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- 230000001256 tonic effect Effects 0.000 description 2
- 239000012581 transferrin Substances 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 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
- HLPBVBAEIVCCLH-USJZOSNVSA-N 2-[[(2s)-2-[[2-[[(2s)-1-[(2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]acetyl]amino]-3-methylbutanoyl]amino]acetic acid Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O HLPBVBAEIVCCLH-USJZOSNVSA-N 0.000 description 1
- LFTRJWKKLPVMNE-RCBQFDQVSA-N 2-[[(2s)-2-[[2-[[(2s)-1-[(2s)-2-amino-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]acetyl]amino]-3-methylbutanoyl]amino]acetic acid Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O LFTRJWKKLPVMNE-RCBQFDQVSA-N 0.000 description 1
- FAWLNURBQMTKEB-URDPEVQOSA-N 213546-53-3 Chemical compound N([C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N1[C@@H](CCC1)C(O)=O)C(C)C)C(C)C)C(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)N)C(C)C FAWLNURBQMTKEB-URDPEVQOSA-N 0.000 description 1
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical compound NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- GIJPBJLOHMBSSM-UHFFFAOYSA-N 5-[ethyl(methoxy)phosphoryl]-2-[3-(trifluoromethyl)phenyl]-1,3-benzoxazole Chemical compound C(C)P(OC)(=O)C=1C=CC2=C(N=C(O2)C2=CC(=CC=C2)C(F)(F)F)C=1 GIJPBJLOHMBSSM-UHFFFAOYSA-N 0.000 description 1
- 201000010053 Alcoholic Cardiomyopathy Diseases 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 201000006058 Arrhythmogenic right ventricular cardiomyopathy Diseases 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 206010007637 Cardiomyopathy alcoholic Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000157855 Cinchona Species 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- 108091026890 Coding region Proteins 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
- 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
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010011985 Decubitus ulcer Diseases 0.000 description 1
- 208000032781 Diabetic cardiomyopathy Diseases 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- 102100036966 Dipeptidyl aminopeptidase-like protein 6 Human genes 0.000 description 1
- 102100020751 Dipeptidyl peptidase 2 Human genes 0.000 description 1
- 101710087005 Dipeptidyl peptidase 9 Proteins 0.000 description 1
- 208000011345 Duchenne and Becker muscular dystrophy Diseases 0.000 description 1
- 102100039368 ER lumen protein-retaining receptor 2 Human genes 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- 101710167764 Elongator complex protein 2 Chemical group 0.000 description 1
- 102100034241 Elongator complex protein 2 Human genes 0.000 description 1
- 102100035074 Elongator complex protein 3 Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 208000018565 Hemochromatosis Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000804935 Homo sapiens Dipeptidyl aminopeptidase-like protein 6 Proteins 0.000 description 1
- 101000931864 Homo sapiens Dipeptidyl peptidase 2 Proteins 0.000 description 1
- 101000931862 Homo sapiens Dipeptidyl peptidase 3 Proteins 0.000 description 1
- 101000804947 Homo sapiens Dipeptidyl peptidase 8 Proteins 0.000 description 1
- 101000804945 Homo sapiens Dipeptidyl peptidase 9 Proteins 0.000 description 1
- 101000812465 Homo sapiens ER lumen protein-retaining receptor 2 Proteins 0.000 description 1
- 101000877382 Homo sapiens Elongator complex protein 3 Proteins 0.000 description 1
- 101000967820 Homo sapiens Inactive dipeptidyl peptidase 10 Proteins 0.000 description 1
- 101500027956 Homo sapiens Vasoactive intestinal peptide Proteins 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- PVHLMTREZMEJCG-GDTLVBQBSA-N Ile(5)-angiotensin II (1-7) Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 PVHLMTREZMEJCG-GDTLVBQBSA-N 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- 201000009342 Limb-girdle muscular dystrophy Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010068836 Metabolic myopathy Diseases 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 206010027727 Mitral valve incompetence Diseases 0.000 description 1
- 206010028594 Myocardial fibrosis Diseases 0.000 description 1
- 102000004472 Myostatin Human genes 0.000 description 1
- 108010056852 Myostatin Proteins 0.000 description 1
- 208000010316 Myotonia congenita Diseases 0.000 description 1
- 208000023137 Myotoxicity Diseases 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- 102100031455 NAD-dependent protein deacetylase sirtuin-1 Human genes 0.000 description 1
- 206010029323 Neuromyopathy Diseases 0.000 description 1
- 102000003797 Neuropeptides Human genes 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 1
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 1
- 229940076380 PDE9 inhibitor Drugs 0.000 description 1
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 208000004301 Sinus Arrhythmia Diseases 0.000 description 1
- 108010041191 Sirtuin 1 Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 208000009609 Takotsubo Cardiomyopathy Diseases 0.000 description 1
- 108020005038 Terminator Codon Proteins 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- 102000002689 Toll-like receptor Human genes 0.000 description 1
- 108020000411 Toll-like receptor Proteins 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- 102000012088 Vasoactive Intestinal Peptide Receptors Human genes 0.000 description 1
- 108010075974 Vasoactive Intestinal Peptide Receptors Proteins 0.000 description 1
- 208000009982 Ventricular Dysfunction Diseases 0.000 description 1
- 206010068767 Viral cardiomyopathy Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003510 anti-fibrotic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000781 anti-lymphocytic effect Effects 0.000 description 1
- 230000003460 anti-nuclear Effects 0.000 description 1
- 230000001494 anti-thymocyte effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- HDRGJRSISASRAJ-WKPMUQCKSA-N bazlitoran Chemical compound CO[C@@H]1[C@H](O)[C@@H](COP(=O)(S)O[C@@H]2[C@@H](COP(=O)(S)O[C@H]3C[C@@H](O[C@@H]3COP(=O)(S)O[C@H]4C[C@@H](O[C@@H]4COP(=O)(S)O[C@H]5C[C@@H](O[C@@H]5COP(=O)(S)O[C@H]6C[C@@H](O[C@@H]6COP(=O)(S)O[C@H]7C[C@@H](O[C@@H]7COP(=O)(S)O[C@H]8C[C@@H](O[C@@H]8COP(=O)(S)O[C@H]9C[C@@H](O[C@@H]9COP(=O)(S)O[C@H]%10C[C@@H](O[C@@H]%10COP(=O)(S)O[C@@H]%11[C@@H](COP(=O)(S)O[C@@H]%12[C@@H](COP(=O)(S)O[C@H]%13C[C@@H](O[C@@H]%13COP(=O)(S)O[C@H]%14C[C@@H](O[C@@H]%14COP(=O)(S)O[C@H]%15C[C@@H](O[C@@H]%15COP(=O)(S)O[C@H]%16C[C@@H](O[C@@H]%16COP(=O)(S)O[C@H]%17C[C@@H](O[C@@H]%17COP(=O)(S)O[C@H]%18C[C@@H](O[C@@H]%18CO)N%19C=CC(=NC%19=O)N)N%20C=C(C)C(=O)NC%20=O)n%21cnc%22c(N)ncnc%21%22)N%23C=C(C)C(=O)NC%23=O)N%24C=CC(=NC%24=O)N)N%25C=C(C)C(=O)NC%25=O)O[C@H]([C@@H]%12OC)n%26cnc%27C(=O)NC(=Nc%26%27)N)O[C@H]([C@@H]%11OC)N%28C=CC(=O)NC%28=O)N%29C=C(C)C(=NC%29=O)N)n%30ccc%31C(=O)NC(=Nc%30%31)N)N%32C=C(C)C(=O)NC%32=O)N%33C=C(C)C(=O)NC%33=O)N%34C=CC(=NC%34=O)N)N%35C=C(C)C(=O)NC%35=O)N%36C=CC(=NC%36=O)N)N%37C=C(C)C(=O)NC%37=O)O[C@H]([C@@H]2OC)n%38cnc%39C(=O)NC(=Nc%38%39)N)O[C@H]1N%40C=CC(=O)NC%40=O HDRGJRSISASRAJ-WKPMUQCKSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 230000007883 bronchodilation Effects 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 230000010221 calcium permeability Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 210000002318 cardia Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000002659 cell therapy Methods 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- RVEJWGYZBXCGGM-DNVCBOLYSA-N chembl2179094 Chemical compound C([C@H]([C@@H](C1)C=2NC(=O)C=3C=NN(C=3N=2)C2CCOCC2)C)N1CC1=CC=CC=C1 RVEJWGYZBXCGGM-DNVCBOLYSA-N 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000001608 connective tissue cell Anatomy 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000009091 contractile dysfunction Effects 0.000 description 1
- 230000008828 contractile function Effects 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- HUGILZFVSVLCAO-XVKRXUDYSA-N drisapersen Chemical compound CO[C@@H]1[C@H](O)[C@@H](COP(=O)(S)O[C@@H]2[C@@H](COP(=O)(S)O[C@@H]3[C@@H](COP(=O)(S)O[C@@H]4[C@@H](COP(=O)(S)O[C@@H]5[C@@H](COP(=O)(S)O[C@@H]6[C@@H](COP(=O)(S)O[C@@H]7[C@@H](COP(=O)(S)O[C@@H]8[C@@H](COP(=O)(S)O[C@@H]9[C@@H](COP(=O)(S)O[C@@H]%10[C@@H](COP(=O)(S)O[C@@H]%11[C@@H](COP(=O)(S)O[C@@H]%12[C@@H](COP(=O)(S)O[C@@H]%13[C@@H](COP(=O)(S)O[C@@H]%14[C@@H](COP(=O)(S)O[C@@H]%15[C@@H](COP(=O)(S)O[C@@H]%16[C@@H](COP(=O)(S)O[C@@H]%17[C@@H](COP(=O)(S)O[C@@H]%18[C@@H](COP(=O)(S)O[C@@H]%19[C@@H](COP(=O)(S)O[C@@H]%20[C@@H](CO)O[C@H]([C@@H]%20OC)N%21C=CC(=O)NC%21=O)O[C@H]([C@@H]%19OC)N%22C=CC(=NC%22=O)N)O[C@H]([C@@H]%18OC)n%23cnc%24c(N)ncnc%23%24)O[C@H]([C@@H]%17OC)n%25cnc%26c(N)ncnc%25%26)O[C@H]([C@@H]%16OC)n%27cnc%28C(=O)NC(=Nc%27%28)N)O[C@H]([C@@H]%15OC)n%29cnc%30C(=O)NC(=Nc%29%30)N)O[C@H]([C@@H]%14OC)n%31cnc%32c(N)ncnc%31%32)O[C@H]([C@@H]%13OC)n%33cnc%34c(N)ncnc%33%34)O[C@H]([C@@H]%12OC)n%35cnc%36C(=O)NC(=Nc%35%36)N)O[C@H]([C@@H]%11OC)n%37cnc%38c(N)ncnc%37%38)O[C@H]([C@@H]%10OC)N%39C=CC(=O)NC%39=O)O[C@H]([C@@H]9OC)n%40cnc%41C(=O)NC(=Nc%40%41)N)O[C@H]([C@@H]8OC)n%42cnc%43C(=O)NC(=Nc%42%43)N)O[C@H]([C@@H]7OC)N%44C=CC(=NC%44=O)N)O[C@H]([C@@H]6OC)n%45cnc%46c(N)ncnc%45%46)O[C@H]([C@@H]5OC)N%47C=CC(=O)NC%47=O)O[C@H]([C@@H]4OC)N%48C=CC(=O)NC%48=O)O[C@H]([C@@H]3OC)N%49C=CC(=O)NC%49=O)O[C@H]([C@@H]2OC)N%50C=CC(=NC%50=O)N)O[C@H]1N%51C=CC(=O)NC%51=O HUGILZFVSVLCAO-XVKRXUDYSA-N 0.000 description 1
- 229960000378 drisapersen Drugs 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 230000010437 erythropoiesis Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000002394 glycogenic effect Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- LVASCWIMLIKXLA-LSDHHAIUSA-N halofuginone Chemical compound O[C@@H]1CCCN[C@H]1CC(=O)CN1C(=O)C2=CC(Cl)=C(Br)C=C2N=C1 LVASCWIMLIKXLA-LSDHHAIUSA-N 0.000 description 1
- 229950010152 halofuginone Drugs 0.000 description 1
- 210000002064 heart cell Anatomy 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- JGPMMRGNQUBGND-UHFFFAOYSA-N idebenone Chemical compound COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O JGPMMRGNQUBGND-UHFFFAOYSA-N 0.000 description 1
- 229960004135 idebenone Drugs 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000008991 intestinal motility Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000003295 lusitropic effect Effects 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000006609 metabolic stress Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 238000007431 microscopic evaluation Methods 0.000 description 1
- 208000037226 minicore myopathy Diseases 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 230000004769 mitochondrial stress Effects 0.000 description 1
- 210000004115 mitral valve Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 208000010924 multiminicore myopathy Diseases 0.000 description 1
- 238000001964 muscle biopsy Methods 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 210000004897 n-terminal region Anatomy 0.000 description 1
- 230000017128 negative regulation of NF-kappaB transcription factor activity Effects 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 238000001584 occupational therapy Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 102000014187 peptide receptors Human genes 0.000 description 1
- 108010011903 peptide receptors Proteins 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 238000000554 physical therapy Methods 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000009090 positive inotropic effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012887 quadratic function Methods 0.000 description 1
- 125000003410 quininyl group Chemical group 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 230000004202 respiratory function Effects 0.000 description 1
- 238000002644 respiratory therapy Methods 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 235000021283 resveratrol Nutrition 0.000 description 1
- 229940016667 resveratrol Drugs 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 230000012232 skeletal muscle contraction Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000002630 speech therapy Methods 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000035322 succinylation Effects 0.000 description 1
- 238000010613 succinylation reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 229960000835 tadalafil Drugs 0.000 description 1
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 1
- 238000009601 thyroid function test Methods 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 230000030968 tissue homeostasis Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 108010003885 valyl-prolyl-glycyl-glycine Proteins 0.000 description 1
- 108010054022 valyl-prolyl-glycyl-valyl-glycine Proteins 0.000 description 1
- ZYTXTXAMMDTYDQ-DGEXFFLYSA-N vamorolone Chemical compound C([C@H]12)CC3=CC(=O)C=C[C@]3(C)C1=CC[C@@]1(C)[C@H]2C[C@@H](C)[C@]1(O)C(=O)CO ZYTXTXAMMDTYDQ-DGEXFFLYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000006815 ventricular dysfunction Effects 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/2278—Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Vascular Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Endocrinology (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Description
[0001] 本出願は2015年2月9日に出願の米国特許仮出願第62/113,943号、2015年4月10日に出願の米国特許仮出願第62/145,770号および2015年4月21日に出願の米国特許仮出願第62/150,679号の権益を主張し、それぞれの内容はここに参照により全体が組み込まれる。
[0002] これに添えて電子的に提出されるテキストファイルの内容は、参照によりその全体が本明細書に組み込まれる:配列表のコンピュータ可読フォーマットコピー(ファイル名:PHAS_032/04WO_SeqList_ST25.txt、記録日:2016年2月9日、ファイルサイズ32キロバイト)。
[0023] 血管作用性小腸ペプチド(VIP)は、2つの受容体、VPAC1およびVPAC2に結合する神経ペプチドである。VIPならびにその機能的および構造的に関連した類似体は、平滑筋弛緩(気管支拡張、腸管運動性)および様々な免疫機能のモジュレーション(消炎、免疫細胞保護)を含む、多くの生理機能を有することが知られている(Hinkle et al.(2005))。
エラスチン様ペプチド
(a)テトラペプチドVal−Pro−Gly−GlyまたはVPGG(配列番号1);
(b)テトラペプチドIle−Pro−Gly−GlyまたはIPGG(配列番号2);
(c)ペンタペプチドVal−Pro−Gly−X−Gly(配列番号3)またはVPGXG、ここでXは任意の天然または非天然のアミノ酸残基であり、Xはポリマーまたはオリゴマー反復配列の間で任意選択により異なる;
(d)ペンタペプチドAla−Val−Gly−Val−ProまたはAVGVP(配列番号4);
(e)ペンタペプチドIle−Pro−Gly−X−GlyまたはIPGXG(配列番号5)、ここでXは任意の天然または非天然のアミノ酸残基であり、Xはポリマーまたはオリゴマー反復配列の間で任意選択により異なる;
(e)ペンタペプチドIle−Pro−Gly−Val−GlyまたはIPGVG(配列番号6);
(f)ペンタペプチドLeu−Pro−Gly−X−GlyまたはLPGXG(配列番号7)、ここでXは任意の天然または非天然のアミノ酸残基であり、Xはポリマーまたはオリゴマー反復配列の間で任意選択により異なる;
(g)ペンタペプチドLeu−Pro−Gly−Val−GlyまたはLPGVG(配列番号8);
(h)ヘキサペプチドVal−Ala−Pro−Gly−Val−GlyまたはVAPGVG(配列番号9);
(i)オクタペプチドGly−Val−Gly−Val−Pro−Gly−Val−GlyまたはGVGVPGVG(配列番号10);
(j)ノナペプチドVal−Pro−Gly−Phe−Gly−Val−Gly−Ala−GlyまたはVPGFGVGAG(配列番号11);
(k)ノナペプチドVal−Pro−Gly−Val−Gly−Val−Pro−Gly−GlyまたはVPGVGVPGG(配列番号12);および
(l)ペンタペプチドXaa−Pro−Gly−Val−GlyまたはXPGVG(配列番号13)、ここでXは任意の天然または非天然のアミノ酸残基であり、Xはポリマーまたはオリゴマー反復配列の間で任意選択により異なる。
[0064] ミオパシーは、筋線維が多くの理由のいずれか1つのために機能しないで筋肉の脱力をもたらす、神経筋疾患である。表現型的に、これらの疾患は、筋肉組織の炎症、骨格筋の消耗、筋肉の減少、ならびに呼吸および心臓不全を通して早発の死を引き起こすことがある線維症によって特徴付けられる。筋肉ミオパシーは、骨格筋、心筋および/または平滑筋を含む任意のタイプの筋肉に影響することができる。一部の実施形態では、ミオパシーは筋肉線維症の増加によって特徴付けられる。一部の実施形態では、ミオパシーは、低下した筋力および/または力収縮性によって特徴付けられる。一部の実施形態では、ミオパシーは減少した筋細胞短縮によって特徴付けられる。一部の実施形態では、ミオパシーは減少した筋細胞再伸長速度によって特徴付けられる。一部の実施形態では、ミオパシーは減少した筋細胞弛緩によって特徴付けられる。一部の実施形態では、筋細胞は骨格筋の筋細胞である。一部の実施形態では、筋細胞は心筋細胞である。
医薬組成物および投与
[00107] 本明細書に開示される医薬組成物は、ミオパシー、筋ジストロフィーおよび/または心筋症を治療、予防、遅延または改善するために使用される、物理的療法、呼吸療法、言語療法、作業療法、矯正手術および/または治療剤を限定されずに含む、様々な療法と投与することができる。本明細書に開示される医薬組成物は、単独で、または1つまたは複数の治療剤と組み合わせて使用することができる。1つまたは複数の治療剤は、それを必要とする対象に治療効果を発揮する任意の化合物、分子または物質であってよい。
[00116] 骨格および心臓の症状の発症の遅延に対するPB1046治療の効能を試験するために、デュシェンヌ筋ジストロフィーおよびベッカー筋ジストロフィー患者で臨床治験を実行する。
[00121] 材料および方法:MDX(C57BL10/ScSnDMDmdx、ジストロフィン欠損、n=21)およびDKO(二重ノックアウト)mdx/utrn−/−(ジストロフィン/ユートロフィン欠損、n=13)マウスに、試験期間(MDXの場合は32週、DKOの場合は最高4週)の間、PB1046(1.5mg/kg)または0.9%NaCl食塩水(対照)を週に3回皮下に投与した。左心室機能(心エコー検査;ECHOを通して)および心電図検査(ECG)の変化を、ルーチン検査の間モニタリングした。終末の評価は、全身/左心室血行動態を測定する圧カテーテルを有する機器を取り付けた動物での麻酔をかけた調製物、または長指伸筋(EDL)での骨格筋力評価(MDXだけ)を含んだ。組織試料は、組織学的評価(シリウス染色ならびにマクロファージおよびCDの計数)のために、瞬間冷凍したかまたはホルマリンで固定した。
[00133] 引用される全ての刊行物、特許および公開特許は、全ての目的のためにここに参照により完全に組み込まれる。
[00135] Ameen V. and Robson LG., Experimental models of Duchenne muscular dystrophy: relationship with cardiovascular disease. The Open Cardiovascular Medicine Journal, 2010; 4:265-277.
[00136] Barp A. et al. Genetic modifiers of Duchenne Muscular Dystrophy and dilated cardiomyopathy. PloS ONE. 2015. 10(10):e0141240. Doi: 10.1371/journalpone.014240.
[00137] Brenman J. et al. Nitric Oxide Synthase complexed with Dystrophin and absent from skeletal muscle sarcolemma in Duchenne Muscular Dystrophy. Cell. 1995. 82:743-752.
[00138] Bujak M. and Frangogiannis NG., The role of TGF-β signaling in myocardial infarction and cardiac remodeling, 2007; 74(2):184-195.
[00139] Burks TN. and Cohn RD., Role of TGF-β signaling in inherited and acquired myopathies, Skeletal Muscle, 2011; 1(19):1-13.
[00140] Bushby, K., et al., Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. The Lancet Neurology, 2010. 9(1): p. 77-93.
[00141] Byers, T.J., L.M. Kunkel, and S.C. Watkins, The subcellular distribution of dystrophin in mouse skeletal, cardiac, and smooth muscle. The Journal of Cell Biology, 1991. 115(2): p. 411-421.
[00142] Chorny, A., et al., Signaling mechanisms of vasoactive intestinal peptide in inflammatory conditions. Regulatory Peptides, 2006. 137(1-2): p. 67-74.
[00143] Finsterer J, Cripe L., Treatment of dystrophin cardiomyopathies. Nature Reviews, 2014 (11): 168-178.
[00144] Heller, KN, Montgomery, CL, Janssen, PM, Clark, KR, Mendell, JR, and Rodino-Klapac, LR (2013). AAV-mediated overexpression of human alpha7 integrin leads to histological and functional improvement in dystrophic mice. Molecular therapy : the journal of the American Society of Gene Therapy 21: 520-525.
[00145] Henning, R.J. and D.R. Sawmiller, Vasoactive intestinal peptide: cardiovascular effects. Cardiovascular Research, 2001. 49(1): p. 27-37.
[00146] Heydemann, A. and E. McNally, NO more muscle fatigue. The Journal of Clinical Investigation, 2009. 119(3): p. 448-450.
[00147] Hinkle et al. Activation of the vasoactive intestinal peptide 2 receptor modulates normal and atrophying skeletal muscle mass and force. Journal of Applied Physiology, 2005. 98(2):655-662.
[00148] Judge, D., et al., Pathophysiology and Therapy of Cardiac Dysfunction in Duchenne Muscular Dystrophy. American Journal of Cardiovascular Drugs, 2011. 11(5): p. 287-294.
[00149] Klingler, W., et al., The role of fibrosis in Duchenne muscular dystrophy. Acta Myologia, 2012. 31(3): p. 184-219.
[00150] Lapidos, K.A., R. Kakkar, and E.M. McNally, The Dystrophin Glycoprotein Complex: Signaling Strength and Integrity for the Sarcolemma. Circulation Research, 2004. 94(8): p. 1023-1031.
[00151] Politano, L. and G. Nigro. Treatment of dystophinopathic cardiomyopathy: a review of the literature and personal results. Acta Myologica. 2012. May 31(1): 24-30.
[00152] Rodino-Klapac, LR, et al. (2007). A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy. Journal of translational medicine 5: 45.
[00153] Rosenberg AS et al. Immune-mediated pathology in Duchenne muscular dystrophy. Science Transl. Med. 2015. 7(299): 299rv4. doi: 10.1126/scitranslmed.aaa7322.
[00154] Schellenberger, V. et al. A recombinant polypeptide extends the in vivo half-life of peptides and proteins in a tunable manner. Nat. Biotechnol. 2009 Dec; 27(12): 1186-90.
[00155] Schlapschy, M. et al. PASylation: a biological alternative to PEGylation for extending the plasma half-life of pharmaceutically active proteins. Protein Engineering, Design and Selection. 2013. 26 (8): 489-501.
[00156] Su, JA et al. (2015) Left Ventricular Tonic Contraction as a Novel Biomarker of Cardiomyopathy in Duchenne Muscular Dystrophy. Pediatr. Cardiol. Dec. 29 [Epub ahead of print].
[00157] Sun, W., et al., Vasoactive intestinal peptide (VIP) inhibits TGF-β1 production in murine macrophages. Journal of neuroimmunology, 2000. 107(1): p. 88-99.
[00158] Townsend, D., et al., Distinct pathophysiological mechanisms of cardiomyopathy in hearts lacking dystrophin or the sarcoglycan complex. The FASEB Journal, 2011. 25(9): p. 3106-3114.
[00159] Villalta, S.A., et al., Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. Science Translational Medicine, 2014. 6(258): p. 258ra142.
[00160] Ye, V.Z. and K.A. Duggan, Vasoactive intestinal peptide down-regulates the intrahepatic renin-angiotensin system in the anaesthetized rat. Clin. Sci., 2000. 99(3):p. 201-206.
[00161] Zhou, L. and H. Lu, Targeting Fibrosis in Duchenne Muscular Dystrophy. Journal of Neuropathology & Experimental Neurology, 2010. 69(8): p. 771-776 10.1097/NEN.0b013e3181e9a34b.
Claims (60)
- 筋肉ミオパシーを治療するための医薬組成物であって、それを必要とする患者に6カ月以上の間投与され、VPAC2選択的血管作用性小腸ペプチド(VIP)と、エラスチン様ペプチド(ELP)とを含む融合タンパク質を含有し、
前記VIPが配列番号14のアミノ酸配列を含み、
前記ELPが、少なくとも90のVPGXG(配列番号3)の反復配列を含み、Xが5:2:3の比でVal、AlaおよびGlyから独立して選択される、
医薬組成物。 - 筋収縮によって誘導される損傷から保護するための医薬組成物であって、それを必要とする患者に6カ月以上の間投与され、VPAC2選択的血管作用性小腸ペプチド(VIP)と、エラスチン様ペプチド(ELP)とを含む融合タンパク質を含有し、
前記VIPが配列番号14のアミノ酸配列を含み、
前記ELPが、少なくとも90のVPGXG(配列番号3)の反復配列を含み、Xが5:2:3の比でVal、AlaおよびGlyから独立して選択される、
医薬組成物。 - 心筋症の進行を遅らせるための医薬組成物であって、それを必要とする患者に6カ月以上の間投与され、VPAC2選択的血管作用性小腸ペプチド(VIP)と、エラスチン様ペプチド(ELP)とを含む融合タンパク質を含有し、
前記VIPが配列番号14のアミノ酸配列を含み、
前記ELPが、少なくとも90のVPGXG(配列番号3)の反復配列を含み、Xが5:2:3の比でVal、AlaおよびGlyから独立して選択される、
医薬組成物。 - 心筋症を治療するための医薬組成物であって、それを必要とする患者に6カ月以上の間投与され、VPAC2選択的血管作用性小腸ペプチド(VIP)と、エラスチン様ペプチド(ELP)とを含む融合タンパク質を含有し、
前記VIPが配列番号14のアミノ酸配列を含み、
前記ELPが、少なくとも90のVPGXG(配列番号3)の反復配列を含み、Xが5:2:3の比でVal、AlaおよびGlyから独立して選択される、
医薬組成物。 - 前記医薬組成物が筋肉線維症を低減する、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記ELPがVPGXG(配列番号3)の120反復配列単位を含む、請求項5に記載の医薬組成物。
- 前記医薬組成物が皮下、筋肉内または静脈内投与のために製剤化される、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が皮下投与される、請求項7に記載の医薬組成物。
- 前記医薬組成物が低用量で投与される、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記用量が1日につき0.1mg/kgから1日につき10mg/kgの間にある、請求項9に記載の医薬組成物。
- 前記医薬組成物が日ごとに投与される、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が週に1〜3回投与される、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が週ごとに投与される、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が月に1〜2回投与される、請求項1〜4のいずれか一項に記載の医薬組成物。
- 未処置の患者と比較して前記筋肉線維症が約5%、10%、20%、30%、40%または50%低減される、請求項5に記載の医薬組成物。
- 未処置の患者と比較して前記筋肉線維症が約1カ月、6カ月、1年または5年の間遅延される、請求項5に記載の医薬組成物。
- 前記患者の筋肉収縮性が保存される、請求項1〜4のいずれか一項に記載の医薬組成物。
- 健康対象と比較して前記患者の前記筋肉収縮性が約90%、80%、70%、60%または50%で保存される、請求項17に記載の医薬組成物。
- 前記患者の筋肉強度が保存される、請求項1〜4のいずれか一項に記載の医薬組成物。
- 健康対象と比較して前記患者の前記筋肉強度が約90%、80%、70%、60%または50%で保存される、請求項19に記載の医薬組成物。
- 前記筋肉が骨格筋である、請求項15〜20のいずれか一項に記載の医薬組成物。
- 前記筋肉が心筋である、請求項15〜20のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が未処置筋細胞のそれと比較して筋細胞短縮を保存する、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が未処置筋細胞のそれと比較して筋細胞再伸長速度を保存する、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が未処置筋細胞のそれと比較して筋細胞収縮性を保存する、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が未処置筋細胞のそれと比較して筋細胞弛緩を保存する、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記筋細胞が心筋細胞である、請求項23〜26のいずれか一項に記載の医薬組成物。
- 前記筋細胞が骨格筋細胞である、請求項23〜26のいずれか一項に記載の医薬組成物。
- 前記患者が筋ジストロフィーを有する、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記筋ジストロフィーが、筋緊張性筋ジストロフィー、デュシェンヌ筋ジストロフィー、ベッカー筋ジストロフィー、肢帯筋ジストロフィー、顔面肩甲上腕筋ジストロフィー、先天性筋ジストロフィー、眼球咽頭筋ジストロフィー、末梢型筋ジストロフィーおよびエメリー−ドライフス筋ジストロフィーからなる群から選択される、請求項29に記載の医薬組成物。
- 前記心筋症が筋ジストロフィーから生じる、請求項3または4に記載の医薬組成物。
- 前記筋ジストロフィーがデュシェンヌ筋ジストロフィー、ベッカー筋ジストロフィーまたはX連鎖拡張型心筋症である、請求項31に記載の医薬組成物。
- 前記医薬組成物が配列番号15または配列番号20を含むタンパク質を含有する、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が対象に皮下投与される、請求項33に記載の医薬組成物。
- 前記医薬組成物が1カ月につき1〜2回対象に投与される、請求項34に記載の医薬組成物。
- 前記医薬組成物が低用量で投与される、請求項35に記載の医薬組成物。
- 前記医薬組成物が1日につき1mg/kgから1日につき9mg/kgの間の用量で投与される、請求項36に記載の医薬組成物。
- 前記対象が筋ジストロフィーを有する、請求項37に記載の医薬組成物。
- 前記筋ジストロフィーがデュシェンヌ筋ジストロフィー、ベッカー筋ジストロフィーまたはX連鎖拡張型心筋症である、請求項38に記載の医薬組成物。
- 前記対象が心筋症を有する、請求項39に記載の医薬組成物。
- 血管作用性小腸ペプチド(VIP)および1つまたは複数のエラスチン様ペプチド(ELP)を含む前記医薬組成物が持続的放出のために製剤化される、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記医薬組成物の投与が未処置のミオパシー対象と比較して短縮率を保存する、請求項3または4に記載の医薬組成物。
- 未処置のミオパシー対象と比較して前記短縮率が約20%〜50%保存される、請求項42に記載の医薬組成物。
- 前記医薬組成物の投与が未処置のミオパシー対象と比較して心室充填速度を増加させる、請求項3または4に記載の医薬組成物。
- 未処置のミオパシー対象と比較して前記心室充填速度が約10〜50%増加する、請求項44に記載の医薬組成物。
- 前記医薬組成物の投与が未処置のミオパシー対象と比較して圧上昇の最大速度を上昇させる、請求項3または4に記載の医薬組成物。
- 未処置のミオパシー対象と比較して圧の前記最大速度が約20%〜約50%上昇する、請求項46に記載の医薬組成物。
- 前記医薬組成物の投与が未処置のミオパシー対象と比較して弛緩のタウ定数を増加させる、請求項3または4に記載の医薬組成物。
- 未処置のミオパシー対象と比較して弛緩のタウ定数が約10%〜約50%増加する、請求項48に記載の医薬組成物。
- 前記医薬組成物の投与が未処置のミオパシー対象と比較して筋肉中のコラーゲン量を低下させる、請求項1〜4のいずれか一項に記載の医薬組成物。
- 未処置のミオパシー対象と比較して筋肉中のコラーゲン量が約20%〜約50%低下する、請求項50に記載の医薬組成物。
- 前記医薬組成物の投与が未処置のミオパシー対象と比較して筋肉中の免疫細胞数を減少させる、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記免疫細胞がマクロファージである、請求項52に記載の医薬組成物。
- 未処置のミオパシー対象と比較して前記マクロファージ細胞数が筋肉中で約20〜50%減少する、請求項53に記載の医薬組成物。
- 前記筋肉が腓腹筋、四頭筋、横隔膜の筋肉、前脛骨筋および/または心筋である、請求項50〜54のいずれか一項に記載の医薬組成物。
- 筋肉ミオパシーを治療するための医薬組成物であって、それを必要とする患者に6カ月以上の間投与され、配列番号15のアミノ酸配列を含むタンパク質を含有する、医薬組成物。
- 筋収縮によって誘導される損傷から保護するための医薬組成物であって、それを必要とする患者に6カ月以上の間投与され、配列番号15のアミノ酸配列を含むタンパク質を含有する、医薬組成物。
- 心筋症の進行を遅らせるための医薬組成物であって、それを必要とする患者に6カ月以上の間投与され、配列番号15のアミノ酸配列を含むタンパク質を含有する、医薬組成物。
- 心筋症を治療するための医薬組成物であって、それを必要とする患者に6カ月以上の間投与され、配列番号15のアミノ酸配列を含むタンパク質を含有する、医薬組成物。
- 前記医薬組成物が筋肉線維症を低減する、請求項56〜59のいずれか一項に記載の医薬組成物。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562113943P | 2015-02-09 | 2015-02-09 | |
US62/113,943 | 2015-02-09 | ||
US201562145770P | 2015-04-10 | 2015-04-10 | |
US62/145,770 | 2015-04-10 | ||
US201562150679P | 2015-04-21 | 2015-04-21 | |
US62/150,679 | 2015-04-21 | ||
PCT/US2016/017102 WO2016130518A2 (en) | 2015-02-09 | 2016-02-09 | Methods and compositions for treating muscle disease and disorders |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2018509395A JP2018509395A (ja) | 2018-04-05 |
JP2018509395A5 JP2018509395A5 (ja) | 2019-03-07 |
JP6824888B2 true JP6824888B2 (ja) | 2021-02-03 |
Family
ID=56614686
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017541619A Active JP6824888B2 (ja) | 2015-02-09 | 2016-02-09 | 筋肉の疾患および障害を治療するための方法および組成物 |
Country Status (9)
Country | Link |
---|---|
US (3) | US10688156B2 (ja) |
EP (1) | EP3256151B1 (ja) |
JP (1) | JP6824888B2 (ja) |
CN (2) | CN107427556B (ja) |
AU (1) | AU2016219513B2 (ja) |
CA (1) | CA2976038A1 (ja) |
ES (1) | ES2822598T3 (ja) |
HK (1) | HK1249402A1 (ja) |
WO (1) | WO2016130518A2 (ja) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2873553C (en) | 2011-06-06 | 2020-01-28 | Phasebio Pharmaceuticals, Inc. | Use of modified vasoactive intestinal peptides in the treatment of hypertension |
EP3139949B1 (en) | 2014-05-08 | 2020-07-29 | Phasebio Pharmaceuticals, Inc. | Compositions comprising a vip-elp fusion protein for use in treating cystic fibrosis |
CA2976038A1 (en) | 2015-02-09 | 2016-08-18 | Phasebio Pharmaceuticals, Inc. | Methods and compositions for treating muscle disease and disorders |
Family Cites Families (149)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4132746A (en) | 1976-07-09 | 1979-01-02 | University Of Alabama, Birmingham Medical & Education Foundation | Synthetic elastomeric insoluble cross-linked polypentapeptide |
US4187852A (en) | 1976-07-09 | 1980-02-12 | The University Of Alabama | Synthetic elastomeric insoluble cross-linked polypentapeptide |
US4500700A (en) | 1981-10-02 | 1985-02-19 | The Board Of Trustees Of The University Of Alabama For The University Of Alabama In Birmingham | Elastomeric composite material comprising a polypentapeptide having an amino acid of opposite chirality in position three |
US4474851A (en) | 1981-10-02 | 1984-10-02 | The University Of Alabama In Birmingham | Elastomeric composite material comprising a polypeptide |
US4589882A (en) | 1983-09-19 | 1986-05-20 | Urry Dan W | Enzymatically crosslinked bioelastomers |
US4752638A (en) | 1983-11-10 | 1988-06-21 | Genetic Systems Corporation | Synthesis and use of polymers containing integral binding-pair members |
US4749647A (en) | 1984-06-22 | 1988-06-07 | Genetic Systems Corporation | Polymerization-induced separation assay using recognition pairs |
US4605641A (en) | 1984-10-09 | 1986-08-12 | Hoffmann-La Roche Inc. | Synthetic vasoactive intestinal peptide analogs |
US4734400A (en) | 1984-10-09 | 1988-03-29 | Hoffmann-La Roche Inc. | Synthetic vasoactive intestinal peptide analogs |
US4870055A (en) | 1986-04-17 | 1989-09-26 | University Of Alabama At Birmingham | Segmented polypeptide bioelastomers to modulate elastic modulus |
US4783523A (en) | 1986-08-27 | 1988-11-08 | Urry Dan W | Temperature correlated force and structure development of elastin polytetrapeptides and polypentapeptides |
US7138486B2 (en) | 1986-05-05 | 2006-11-21 | The General Hospital Corporation | Insulinotropic hormone derivatives and uses thereof |
US4898926A (en) | 1987-06-15 | 1990-02-06 | The University Of Alabama At Birmingham/Research Foundation | Bioelastomer containing tetra/penta-peptide units |
US5496712A (en) | 1990-11-06 | 1996-03-05 | Protein Polymer | High molecular weight collagen-like protein polymers |
US5773249A (en) | 1986-11-04 | 1998-06-30 | Protein Polymer Technologies, Inc. | High molecular weight collagen-like protein polymers |
US5641648A (en) | 1986-11-04 | 1997-06-24 | Protein Polymer Technologies, Inc. | Methods for preparing synthetic repetitive DNA |
US5243038A (en) | 1986-11-04 | 1993-09-07 | Protein Polymer Technologies, Inc. | Construction of synthetic DNA and its use in large polypeptide synthesis |
US5770697A (en) | 1986-11-04 | 1998-06-23 | Protein Polymer Technologies, Inc. | Peptides comprising repetitive units of amino acids and DNA sequences encoding the same |
US5514581A (en) | 1986-11-04 | 1996-05-07 | Protein Polymer Technologies, Inc. | Functional recombinantly prepared synthetic protein polymer |
US6184348B1 (en) | 1986-11-04 | 2001-02-06 | Protein Polymer Technologies | Functional recombinantly prepared synthetic protein polymer |
US6018030A (en) | 1986-11-04 | 2000-01-25 | Protein Polymer Technologies, Inc. | Peptides comprising repetitive units of amino acids and DNA sequences encoding the same |
US5830713A (en) | 1986-11-04 | 1998-11-03 | Protein Polymer Technologies, Inc. | Methods for preparing synthetic repetitive DNA |
US4835252A (en) | 1987-02-26 | 1989-05-30 | The Salk Institute Biotechnology/Industrial Associates, Inc. | Vasoactive intestinal peptide analogs |
US4939224A (en) | 1987-02-26 | 1990-07-03 | The Salk Institute Biotechnology/Industrial Associates, Inc. | Vasoactive intestinal peptide analogs |
US5606019A (en) | 1987-10-29 | 1997-02-25 | Protien Polymer Technologies, Inc. | Synthetic protein as implantables |
IL87055A (en) | 1988-07-08 | 1994-06-24 | Illana Gozes | Conjugates of vasoactive intestinal peptide (vip) and of fragments thereof and pharmaceutical compositions comprising them |
US5766883A (en) | 1989-04-29 | 1998-06-16 | Delta Biotechnology Limited | Polypeptides |
US5143854A (en) | 1989-06-07 | 1992-09-01 | Affymax Technologies N.V. | Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof |
US5141924A (en) | 1989-06-30 | 1992-08-25 | Hoffmann-La Roche, Inc. | Synthetic vasoactive intestinal peptide analogs |
US5234907A (en) | 1989-06-30 | 1993-08-10 | Hoffmann-La Roche Inc. | Synthetic vasoactive intestinal peptide analogs |
US5236904A (en) | 1989-09-18 | 1993-08-17 | Senetek, Plc | Erection-inducing methods and compositions |
US5447912A (en) | 1989-09-18 | 1995-09-05 | Senetek, Plc | Erection-inducing methods and compositions |
DE69105323T2 (de) | 1990-03-27 | 1995-06-01 | Bioelastics Res Ltd | Bioelastomeres Arzneimittelabgabesystem. |
ES2063406T3 (es) | 1990-06-26 | 1995-01-01 | Sanwa Kagaku Kenkyusho Co | Procedimiento para la preparacion de analogos de polipeptido intestinal vasoactivo. |
JPH07108232B2 (ja) | 1990-10-09 | 1995-11-22 | エム・ディ・リサーチ株式会社 | ペプチド又は蛋白質の製造方法 |
US5235041A (en) | 1990-12-28 | 1993-08-10 | Protein Polymer Technologies, Inc. | Purification of structurally ordered recombinant protein polymers |
US5595732A (en) | 1991-03-25 | 1997-01-21 | Hoffmann-La Roche Inc. | Polyethylene-protein conjugates |
US5393602A (en) | 1991-04-19 | 1995-02-28 | Bioelastics Research Ltd. | Superabsorbent materials and uses thereof |
JPH05238950A (ja) | 1991-04-22 | 1993-09-17 | Sanwa Kagaku Kenkyusho Co Ltd | 易吸収性vip製剤 |
US5958881A (en) | 1991-04-25 | 1999-09-28 | Korman; Louis Y. | Composition containing VIP for injection and a method of enhancing visualization of tissues during medical procedures |
AU656230B2 (en) | 1991-10-11 | 1995-01-27 | F. Hoffmann-La Roche Ag | Cyclic vasoactive peptides |
US5681816A (en) | 1992-04-24 | 1997-10-28 | Korman; Louis Y. | Method of inducing temporary paralysis of the gastrointestinal tract during medical procedure |
US5288514A (en) | 1992-09-14 | 1994-02-22 | The Regents Of The University Of California | Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support |
US5972883A (en) | 1993-03-16 | 1999-10-26 | Yeda Research And Development Co. Ltd. | Method for the treatment of neurodegenerative diseases by administering VIP, an analogue, fragment or a conjugate thereof |
US5545617A (en) | 1993-11-12 | 1996-08-13 | The Schepens Eye Research Institute, Inc. | Therapeutic regulation of abnormal conjunctival goblet cell mucous secretion |
US5705483A (en) | 1993-12-09 | 1998-01-06 | Eli Lilly And Company | Glucagon-like insulinotropic peptides, compositions and methods |
US5900405A (en) | 1994-01-24 | 1999-05-04 | Bioelastics Research, Ltd. | Polymers responsive to electrical energy |
WO1995027496A1 (en) | 1994-04-07 | 1995-10-19 | Proteinix Company | Vasoactive intestinal polypeptide |
US5527610A (en) | 1994-05-20 | 1996-06-18 | The Uab Research Foundation | Elastomeric polypeptide matrices for preventing adhesion of biological materials |
US6004782A (en) | 1995-04-14 | 1999-12-21 | Bioelastics Research Ltd. | Hyperexpression of bioelastic polypeptides |
US5972406A (en) | 1995-04-14 | 1999-10-26 | Bioelastics Research Ltd. | Bioelastomers suitable as food product additives |
US5854387A (en) | 1995-04-14 | 1998-12-29 | Bioelastics Research, Ltd. | Simple method for the purification of a bioelastic polymer |
US5624711A (en) | 1995-04-27 | 1997-04-29 | Affymax Technologies, N.V. | Derivatization of solid supports and methods for oligomer synthesis |
US6037321A (en) | 1995-05-03 | 2000-03-14 | Biostar Inc. | Fusion proteins comprising vasoactive intestinal peptide or PACAP |
WO1997009068A2 (en) | 1995-09-01 | 1997-03-13 | University Of Washington | Interactive molecular conjugates |
US5702717A (en) | 1995-10-25 | 1997-12-30 | Macromed, Inc. | Thermosensitive biodegradable polymers based on poly(ether-ester)block copolymers |
BRPI9715219B8 (pt) | 1996-02-09 | 2015-07-07 | Abbvie Biotechnology Ltd | Vetor recombinante de expressão, e célula hospedeira procariótica. |
KR100493795B1 (ko) | 1996-02-09 | 2005-09-09 | 에프. 호프만-라 로슈 아게 | 혈관활성장펩타이드유사체의합성방법 |
US6063061A (en) | 1996-08-27 | 2000-05-16 | Fusion Medical Technologies, Inc. | Fragmented polymeric compositions and methods for their use |
US5816259A (en) | 1997-01-13 | 1998-10-06 | Rose; Samuel | Method for the diagnosis and treatment of cancer by the accumulation of radioactive precipitates in targeted cells |
US20020099003A1 (en) | 1997-10-28 | 2002-07-25 | Wilson Leland F. | Treatment of female sexual dysfunction with vasoactive agents, particularly vasoactive intestinal polypeptide and agonists thereof |
US6703359B1 (en) | 1998-02-13 | 2004-03-09 | Amylin Pharmaceuticals, Inc. | Inotropic and diuretic effects of exendin and GLP-1 |
JP2002507437A (ja) | 1998-02-27 | 2002-03-12 | バイオエラスチックス・リサーチ・リミテッド | 組織の増強及び回復のための注射可能インプラント |
US6998387B1 (en) | 1998-03-19 | 2006-02-14 | Amylin Pharmaceuticals, Inc. | Human appetite control by glucagon-like peptide receptor binding compounds |
FR2776520B1 (fr) | 1998-03-25 | 2000-05-05 | Sod Conseils Rech Applic | Nouvelles compositions pharmaceutiques destinees a la liberation prolongee de peptides et leur procede de preparation |
US20020151458A1 (en) | 1998-04-17 | 2002-10-17 | Perez Gomariz Rosa Maria | Method for treating and preventing septic shock with VPAC1R, VPAC2R and PAC1R agonists |
US6153655A (en) | 1998-04-17 | 2000-11-28 | Enzon, Inc. | Terminally-branched polymeric linkers and polymeric conjugates containing the same |
ES2138561B1 (es) | 1998-04-17 | 2000-07-01 | Univ Madrid Complutense | Uso de los peptidos vip y pacap en el tratamiento del shock endotoxico en mamiferos. |
US6200598B1 (en) | 1998-06-18 | 2001-03-13 | Duke University | Temperature-sensitive liposomal formulation |
US6541033B1 (en) | 1998-06-30 | 2003-04-01 | Amgen Inc. | Thermosensitive biodegradable hydrogels for sustained delivery of leptin |
US6406921B1 (en) | 1998-07-14 | 2002-06-18 | Zyomyx, Incorporated | Protein arrays for high-throughput screening |
AU3867400A (en) | 1999-03-19 | 2000-10-09 | Duke University | Methods of using bioelastomers |
US20090175821A1 (en) | 1999-05-17 | 2009-07-09 | Bridon Dominique P | Modified therapeutic peptides with extended half-lives in vivo |
JP2004500906A (ja) | 1999-11-12 | 2004-01-15 | ルーベン, レオ | 電気的調節および化学的調節のための心臓デバイス、ならびに心肺障害の処置のための血管作用性腸ペプチド |
US6235264B1 (en) | 1999-12-01 | 2001-05-22 | General Electric Company | Medical imaging method for characterizing tumor angiogenesis using polymeric contrast agents |
JP2001161363A (ja) | 1999-12-03 | 2001-06-19 | Hisamitsu Pharmaceut Co Inc | 新規な小胞体局在タンパク質およびそれを含む糖タンパク質異常症治療薬、並びに該タンパク質をコードするdnaおよびそれを含む糖タンパク質異常症治療のための遺伝子治療薬。 |
US6593394B1 (en) | 2000-01-03 | 2003-07-15 | Prosperous Kingdom Limited | Bioactive and osteoporotic bone cement |
US7833992B2 (en) | 2001-05-18 | 2010-11-16 | Merck Sharpe & Dohme | Conjugates and compositions for cellular delivery |
WO2001060862A1 (en) | 2000-02-18 | 2001-08-23 | Dabur Research Foundation | Vasoactive intestinal peptide analogs |
DE60033697D1 (de) | 2000-02-18 | 2007-04-12 | Dabur Res Foundation Sahibabad | Radiomarkierte vip-analoge zur diagnose und therapie |
US6852834B2 (en) | 2000-03-20 | 2005-02-08 | Ashutosh Chilkoti | Fusion peptides isolatable by phase transition |
US20050255554A1 (en) | 2000-03-20 | 2005-11-17 | Ashutosh Chilkoti | Fusion peptides isolatable by phase transition |
HU229208B1 (en) | 2000-06-16 | 2013-09-30 | Lilly Co Eli | Glucagon-like peptide-1 analogs |
CN1487952A (zh) | 2000-11-28 | 2004-04-07 | �ɶ����\��ʵ���� | 具有血管活性肠肽的生物学活性的用于治疗肺动脉和小动脉高压的化合物 |
JP2004528014A (ja) | 2000-12-07 | 2004-09-16 | イーライ・リリー・アンド・カンパニー | Glp−1融合タンパク質 |
CN1501809B (zh) | 2000-12-13 | 2012-10-10 | 伊莱利利公司 | 应用胰高血糖素样促胰岛肽的长期治疗方案 |
US7144863B2 (en) | 2001-06-01 | 2006-12-05 | Eli Lilly And Company | GLP-1 formulations with protracted time action |
AU2002323217B2 (en) | 2001-08-15 | 2008-04-10 | Brown University Research Foundation | Treatment of muscular dystrophies and related disorders |
BR0212080A (pt) | 2001-08-23 | 2006-04-04 | Lilly Co Eli | composto de glp-1, método de estimulação de receptor de glp-1 em um indivìduo necessitando de tal estimulação, e, uso de um composto de glp-1 |
US7176278B2 (en) | 2001-08-30 | 2007-02-13 | Biorexis Technology, Inc. | Modified transferrin fusion proteins |
US7459441B2 (en) | 2001-11-06 | 2008-12-02 | Senju Pharmaceutical Co., Ltd. | Remedies for dry eye and diseases associated with dry eye |
CA2471363C (en) | 2001-12-21 | 2014-02-11 | Human Genome Sciences, Inc. | Albumin fusion proteins |
US20060241028A1 (en) | 2002-06-10 | 2006-10-26 | Dorian Bevec | Use of compounds having the biological activity of vasoactive intestinal peptide for the treatment of sarcoidosis |
ATE521624T1 (de) | 2002-11-27 | 2011-09-15 | Ils Inc | Peptide und medizinische zusammensetzungen mit denselben |
WO2004104020A2 (en) | 2003-05-14 | 2004-12-02 | Dow Corning Corporation | Repeat sequence protein polymer active agent conjugates, methods and uses |
JP2007524592A (ja) | 2003-06-03 | 2007-08-30 | ノボ・ノルデイスク・エー/エス | 安定化された薬学的ペプチド組成物 |
CA2532135A1 (en) | 2003-07-14 | 2005-01-20 | Mondobiotech Laboratories Anstalt | Biologically active substance of a vasoactive intestinal peptide for treating interstitial lung infections |
WO2005014030A1 (en) | 2003-07-24 | 2005-02-17 | Lutz-Henning Block | Method for treating lung diseases associated with ventilation-perfusion mismatches |
US7928059B2 (en) | 2004-02-24 | 2011-04-19 | Wisconsin Alumni Research Foundation | Use of neuropeptides for traumatic cartilage injury |
US7776815B2 (en) | 2004-02-24 | 2010-08-17 | Wisconsin Alumni Research Foundation | Use of neuropeptides for ligament healing |
US20050203009A1 (en) | 2004-03-12 | 2005-09-15 | Bayer Pharmaceuticals Corporation | VPAC1 selective antagonists and their pharmacological methods of use |
WO2005097158A1 (en) | 2004-03-29 | 2005-10-20 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Amphipathic glycopeptides |
CA2567635A1 (en) | 2004-05-21 | 2005-12-01 | Eli Lilly And Company | Selective vpac2 receptor peptide agonists |
RU2387454C2 (ru) | 2004-06-11 | 2010-04-27 | Вектас Байосистемз Лимитед | Композиции и способы лечения сердечно-сосудистого заболевания |
EP1768686A4 (en) | 2004-06-12 | 2007-11-14 | Bayer Pharmaceuticals Corp | PEGYLATION OF VASOACTIVE INTESTINAL PEPTIDE (VIP) / HYPOPHYDE-ADENYLATE CYCLASE-ACTIVATING PEPTIDE (PACAP) RECEPTOR 2 (VPAC2) AGONISTS AND METHOD OF USE |
US20080085860A1 (en) | 2004-08-18 | 2008-04-10 | Eli Lilly And Company | Selective Vpac2 Receptor Peptide Agonists |
CA2577010A1 (en) | 2004-08-18 | 2006-03-02 | Eli Lilly And Company | Selective vpac2 receptor peptide agonists |
AU2005294125A1 (en) | 2004-10-08 | 2006-04-20 | Transition Therapeutics Inc. | Vasoactive intestinal polypeptide pharmaceuticals |
US20080312156A1 (en) * | 2005-01-18 | 2008-12-18 | Duke University | In-Situ Crosslinkable Elastin-Like Polypeptides for Defect Filling in Cartilaginous Tissue Repair |
US7723472B2 (en) | 2005-02-28 | 2010-05-25 | The Regents Of The University Of California | Extracellular matrix binding chimeric proteins and methods of use thereof |
KR101446503B1 (ko) | 2005-06-24 | 2014-10-06 | 듀크 유니버시티 | 열 반응성 생중합체에 기초한 직접 약물 전달 시스템 |
US7846445B2 (en) | 2005-09-27 | 2010-12-07 | Amunix Operating, Inc. | Methods for production of unstructured recombinant polymers and uses thereof |
AU2006306236B2 (en) | 2005-10-26 | 2011-12-01 | Eli Lilly And Company | Selective VPAC2 receptor peptide agonists |
WO2007057922A1 (en) | 2005-11-18 | 2007-05-24 | Dabur Pharma Limited | Targeted fusion proteins for cancer therapy |
US8470778B2 (en) | 2005-12-09 | 2013-06-25 | Vectus Biosystems Limited | VIP fragments and methods of use |
US8841255B2 (en) | 2005-12-20 | 2014-09-23 | Duke University | Therapeutic agents comprising fusions of vasoactive intestinal peptide and elastic peptides |
US20130172274A1 (en) | 2005-12-20 | 2013-07-04 | Duke University | Methods and compositions for delivering active agents with enhanced pharmacological properties |
EP1971355B1 (en) | 2005-12-20 | 2020-03-11 | Duke University | Methods and compositions for delivering active agents with enhanced pharmacological properties |
US7709227B2 (en) | 2006-01-04 | 2010-05-04 | Phasebio Pharmaceuticals, Inc. | Multimeric ELP fusion constructs |
US8367626B2 (en) | 2006-05-12 | 2013-02-05 | Wisconsin Alumni Research Foundation | Elastin-like polymer delivery vehicles |
AU2007292295B2 (en) | 2006-09-06 | 2013-06-06 | Immunoforge Co., Ltd. | Fusion peptide therapeutic compositions |
US8329640B2 (en) | 2007-05-21 | 2012-12-11 | Res International Sarl | Peptides with improved properties having the biological activity of vasoactive intestinal peptide (VIP) and their use for the treatment of lung diseases |
EP2369005B1 (en) | 2007-06-21 | 2013-04-03 | Technische Universität München | Biological active proteins having increased in vivo and/or in vitro stability |
KR20100058541A (ko) | 2007-08-15 | 2010-06-03 | 아뮤닉스 인코포레이티드 | 생물학적 활성 폴리펩티드의 특성을 변경하기 위한 조성물 및 방법 |
WO2009067584A1 (en) | 2007-11-20 | 2009-05-28 | Duke University | Methods and compositions for modulating drug-polymer architecture, pharmacokinetics and biodistribution |
WO2009135184A2 (en) | 2008-05-01 | 2009-11-05 | The Trustees Of Columbia University In The City Of New York | Methods for treating and/or preventing cardiomyopathies by erk or jnk inhibition |
WO2009158704A2 (en) | 2008-06-27 | 2009-12-30 | Duke University | Therapeutic agents comprising elastin-like peptides |
US20110219462A1 (en) | 2008-07-15 | 2011-09-08 | Bayer Schering Pharma Aktiengesellschaft | G-Protein Coupled Receptor 30 (GPR30) transgenic animals as a model for cardiovascular diseases |
US9333235B2 (en) | 2008-10-22 | 2016-05-10 | Trustees Of Dartmouth College | Combination therapy and kit for the prevention and treatment of cystic fibrosis |
CA2742042A1 (en) | 2008-10-23 | 2010-04-29 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
US20110288001A1 (en) | 2008-12-18 | 2011-11-24 | Homayoun Sadeghi | Biologically active proteins activatable by peptidase |
EP2464370B1 (en) * | 2009-08-14 | 2017-03-29 | Phasebio Pharmaceuticals, Inc. | Modified vasoactive intestinal peptides |
CN102883739B (zh) | 2009-11-02 | 2015-11-25 | 图兰恩教育基金管理人 | 垂体腺苷酸环化酶激活多肽(pacap)的类似物和它们的应用方法 |
WO2011123652A1 (en) | 2010-04-02 | 2011-10-06 | The Regents Of The University Of Michigan | Rfamide-related peptides and methods thereof |
WO2012071648A1 (en) | 2010-11-30 | 2012-06-07 | London Health Sciences Centre Research Inc. | Egfr antagonist for the treatment of heart disease |
US20140039053A1 (en) | 2011-02-07 | 2014-02-06 | Mochida Pharmaceutical Co., Ltd. | Therapeutic agent for diastolic congestive heart failure |
HUE047354T2 (hu) | 2011-05-18 | 2020-04-28 | Vertex Pharmaceuticals Europe Ltd | Ivacaftor deuterizált származékai |
CA2873553C (en) | 2011-06-06 | 2020-01-28 | Phasebio Pharmaceuticals, Inc. | Use of modified vasoactive intestinal peptides in the treatment of hypertension |
WO2013028989A1 (en) | 2011-08-24 | 2013-02-28 | Phasebio Pharmaceuticals, Inc. | Formulations of active agents for sustained release |
BR112014012789A2 (pt) | 2011-11-28 | 2019-09-24 | Phasebio Pharmaceuticals Inc | agentes terapêuticos compreendendo sequências de aminoácidos de insulina |
EP2664326B1 (en) | 2012-05-17 | 2017-11-01 | I.E.R.F.C. European Institute for Cystic Fibrosis Research | Combined therapy for cystic fibrosis |
WO2013177428A1 (en) | 2012-05-23 | 2013-11-28 | Valerion Therapeutics, Inc. | Methods for increasing muscle contractility |
US10159741B2 (en) | 2012-05-25 | 2018-12-25 | National Cheng Kung University | Methods and compositions comprising hyaluronan for enhancing bone marrow cell therapy |
US9605186B2 (en) | 2012-09-19 | 2017-03-28 | Exxonmobil Chemical Patents Inc. | Adhesive compositions of ethylene-based and propylene-based polymers |
US20150290328A1 (en) * | 2012-11-20 | 2015-10-15 | Phasebio Pharmaceuticals, Inc. | Formulations of active agents for sustained release |
US20150361154A1 (en) | 2013-01-15 | 2015-12-17 | Phasebio Pharmaceuticals, Inc. | Therapeutic agents, compositions, and methods for glycemic control |
EP3139949B1 (en) | 2014-05-08 | 2020-07-29 | Phasebio Pharmaceuticals, Inc. | Compositions comprising a vip-elp fusion protein for use in treating cystic fibrosis |
US10722590B2 (en) | 2014-11-21 | 2020-07-28 | Phasebio Pharmaceuticals, Inc. | ELP fusion proteins for controlled and sustained release |
CA2976038A1 (en) | 2015-02-09 | 2016-08-18 | Phasebio Pharmaceuticals, Inc. | Methods and compositions for treating muscle disease and disorders |
-
2016
- 2016-02-09 CA CA2976038A patent/CA2976038A1/en active Pending
- 2016-02-09 CN CN201680020418.6A patent/CN107427556B/zh active Active
- 2016-02-09 US US15/546,037 patent/US10688156B2/en active Active
- 2016-02-09 ES ES16749691T patent/ES2822598T3/es active Active
- 2016-02-09 WO PCT/US2016/017102 patent/WO2016130518A2/en active Application Filing
- 2016-02-09 AU AU2016219513A patent/AU2016219513B2/en active Active
- 2016-02-09 CN CN202210124652.0A patent/CN114652817A/zh active Pending
- 2016-02-09 EP EP16749691.8A patent/EP3256151B1/en active Active
- 2016-02-09 JP JP2017541619A patent/JP6824888B2/ja active Active
-
2018
- 2018-06-20 HK HK18107899.7A patent/HK1249402A1/zh unknown
-
2020
- 2020-06-22 US US16/907,759 patent/US11266719B2/en active Active
-
2022
- 2022-01-25 US US17/583,883 patent/US20220288170A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
US10688156B2 (en) | 2020-06-23 |
CN107427556A (zh) | 2017-12-01 |
AU2016219513B2 (en) | 2021-09-30 |
EP3256151A4 (en) | 2018-08-22 |
WO2016130518A2 (en) | 2016-08-18 |
CA2976038A1 (en) | 2016-08-18 |
ES2822598T3 (es) | 2021-05-04 |
EP3256151A2 (en) | 2017-12-20 |
US20180333467A1 (en) | 2018-11-22 |
JP2018509395A (ja) | 2018-04-05 |
AU2016219513A1 (en) | 2017-08-17 |
US20220288170A1 (en) | 2022-09-15 |
CN114652817A (zh) | 2022-06-24 |
US20210069299A1 (en) | 2021-03-11 |
WO2016130518A3 (en) | 2016-09-15 |
US11266719B2 (en) | 2022-03-08 |
HK1249402A1 (zh) | 2018-11-02 |
CN107427556B (zh) | 2022-02-25 |
EP3256151B1 (en) | 2020-08-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20220288170A1 (en) | Methods and compositions for treating muscle disease and disorders | |
JP5792925B2 (ja) | 過剰体重を防止または治療するためのオキシンソモジュリン | |
RU2765288C2 (ru) | Антагонисты миостатина, активина или рецепторов активина для применения в лечении ожирения и связанных с ним состояний | |
KR102253597B1 (ko) | 듀켄씨 근이영양증의 치료에서의 폴리스타틴 | |
HUE027216T2 (en) | Co-administration of an agent associated with a tat internalizing peptide with an anti-inflammatory agent | |
KR20120103606A (ko) | 스트레스코핀-유사 펩타이드를 이용해 심부전을 치료하는 방법 | |
ES2732077T3 (es) | Método para tratar trastornos asociados con el receptor de melanocortina-4 en portadores heterocigotos | |
JP6262661B2 (ja) | 筋萎縮性側索硬化症治療剤 | |
ES2892957T3 (es) | Composiciones y métodos de modulación de la actividad de AT2R | |
US20200000874A1 (en) | Peptides and methods of treating dystrophy-related disorders using the same | |
ES2701444T3 (es) | Usos de bremelanotida en una terapia para la disfunción sexual femenina | |
EP2911686B1 (en) | Peptides for preventing ischemic tissue injury | |
JP7235658B2 (ja) | 疼痛治療のためのang(1-7)誘導体オリゴペプチド | |
JP2024519893A (ja) | 変形性関節症の治療方法 | |
EP4066850A2 (en) | Peptides and methods of treating dystrophy-related disorders using the same | |
EP4304626A1 (en) | Trem-1 inhibitors for the treatment of marfan syndrome | |
KR20230141958A (ko) | 개선된 치료 지수를 위한 플라스민-내성 펩티드 | |
WO2016144968A1 (en) | Relaxin therapy for disorders of the diaphragm |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190128 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190128 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20191118 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200218 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200727 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20201027 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20201224 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210113 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6824888 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |