CN101522222B - 激活β-肌球蛋白重链表达的微RNA的鉴定 - Google Patents
激活β-肌球蛋白重链表达的微RNA的鉴定 Download PDFInfo
- Publication number
- CN101522222B CN101522222B CN2007800367837A CN200780036783A CN101522222B CN 101522222 B CN101522222 B CN 101522222B CN 2007800367837 A CN2007800367837 A CN 2007800367837A CN 200780036783 A CN200780036783 A CN 200780036783A CN 101522222 B CN101522222 B CN 101522222B
- Authority
- CN
- China
- Prior art keywords
- mir
- cell
- heart
- expression
- gene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 230000014509 gene expression Effects 0.000 title claims abstract description 165
- 239000002679 microRNA Substances 0.000 title abstract description 16
- 108010051583 Ventricular Myosins Proteins 0.000 title abstract description 3
- 108091070501 miRNA Proteins 0.000 title description 9
- 108091092539 MiR-208 Proteins 0.000 claims abstract description 286
- 206010019280 Heart failures Diseases 0.000 claims abstract description 58
- 238000011282 treatment Methods 0.000 claims abstract description 39
- 239000003814 drug Substances 0.000 claims description 86
- 206010007572 Cardiac hypertrophy Diseases 0.000 claims description 63
- 208000006029 Cardiomegaly Diseases 0.000 claims description 61
- 239000003112 inhibitor Substances 0.000 claims description 29
- 239000005557 antagonist Substances 0.000 claims description 26
- 230000001575 pathological effect Effects 0.000 claims description 25
- 239000002876 beta blocker Substances 0.000 claims description 19
- 210000005003 heart tissue Anatomy 0.000 claims description 14
- 208000024891 symptom Diseases 0.000 claims description 14
- 229940097320 beta blocking agent Drugs 0.000 claims description 13
- 239000002934 diuretic Substances 0.000 claims description 12
- 230000001882 diuretic effect Effects 0.000 claims description 12
- 208000010125 myocardial infarction Diseases 0.000 claims description 11
- 230000002265 prevention Effects 0.000 claims description 11
- 206010020772 Hypertension Diseases 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 230000000295 complement effect Effects 0.000 claims description 7
- 208000019622 heart disease Diseases 0.000 claims description 7
- 230000003387 muscular Effects 0.000 claims description 7
- 229940118365 Endothelin receptor antagonist Drugs 0.000 claims description 6
- 239000002308 endothelin receptor antagonist Substances 0.000 claims description 6
- 230000003130 cardiopathic effect Effects 0.000 claims description 5
- 108091034117 Oligonucleotide Proteins 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- 208000018578 heart valve disease Diseases 0.000 claims description 4
- 230000007774 longterm Effects 0.000 claims description 4
- 229940121372 histone deacetylase inhibitor Drugs 0.000 claims description 3
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims description 3
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- 238000013270 controlled release Methods 0.000 claims description 2
- 238000001990 intravenous administration Methods 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 108020000948 Antisense Oligonucleotides Proteins 0.000 claims 1
- 239000000074 antisense oligonucleotide Substances 0.000 claims 1
- 238000012230 antisense oligonucleotides Methods 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 abstract description 176
- 210000002027 skeletal muscle Anatomy 0.000 abstract description 43
- 239000000835 fiber Substances 0.000 abstract description 17
- 206010020880 Hypertrophy Diseases 0.000 abstract description 16
- 108700011259 MicroRNAs Proteins 0.000 abstract description 15
- 108010068426 Contractile Proteins Proteins 0.000 abstract description 10
- 230000009787 cardiac fibrosis Effects 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 208000023178 Musculoskeletal disease Diseases 0.000 abstract description 4
- 230000003416 augmentation Effects 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 239
- 238000000034 method Methods 0.000 description 109
- 210000002216 heart Anatomy 0.000 description 104
- 241000699670 Mus sp. Species 0.000 description 79
- 150000001875 compounds Chemical class 0.000 description 67
- 230000000694 effects Effects 0.000 description 60
- 241001465754 Metazoa Species 0.000 description 57
- 239000000203 mixture Substances 0.000 description 44
- 239000003795 chemical substances by application Substances 0.000 description 39
- 230000000747 cardiac effect Effects 0.000 description 38
- 241000701161 unidentified adenovirus Species 0.000 description 38
- 108020004414 DNA Proteins 0.000 description 35
- 230000006870 function Effects 0.000 description 33
- 241000700605 Viruses Species 0.000 description 32
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 31
- 102000004169 proteins and genes Human genes 0.000 description 31
- 201000010099 disease Diseases 0.000 description 30
- 230000001105 regulatory effect Effects 0.000 description 30
- 238000012360 testing method Methods 0.000 description 28
- 102000039446 nucleic acids Human genes 0.000 description 27
- 108020004707 nucleic acids Proteins 0.000 description 27
- 150000007523 nucleic acids Chemical class 0.000 description 27
- KNAHARQHSZJURB-UHFFFAOYSA-N Propylthiouracile Chemical compound CCCC1=CC(=O)NC(=S)N1 KNAHARQHSZJURB-UHFFFAOYSA-N 0.000 description 26
- 210000003205 muscle Anatomy 0.000 description 26
- 230000008569 process Effects 0.000 description 26
- 108091056170 miR-499 stem-loop Proteins 0.000 description 25
- 108091050885 miR-499-1 stem-loop Proteins 0.000 description 25
- 108091038523 miR-499-2 stem-loop Proteins 0.000 description 25
- 229960002662 propylthiouracil Drugs 0.000 description 25
- 210000001519 tissue Anatomy 0.000 description 24
- 230000009261 transgenic effect Effects 0.000 description 24
- 108020004999 messenger RNA Proteins 0.000 description 23
- 102000005962 receptors Human genes 0.000 description 23
- 108020003175 receptors Proteins 0.000 description 23
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 22
- 230000008859 change Effects 0.000 description 22
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 21
- 230000009467 reduction Effects 0.000 description 21
- 239000013598 vector Substances 0.000 description 21
- -1 TnT 3 Proteins 0.000 description 20
- 210000002064 heart cell Anatomy 0.000 description 20
- 241001597008 Nomeidae Species 0.000 description 18
- 238000004458 analytical method Methods 0.000 description 18
- 230000003288 anthiarrhythmic effect Effects 0.000 description 18
- 239000002502 liposome Substances 0.000 description 17
- 108091007431 miR-29 Proteins 0.000 description 17
- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 description 16
- 238000002560 therapeutic procedure Methods 0.000 description 16
- 102000004217 thyroid hormone receptors Human genes 0.000 description 16
- 108090000721 thyroid hormone receptors Proteins 0.000 description 16
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 15
- 239000000523 sample Substances 0.000 description 15
- 206010016654 Fibrosis Diseases 0.000 description 14
- 241000699666 Mus <mouse, genus> Species 0.000 description 14
- 241000700159 Rattus Species 0.000 description 14
- 239000000556 agonist Substances 0.000 description 14
- 239000003146 anticoagulant agent Substances 0.000 description 14
- 230000004761 fibrosis Effects 0.000 description 14
- 210000005240 left ventricle Anatomy 0.000 description 14
- 230000000630 rising effect Effects 0.000 description 14
- 238000012546 transfer Methods 0.000 description 14
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 13
- 230000001225 therapeutic effect Effects 0.000 description 13
- 230000024883 vasodilation Effects 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- 230000008685 targeting Effects 0.000 description 12
- 229940127291 Calcium channel antagonist Drugs 0.000 description 11
- 108091036066 Three prime untranslated region Proteins 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 239000000480 calcium channel blocker Substances 0.000 description 11
- 230000012010 growth Effects 0.000 description 11
- 230000001939 inductive effect Effects 0.000 description 11
- 238000002347 injection Methods 0.000 description 11
- 239000007924 injection Substances 0.000 description 11
- 229960001632 labetalol Drugs 0.000 description 11
- 210000004185 liver Anatomy 0.000 description 11
- 230000002107 myocardial effect Effects 0.000 description 11
- 238000012216 screening Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000013519 translation Methods 0.000 description 11
- 230000003612 virological effect Effects 0.000 description 11
- 101100456626 Homo sapiens MEF2A gene Proteins 0.000 description 10
- 241000699660 Mus musculus Species 0.000 description 10
- 101100079042 Mus musculus Myef2 gene Proteins 0.000 description 10
- 102100021148 Myocyte-specific enhancer factor 2A Human genes 0.000 description 10
- 230000003276 anti-hypertensive effect Effects 0.000 description 10
- 230000008034 disappearance Effects 0.000 description 10
- 239000003623 enhancer Substances 0.000 description 10
- 239000003527 fibrinolytic agent Substances 0.000 description 10
- 230000002068 genetic effect Effects 0.000 description 10
- 210000001161 mammalian embryo Anatomy 0.000 description 10
- 230000007246 mechanism Effects 0.000 description 10
- 101150014102 mef-2 gene Proteins 0.000 description 10
- 238000010208 microarray analysis Methods 0.000 description 10
- 210000001087 myotubule Anatomy 0.000 description 10
- 238000012545 processing Methods 0.000 description 10
- 238000011830 transgenic mouse model Methods 0.000 description 10
- 239000005541 ACE inhibitor Substances 0.000 description 9
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 9
- 102000002585 Contractile Proteins Human genes 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 108010029485 Protein Isoforms Proteins 0.000 description 9
- 102000001708 Protein Isoforms Human genes 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 230000004913 activation Effects 0.000 description 9
- 239000000674 adrenergic antagonist Substances 0.000 description 9
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 230000006378 damage Effects 0.000 description 9
- 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 9
- 239000013604 expression vector Substances 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 230000001404 mediated effect Effects 0.000 description 9
- 230000004044 response Effects 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 241000124008 Mammalia Species 0.000 description 8
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 8
- 239000000219 Sympatholytic Substances 0.000 description 8
- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical compound CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 description 8
- NWIUTZDMDHAVTP-UHFFFAOYSA-N betaxolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-UHFFFAOYSA-N 0.000 description 8
- LWAFSWPYPHEXKX-UHFFFAOYSA-N carteolol Chemical compound N1C(=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C LWAFSWPYPHEXKX-UHFFFAOYSA-N 0.000 description 8
- 230000002950 deficient Effects 0.000 description 8
- 229960002474 hydralazine Drugs 0.000 description 8
- WDKXLLJDNUBYCY-UHFFFAOYSA-N ibopamine Chemical compound CNCCC1=CC=C(OC(=O)C(C)C)C(OC(=O)C(C)C)=C1 WDKXLLJDNUBYCY-UHFFFAOYSA-N 0.000 description 8
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 8
- 238000000520 microinjection Methods 0.000 description 8
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 description 8
- 210000000056 organ Anatomy 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 8
- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 8
- 230000000948 sympatholitic effect Effects 0.000 description 8
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 8
- 230000002861 ventricular Effects 0.000 description 8
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 7
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 7
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 7
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 7
- 102000002045 Endothelin Human genes 0.000 description 7
- 108050009340 Endothelin Proteins 0.000 description 7
- 108010007859 Lisinopril Proteins 0.000 description 7
- 101150076359 Mhc gene Proteins 0.000 description 7
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 7
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 7
- 239000002160 alpha blocker Substances 0.000 description 7
- 230000002785 anti-thrombosis Effects 0.000 description 7
- 229940127219 anticoagulant drug Drugs 0.000 description 7
- 229960002274 atenolol Drugs 0.000 description 7
- 230000033228 biological regulation Effects 0.000 description 7
- 229960001222 carteolol Drugs 0.000 description 7
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 229960002394 lisinopril Drugs 0.000 description 7
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 description 7
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 7
- 229960002237 metoprolol Drugs 0.000 description 7
- 229960004255 nadolol Drugs 0.000 description 7
- 229960002035 penbutolol Drugs 0.000 description 7
- KQXKVJAGOJTNJS-HNNXBMFYSA-N penbutolol Chemical compound CC(C)(C)NC[C@H](O)COC1=CC=CC=C1C1CCCC1 KQXKVJAGOJTNJS-HNNXBMFYSA-N 0.000 description 7
- JZQKKSLKJUAGIC-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1C=CN2 JZQKKSLKJUAGIC-UHFFFAOYSA-N 0.000 description 7
- 229960001289 prazosin Drugs 0.000 description 7
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 7
- 229960003147 reserpine Drugs 0.000 description 7
- 230000001177 retroviral effect Effects 0.000 description 7
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 7
- 229960000103 thrombolytic agent Drugs 0.000 description 7
- 229960004605 timolol Drugs 0.000 description 7
- 241001430294 unidentified retrovirus Species 0.000 description 7
- 206010007559 Cardiac failure congestive Diseases 0.000 description 6
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 6
- 229920002307 Dextran Polymers 0.000 description 6
- WDJUZGPOPHTGOT-OAXVISGBSA-N Digitoxin 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](C6=CC(=O)OC6)CC5)CC4)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 WDJUZGPOPHTGOT-OAXVISGBSA-N 0.000 description 6
- 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 6
- 201000010046 Dilated cardiomyopathy Diseases 0.000 description 6
- JRWZLRBJNMZMFE-UHFFFAOYSA-N Dobutamine Chemical compound C=1C=C(O)C(O)=CC=1CCNC(C)CCC1=CC=C(O)C=C1 JRWZLRBJNMZMFE-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- VXLCNTLWWUDBSO-UHFFFAOYSA-N Ethiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)NC(CC)NC2=C1 VXLCNTLWWUDBSO-UHFFFAOYSA-N 0.000 description 6
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 6
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 6
- 229960002122 acebutolol Drugs 0.000 description 6
- LVEXHFZHOIWIIP-UHFFFAOYSA-N amosulalol Chemical compound COC1=CC=CC=C1OCCNCC(O)C1=CC=C(C)C(S(N)(=O)=O)=C1 LVEXHFZHOIWIIP-UHFFFAOYSA-N 0.000 description 6
- 229950010351 amosulalol Drugs 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- BHIAIPWSVYSKJS-UHFFFAOYSA-N arotinolol Chemical compound S1C(SCC(O)CNC(C)(C)C)=NC(C=2SC(=CC=2)C(N)=O)=C1 BHIAIPWSVYSKJS-UHFFFAOYSA-N 0.000 description 6
- 229950010731 arotinolol Drugs 0.000 description 6
- 208000020538 atrophic muscular disease Diseases 0.000 description 6
- 229960004324 betaxolol Drugs 0.000 description 6
- 229960002155 chlorothiazide Drugs 0.000 description 6
- 238000012217 deletion Methods 0.000 description 6
- 230000037430 deletion Effects 0.000 description 6
- 229960002086 dextran Drugs 0.000 description 6
- 238000003745 diagnosis Methods 0.000 description 6
- 229960005156 digoxin Drugs 0.000 description 6
- 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 6
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 6
- 229960002768 dipyridamole Drugs 0.000 description 6
- 229960003638 dopamine Drugs 0.000 description 6
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 229950007164 ethiazide Drugs 0.000 description 6
- 230000003176 fibrotic effect Effects 0.000 description 6
- 229960003602 guanethidine Drugs 0.000 description 6
- ACGDKVXYNVEAGU-UHFFFAOYSA-N guanethidine Chemical compound NC(N)=NCCN1CCCCCCC1 ACGDKVXYNVEAGU-UHFFFAOYSA-N 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 230000010354 integration Effects 0.000 description 6
- 238000002372 labelling Methods 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 239000003550 marker Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 229960003632 minoxidil Drugs 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- CYXKNKQEMFBLER-UHFFFAOYSA-N perhexiline Chemical compound C1CCCNC1CC(C1CCCCC1)C1CCCCC1 CYXKNKQEMFBLER-UHFFFAOYSA-N 0.000 description 6
- 229960000989 perhexiline Drugs 0.000 description 6
- 230000035479 physiological effects, processes and functions Effects 0.000 description 6
- 229960002508 pindolol Drugs 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 238000003757 reverse transcription PCR Methods 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- 210000002363 skeletal muscle cell Anatomy 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229960002370 sotalol Drugs 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 229960001693 terazosin Drugs 0.000 description 6
- 238000001890 transfection Methods 0.000 description 6
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 5
- 108010058207 Anistreplase Proteins 0.000 description 5
- 208000031229 Cardiomyopathies Diseases 0.000 description 5
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 5
- 108091026890 Coding region Proteins 0.000 description 5
- 108010061435 Enalapril Proteins 0.000 description 5
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 5
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 5
- INJOMKTZOLKMBF-UHFFFAOYSA-N Guanfacine Chemical compound NC(=N)NC(=O)CC1=C(Cl)C=CC=C1Cl INJOMKTZOLKMBF-UHFFFAOYSA-N 0.000 description 5
- 108060001084 Luciferase Proteins 0.000 description 5
- 239000005089 Luciferase Substances 0.000 description 5
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 5
- 108060008487 Myosin Proteins 0.000 description 5
- 102000003505 Myosin Human genes 0.000 description 5
- 229930193140 Neomycin Natural products 0.000 description 5
- 108700026244 Open Reading Frames Proteins 0.000 description 5
- 241000009328 Perro Species 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- RNLQIBCLLYYYFJ-UHFFFAOYSA-N amrinone Chemical compound N1C(=O)C(N)=CC(C=2C=CN=CC=2)=C1 RNLQIBCLLYYYFJ-UHFFFAOYSA-N 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 229940124572 antihypotensive agent Drugs 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- 239000012736 aqueous medium Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 229940030611 beta-adrenergic blocking agent Drugs 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 244000144987 brood Species 0.000 description 5
- 229960000830 captopril Drugs 0.000 description 5
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 5
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 5
- 230000008828 contractile function Effects 0.000 description 5
- 210000004351 coronary vessel Anatomy 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 230000002638 denervation Effects 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 229960004042 diazoxide Drugs 0.000 description 5
- 229960000648 digitoxin Drugs 0.000 description 5
- WDJUZGPOPHTGOT-XUDUSOBPSA-N digitoxin 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)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O WDJUZGPOPHTGOT-XUDUSOBPSA-N 0.000 description 5
- UVTNFZQICZKOEM-UHFFFAOYSA-N disopyramide Chemical compound C=1C=CC=NC=1C(C(N)=O)(CCN(C(C)C)C(C)C)C1=CC=CC=C1 UVTNFZQICZKOEM-UHFFFAOYSA-N 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 229960001089 dobutamine Drugs 0.000 description 5
- 229960001389 doxazosin Drugs 0.000 description 5
- 229960000873 enalapril Drugs 0.000 description 5
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 5
- 229960002490 fosinopril Drugs 0.000 description 5
- 230000004217 heart function Effects 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 230000000977 initiatory effect Effects 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 210000004165 myocardium Anatomy 0.000 description 5
- 229960004927 neomycin Drugs 0.000 description 5
- 235000001968 nicotinic acid Nutrition 0.000 description 5
- 239000011664 nicotinic acid Substances 0.000 description 5
- 229960001597 nifedipine Drugs 0.000 description 5
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 5
- 229960003712 propranolol Drugs 0.000 description 5
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 5
- 229960001455 quinapril Drugs 0.000 description 5
- 229960003401 ramipril Drugs 0.000 description 5
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 5
- 230000010076 replication Effects 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 5
- 238000013518 transcription Methods 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- 210000002845 virion Anatomy 0.000 description 5
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 description 4
- CEMAWMOMDPGJMB-UHFFFAOYSA-N (+-)-Oxprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1OCC=C CEMAWMOMDPGJMB-UHFFFAOYSA-N 0.000 description 4
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 4
- SSEBTPPFLLCUMN-CYBMUJFWSA-N (1r)-2-(tert-butylamino)-1-(7-ethyl-1-benzofuran-2-yl)ethanol Chemical compound CCC1=CC=CC2=C1OC([C@H](O)CNC(C)(C)C)=C2 SSEBTPPFLLCUMN-CYBMUJFWSA-N 0.000 description 4
- NXQMNKUGGYNLBY-GFCCVEGCSA-N (2r)-1-(3-methylphenoxy)-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NC[C@@H](O)COC1=CC=CC(C)=C1 NXQMNKUGGYNLBY-GFCCVEGCSA-N 0.000 description 4
- NXWGWUVGUSFQJC-GFCCVEGCSA-N (2r)-1-[(2-methyl-1h-indol-4-yl)oxy]-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NC[C@@H](O)COC1=CC=CC2=C1C=C(C)N2 NXWGWUVGUSFQJC-GFCCVEGCSA-N 0.000 description 4
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 description 4
- SGUAFYQXFOLMHL-ACJLOTCBSA-N (R,R)-labetalol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(C(O)=CC=1)C(N)=O)CC1=CC=CC=C1 SGUAFYQXFOLMHL-ACJLOTCBSA-N 0.000 description 4
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 4
- UUOJIACWOAYWEZ-UHFFFAOYSA-N 1-(tert-butylamino)-3-[(2-methyl-1H-indol-4-yl)oxy]propan-2-yl benzoate Chemical compound C1=CC=C2NC(C)=CC2=C1OCC(CNC(C)(C)C)OC(=O)C1=CC=CC=C1 UUOJIACWOAYWEZ-UHFFFAOYSA-N 0.000 description 4
- CJDRUOGAGYHKKD-RQBLFBSQSA-N 1pon08459r Chemical compound CN([C@H]1[C@@]2(C[C@@]3([H])[C@@H]([C@@H](O)N42)CC)[H])C2=CC=CC=C2[C@]11C[C@@]4([H])[C@H]3[C@H]1O CJDRUOGAGYHKKD-RQBLFBSQSA-N 0.000 description 4
- HCYFGRCYSCXKNQ-UHFFFAOYSA-N 2-(1,3-dimethyl-2,6-dioxo-7-purinyl)acetic acid Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CC(O)=O)C=N2 HCYFGRCYSCXKNQ-UHFFFAOYSA-N 0.000 description 4
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 4
- NMKSAYKQLCHXDK-UHFFFAOYSA-N 3,3-diphenyl-N-(1-phenylethyl)-1-propanamine Chemical compound C=1C=CC=CC=1C(C)NCCC(C=1C=CC=CC=1)C1=CC=CC=C1 NMKSAYKQLCHXDK-UHFFFAOYSA-N 0.000 description 4
- URIZBPYQIRFMBF-UHFFFAOYSA-N 4-[1-[3-methyl-5-(5-oxo-2h-furan-3-yl)-1-benzofuran-2-yl]ethoxy]-4-oxobutanoic acid Chemical compound C1=C2C(C)=C(C(OC(=O)CCC(O)=O)C)OC2=CC=C1C1=CC(=O)OC1 URIZBPYQIRFMBF-UHFFFAOYSA-N 0.000 description 4
- LTSOENFXCPOCHG-GQCTYLIASA-N 4-chloro-6-[[(e)-3-oxobut-1-enyl]amino]-1-n-prop-2-enylbenzene-1,3-disulfonamide Chemical compound CC(=O)\C=C\NC1=CC(Cl)=C(S(N)(=O)=O)C=C1S(=O)(=O)NCC=C LTSOENFXCPOCHG-GQCTYLIASA-N 0.000 description 4
- LBXHRAWDUMTPSE-AOOOYVTPSA-N 4-chloro-N-[(2S,6R)-2,6-dimethyl-1-piperidinyl]-3-sulfamoylbenzamide Chemical compound C[C@H]1CCC[C@@H](C)N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 LBXHRAWDUMTPSE-AOOOYVTPSA-N 0.000 description 4
- KYWCWBXGRWWINE-UHFFFAOYSA-N 4-methoxy-N1,N3-bis(3-pyridinylmethyl)benzene-1,3-dicarboxamide Chemical compound COC1=CC=C(C(=O)NCC=2C=NC=CC=2)C=C1C(=O)NCC1=CC=CN=C1 KYWCWBXGRWWINE-UHFFFAOYSA-N 0.000 description 4
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 description 4
- VGLGVJVUHYTIIU-UHFFFAOYSA-N 6-chloro-1,1-dioxo-3-[(prop-2-enylthio)methyl]-3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(CSCC=C)NS2(=O)=O VGLGVJVUHYTIIU-UHFFFAOYSA-N 0.000 description 4
- BKYKPTRYDKTTJY-UHFFFAOYSA-N 6-chloro-3-(cyclopentylmethyl)-1,1-dioxo-3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1CCCC1 BKYKPTRYDKTTJY-UHFFFAOYSA-N 0.000 description 4
- JDCJFONQCRLHND-UHFFFAOYSA-N 6-chloro-3-[(4-fluorophenyl)methyl]-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=C(F)C=C1 JDCJFONQCRLHND-UHFFFAOYSA-N 0.000 description 4
- FHHHOYXPRDYHEZ-COXVUDFISA-N Alacepril Chemical compound CC(=O)SC[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FHHHOYXPRDYHEZ-COXVUDFISA-N 0.000 description 4
- 108700028369 Alleles Proteins 0.000 description 4
- 206010002027 Amyotrophy Diseases 0.000 description 4
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 4
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 4
- BWSSMIJUDVUASQ-UHFFFAOYSA-N Benzylhydrochlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 BWSSMIJUDVUASQ-UHFFFAOYSA-N 0.000 description 4
- JOATXPAWOHTVSZ-UHFFFAOYSA-N Celiprolol Chemical compound CCN(CC)C(=O)NC1=CC=C(OCC(O)CNC(C)(C)C)C(C(C)=O)=C1 JOATXPAWOHTVSZ-UHFFFAOYSA-N 0.000 description 4
- 229920001268 Cholestyramine Polymers 0.000 description 4
- 230000004543 DNA replication Effects 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- YARKMNAWFIMDKV-UHFFFAOYSA-N Epanolol Chemical compound C=1C=CC=C(C#N)C=1OCC(O)CNCCNC(=O)CC1=CC=C(O)C=C1 YARKMNAWFIMDKV-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WDZVGELJXXEGPV-YIXHJXPBSA-N Guanabenz Chemical compound NC(N)=N\N=C\C1=C(Cl)C=CC=C1Cl WDZVGELJXXEGPV-YIXHJXPBSA-N 0.000 description 4
- OMCPLEZZPVJJIS-UHFFFAOYSA-N Hypadil (TN) Chemical compound C1C(O[N+]([O-])=O)COC2=C1C=CC=C2OCC(O)CNC(C)C OMCPLEZZPVJJIS-UHFFFAOYSA-N 0.000 description 4
- CJDRUOGAGYHKKD-UHFFFAOYSA-N Iso-ajmalin Natural products CN1C2=CC=CC=C2C2(C(C34)O)C1C1CC3C(CC)C(O)N1C4C2 CJDRUOGAGYHKKD-UHFFFAOYSA-N 0.000 description 4
- CESYKOGBSMNBPD-UHFFFAOYSA-N Methyclothiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CCl)NC2=C1 CESYKOGBSMNBPD-UHFFFAOYSA-N 0.000 description 4
- FNQQBFNIYODEMB-UHFFFAOYSA-N Meticrane Chemical compound C1CCS(=O)(=O)C2=C1C=C(C)C(S(N)(=O)=O)=C2 FNQQBFNIYODEMB-UHFFFAOYSA-N 0.000 description 4
- 101100025408 Mus musculus Myh7b gene Proteins 0.000 description 4
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 4
- 241001028048 Nicola Species 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- HRSANNODOVBCST-UHFFFAOYSA-N Pronethalol Chemical compound C1=CC=CC2=CC(C(O)CNC(C)C)=CC=C21 HRSANNODOVBCST-UHFFFAOYSA-N 0.000 description 4
- 244000061121 Rauvolfia serpentina Species 0.000 description 4
- 108020004459 Small interfering RNA Proteins 0.000 description 4
- HTWFXPCUFWKXOP-UHFFFAOYSA-N Tertatalol Chemical compound C1CCSC2=C1C=CC=C2OCC(O)CNC(C)(C)C HTWFXPCUFWKXOP-UHFFFAOYSA-N 0.000 description 4
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- DXPOSRCHIDYWHW-UHFFFAOYSA-N Xamoterol Chemical compound C=1C=C(O)C=CC=1OCC(O)CNCCNC(=O)N1CCOCC1 DXPOSRCHIDYWHW-UHFFFAOYSA-N 0.000 description 4
- 229950003769 acefylline Drugs 0.000 description 4
- 229960001138 acetylsalicylic acid Drugs 0.000 description 4
- 229960004332 ajmaline Drugs 0.000 description 4
- 229950007884 alacepril Drugs 0.000 description 4
- 229960002213 alprenolol Drugs 0.000 description 4
- PAZJSJFMUHDSTF-UHFFFAOYSA-N alprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1CC=C PAZJSJFMUHDSTF-UHFFFAOYSA-N 0.000 description 4
- 229950007522 altizide Drugs 0.000 description 4
- 229950007019 ambuside Drugs 0.000 description 4
- IYIKLHRQXLHMJQ-UHFFFAOYSA-N amiodarone Chemical compound CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCCN(CC)CC)C(I)=C1 IYIKLHRQXLHMJQ-UHFFFAOYSA-N 0.000 description 4
- 229960002105 amrinone Drugs 0.000 description 4
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 230000000692 anti-sense effect Effects 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- HDWIHXWEUNVBIY-UHFFFAOYSA-N bendroflumethiazidum Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 HDWIHXWEUNVBIY-UHFFFAOYSA-N 0.000 description 4
- 229950010443 benfurodil hemisuccinate Drugs 0.000 description 4
- NDTSRXAMMQDVSW-UHFFFAOYSA-N benzthiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1N=C2CSCC1=CC=CC=C1 NDTSRXAMMQDVSW-UHFFFAOYSA-N 0.000 description 4
- 229960001541 benzthiazide Drugs 0.000 description 4
- 229950007003 benzylhydrochlorothiazide Drugs 0.000 description 4
- 229960003588 bevantolol Drugs 0.000 description 4
- HXLAFSUPPDYFEO-UHFFFAOYSA-N bevantolol Chemical compound C1=C(OC)C(OC)=CC=C1CCNCC(O)COC1=CC=CC(C)=C1 HXLAFSUPPDYFEO-UHFFFAOYSA-N 0.000 description 4
- 229960002781 bisoprolol Drugs 0.000 description 4
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 description 4
- 229960001035 bopindolol Drugs 0.000 description 4
- 229950006886 bufuralol Drugs 0.000 description 4
- VCVQSRCYSKKPBA-UHFFFAOYSA-N bunitrolol Chemical compound CC(C)(C)NCC(O)COC1=CC=CC=C1C#N VCVQSRCYSKKPBA-UHFFFAOYSA-N 0.000 description 4
- 229950008581 bunitrolol Drugs 0.000 description 4
- HGBFRHCDYZJRAO-UHFFFAOYSA-N butizide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)NC(CC(C)C)NC2=C1 HGBFRHCDYZJRAO-UHFFFAOYSA-N 0.000 description 4
- 229950008955 butizide Drugs 0.000 description 4
- NMBNQRJDEPOXCP-UHFFFAOYSA-N butofilolol Chemical compound CCCC(=O)C1=CC(F)=CC=C1OCC(O)CNC(C)(C)C NMBNQRJDEPOXCP-UHFFFAOYSA-N 0.000 description 4
- 229950009191 butofilolol Drugs 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 239000001506 calcium phosphate Substances 0.000 description 4
- 229910000389 calcium phosphate Inorganic materials 0.000 description 4
- 235000011010 calcium phosphates Nutrition 0.000 description 4
- BQXQGZPYHWWCEB-UHFFFAOYSA-N carazolol Chemical compound N1C2=CC=CC=C2C2=C1C=CC=C2OCC(O)CNC(C)C BQXQGZPYHWWCEB-UHFFFAOYSA-N 0.000 description 4
- 229960004634 carazolol Drugs 0.000 description 4
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 description 4
- 229960004195 carvedilol Drugs 0.000 description 4
- 229960002320 celiprolol Drugs 0.000 description 4
- UWCBNAVPISMFJZ-UHFFFAOYSA-N cetamolol Chemical compound CNC(=O)COC1=CC=CC=C1OCC(O)CNC(C)(C)C UWCBNAVPISMFJZ-UHFFFAOYSA-N 0.000 description 4
- 229950003205 cetamolol Drugs 0.000 description 4
- 229960001523 chlortalidone Drugs 0.000 description 4
- 229960005025 cilazapril Drugs 0.000 description 4
- HHHKFGXWKKUNCY-FHWLQOOXSA-N cilazapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 HHHKFGXWKKUNCY-FHWLQOOXSA-N 0.000 description 4
- 229960002896 clonidine Drugs 0.000 description 4
- 229960004070 clopamide Drugs 0.000 description 4
- 230000008602 contraction Effects 0.000 description 4
- 229960003206 cyclopenthiazide Drugs 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 229960005227 delapril Drugs 0.000 description 4
- WOUOLAUOZXOLJQ-MBSDFSHPSA-N delapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N(CC(O)=O)C1CC2=CC=CC=C2C1)CC1=CC=CC=C1 WOUOLAUOZXOLJQ-MBSDFSHPSA-N 0.000 description 4
- VHSBBVZJABQOSG-MRXNPFEDSA-N denopamine Chemical compound C1=C(OC)C(OC)=CC=C1CCNC[C@@H](O)C1=CC=C(O)C=C1 VHSBBVZJABQOSG-MRXNPFEDSA-N 0.000 description 4
- 229950007304 denopamine Drugs 0.000 description 4
- 229950007942 dilevalol Drugs 0.000 description 4
- 229960001066 disopyramide Drugs 0.000 description 4
- 229960001857 dopexamine Drugs 0.000 description 4
- RYBJORHCUPVNMB-UHFFFAOYSA-N dopexamine Chemical compound C1=C(O)C(O)=CC=C1CCNCCCCCCNCCC1=CC=CC=C1 RYBJORHCUPVNMB-UHFFFAOYSA-N 0.000 description 4
- 230000002526 effect on cardiovascular system Effects 0.000 description 4
- 229960002711 epanolol Drugs 0.000 description 4
- AQNDDEOPVVGCPG-UHFFFAOYSA-N esmolol Chemical compound COC(=O)CCC1=CC=C(OCC(O)CNC(C)C)C=C1 AQNDDEOPVVGCPG-UHFFFAOYSA-N 0.000 description 4
- 229960004351 etafenone Drugs 0.000 description 4
- OEGDFSLNGABBKJ-UHFFFAOYSA-N etafenone Chemical compound CCN(CC)CCOC1=CC=CC=C1C(=O)CCC1=CC=CC=C1 OEGDFSLNGABBKJ-UHFFFAOYSA-N 0.000 description 4
- 229960003580 felodipine Drugs 0.000 description 4
- 229960002602 fendiline Drugs 0.000 description 4
- 229960002637 fenquizone Drugs 0.000 description 4
- DBDTUXMDTSTPQZ-UHFFFAOYSA-N fenquizone Chemical compound N1C=2C=C(Cl)C(S(=O)(=O)N)=CC=2C(=O)NC1C1=CC=CC=C1 DBDTUXMDTSTPQZ-UHFFFAOYSA-N 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 229960003883 furosemide Drugs 0.000 description 4
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 4
- 238000001415 gene therapy Methods 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 229960004553 guanabenz Drugs 0.000 description 4
- 229960002048 guanfacine Drugs 0.000 description 4
- BPMFZUMJYQTVII-UHFFFAOYSA-N guanidinoacetic acid Chemical compound NC(=N)NCC(O)=O BPMFZUMJYQTVII-UHFFFAOYSA-N 0.000 description 4
- 229960002897 heparin Drugs 0.000 description 4
- 229920000669 heparin Polymers 0.000 description 4
- WRYZEGZNBYOMLE-UHFFFAOYSA-N hydracarbazine Chemical compound NNC1=CC=C(C(N)=O)N=N1 WRYZEGZNBYOMLE-UHFFFAOYSA-N 0.000 description 4
- 229950002598 hydracarbazine Drugs 0.000 description 4
- DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 description 4
- BJRNKVDFDLYUGJ-RMPHRYRLSA-N hydroquinone O-beta-D-glucopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-RMPHRYRLSA-N 0.000 description 4
- 229960004370 ibopamine Drugs 0.000 description 4
- 230000008676 import Effects 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 229960004569 indapamide Drugs 0.000 description 4
- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 description 4
- MPGBPFMOOXKQRX-UHFFFAOYSA-N indenolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1C=CC2 MPGBPFMOOXKQRX-UHFFFAOYSA-N 0.000 description 4
- 229950008838 indenolol Drugs 0.000 description 4
- 229940102223 injectable solution Drugs 0.000 description 4
- 208000014674 injury Diseases 0.000 description 4
- 239000004041 inotropic agent Substances 0.000 description 4
- 238000003780 insertion Methods 0.000 description 4
- 230000037431 insertion Effects 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 229960004427 isradipine Drugs 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- 229960004194 lidocaine Drugs 0.000 description 4
- 210000004962 mammalian cell Anatomy 0.000 description 4
- IMYZQPCYWPFTAG-IQJOONFLSA-N mecamylamine Chemical compound C1C[C@@H]2C(C)(C)[C@@](NC)(C)[C@H]1C2 IMYZQPCYWPFTAG-IQJOONFLSA-N 0.000 description 4
- 229960002525 mecamylamine Drugs 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 229960003134 mepindolol Drugs 0.000 description 4
- 229960003739 methyclothiazide Drugs 0.000 description 4
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 description 4
- 229960003738 meticrane Drugs 0.000 description 4
- 229960002704 metipranolol Drugs 0.000 description 4
- BQIPXWYNLPYNHW-UHFFFAOYSA-N metipranolol Chemical compound CC(C)NCC(O)COC1=CC(C)=C(OC(C)=O)C(C)=C1C BQIPXWYNLPYNHW-UHFFFAOYSA-N 0.000 description 4
- 229960002817 metolazone Drugs 0.000 description 4
- AQCHWTWZEMGIFD-UHFFFAOYSA-N metolazone Chemical compound CC1NC2=CC(Cl)=C(S(N)(=O)=O)C=C2C(=O)N1C1=CC=CC=C1C AQCHWTWZEMGIFD-UHFFFAOYSA-N 0.000 description 4
- LFTFGCDECFPSQD-UHFFFAOYSA-N moprolol Chemical compound COC1=CC=CC=C1OCC(O)CNC(C)C LFTFGCDECFPSQD-UHFFFAOYSA-N 0.000 description 4
- 229950002481 moprolol Drugs 0.000 description 4
- RLWRMIYXDPXIEX-UHFFFAOYSA-N muzolimine Chemical compound C=1C=C(Cl)C(Cl)=CC=1C(C)N1N=C(N)CC1=O RLWRMIYXDPXIEX-UHFFFAOYSA-N 0.000 description 4
- 229960001788 muzolimine Drugs 0.000 description 4
- 239000005645 nematicide Substances 0.000 description 4
- 229960001783 nicardipine Drugs 0.000 description 4
- 229950000754 nipradilol Drugs 0.000 description 4
- 229960000227 nisoldipine Drugs 0.000 description 4
- 229960005425 nitrendipine Drugs 0.000 description 4
- JLPDBLFIVFSOCC-XYXFTTADSA-N oleandrin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1C[C@@H](CC[C@H]2[C@]3(C[C@@H]([C@@H]([C@@]3(C)CC[C@H]32)C=2COC(=O)C=2)OC(C)=O)O)[C@]3(C)CC1 JLPDBLFIVFSOCC-XYXFTTADSA-N 0.000 description 4
- 229950010050 oleandrin Drugs 0.000 description 4
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 description 4
- 210000003101 oviduct Anatomy 0.000 description 4
- 229960004570 oxprenolol Drugs 0.000 description 4
- 229960001818 oxyfedrine Drugs 0.000 description 4
- GDYUVHBMFVMBAF-LIRRHRJNSA-N oxyfedrine Chemical compound COC1=CC=CC(C(=O)CCN[C@@H](C)[C@H](O)C=2C=CC=CC=2)=C1 GDYUVHBMFVMBAF-LIRRHRJNSA-N 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- 238000012856 packing Methods 0.000 description 4
- 229950006493 paraflutizide Drugs 0.000 description 4
- 239000011049 pearl Substances 0.000 description 4
- 229960002582 perindopril Drugs 0.000 description 4
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 description 4
- 238000011458 pharmacological treatment Methods 0.000 description 4
- 230000008488 polyadenylation Effects 0.000 description 4
- 102000040430 polynucleotide Human genes 0.000 description 4
- 108091033319 polynucleotide Proteins 0.000 description 4
- 239000002157 polynucleotide Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 229950000992 pronetalol Drugs 0.000 description 4
- 229960000577 quinethazone Drugs 0.000 description 4
- AGMMTXLNIQSRCG-UHFFFAOYSA-N quinethazone Chemical compound NS(=O)(=O)C1=C(Cl)C=C2NC(CC)NC(=O)C2=C1 AGMMTXLNIQSRCG-UHFFFAOYSA-N 0.000 description 4
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 4
- 239000003087 receptor blocking agent Substances 0.000 description 4
- 230000003938 response to stress Effects 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- PAQZZCOZHPGCFW-UHFFFAOYSA-N sulfinalol Chemical compound C1=CC(OC)=CC=C1CCC(C)NCC(O)C1=CC=C(O)C(S(C)=O)=C1 PAQZZCOZHPGCFW-UHFFFAOYSA-N 0.000 description 4
- 229950005165 sulfinalol Drugs 0.000 description 4
- YRCWQPVGYLYSOX-UHFFFAOYSA-N synephrine Chemical compound CNCC(O)C1=CC=C(O)C=C1 YRCWQPVGYLYSOX-UHFFFAOYSA-N 0.000 description 4
- 229960003658 talinolol Drugs 0.000 description 4
- MXFWWQICDIZSOA-UHFFFAOYSA-N talinolol Chemical compound C1=CC(OCC(O)CNC(C)(C)C)=CC=C1NC(=O)NC1CCCCC1 MXFWWQICDIZSOA-UHFFFAOYSA-N 0.000 description 4
- 229960003352 tertatolol Drugs 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 4
- 229960005001 ticlopidine Drugs 0.000 description 4
- 229950000245 toliprolol Drugs 0.000 description 4
- 230000002103 transcriptional effect Effects 0.000 description 4
- 229960001288 triamterene Drugs 0.000 description 4
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 4
- 229960004813 trichlormethiazide Drugs 0.000 description 4
- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 4
- 229960002906 trimazosin Drugs 0.000 description 4
- YNZXWQJZEDLQEG-UHFFFAOYSA-N trimazosin Chemical compound N1=C2C(OC)=C(OC)C(OC)=CC2=C(N)N=C1N1CCN(C(=O)OCC(C)(C)O)CC1 YNZXWQJZEDLQEG-UHFFFAOYSA-N 0.000 description 4
- UHLOVGKIEARANS-QZHINBJYSA-N tripamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)NN2C[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3C2)=C1 UHLOVGKIEARANS-QZHINBJYSA-N 0.000 description 4
- 229950004678 tripamide Drugs 0.000 description 4
- 239000005526 vasoconstrictor agent Substances 0.000 description 4
- 229960001722 verapamil Drugs 0.000 description 4
- 229960004928 xamoterol Drugs 0.000 description 4
- 229960000537 xipamide Drugs 0.000 description 4
- MTZBBNMLMNBNJL-UHFFFAOYSA-N xipamide Chemical compound CC1=CC=CC(C)=C1NC(=O)C1=CC(S(N)(=O)=O)=C(Cl)C=C1O MTZBBNMLMNBNJL-UHFFFAOYSA-N 0.000 description 4
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 3
- BUJAGSGYPOAWEI-SECBINFHSA-N (2r)-2-amino-n-(2,6-dimethylphenyl)propanamide Chemical compound C[C@@H](N)C(=O)NC1=C(C)C=CC=C1C BUJAGSGYPOAWEI-SECBINFHSA-N 0.000 description 3
- QIJLJZOGPPQCOG-NFAWXSAZSA-N (2s)-1-[(2s)-3-[(2r)-2-(cyclohexanecarbonylamino)propanoyl]sulfanyl-2-methylpropanoyl]pyrrolidine-2-carboxylic acid Chemical compound N([C@H](C)C(=O)SC[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)C(=O)C1CCCCC1 QIJLJZOGPPQCOG-NFAWXSAZSA-N 0.000 description 3
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 3
- RSWGJHLUYNHPMX-UHFFFAOYSA-N 1,4a-dimethyl-7-propan-2-yl-2,3,4,4b,5,6,10,10a-octahydrophenanthrene-1-carboxylic acid Chemical compound C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 3
- ZBIAKUMOEKILTF-UHFFFAOYSA-N 2-[4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazinyl]-N-(2,6-dimethylphenyl)acetamide Chemical compound CC1=CC=CC(C)=C1NC(=O)CN1CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 ZBIAKUMOEKILTF-UHFFFAOYSA-N 0.000 description 3
- ZSZKJARKHWCBJK-UHFFFAOYSA-N 2-[[3-(2-chloroethyl)-2-oxo-1,3,2$l^{5}-oxazaphosphinan-2-yl]amino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCNP1(=O)OCCCN1CCCl ZSZKJARKHWCBJK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102000007469 Actins Human genes 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- 101100348617 Candida albicans (strain SC5314 / ATCC MYA-2876) NIK1 gene Proteins 0.000 description 3
- 229920002911 Colestipol Polymers 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 206010056533 Congenital hepatic fibrosis Diseases 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- 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 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- 108010066671 Enalaprilat Proteins 0.000 description 3
- DJBNUMBKLMJRSA-UHFFFAOYSA-N Flecainide Chemical compound FC(F)(F)COC1=CC=C(OCC(F)(F)F)C(C(=O)NCC2NCCCC2)=C1 DJBNUMBKLMJRSA-UHFFFAOYSA-N 0.000 description 3
- 241000287828 Gallus gallus Species 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- 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 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 241000282577 Pan troglodytes Species 0.000 description 3
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 101100007329 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) COS1 gene Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 108091023040 Transcription factor Proteins 0.000 description 3
- 102000040945 Transcription factor Human genes 0.000 description 3
- 108700019146 Transgenes Proteins 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 3
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 3
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 3
- 230000001800 adrenalinergic effect Effects 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 3
- 239000004004 anti-anginal agent Substances 0.000 description 3
- 229940127218 antiplatelet drug Drugs 0.000 description 3
- 210000002376 aorta thoracic Anatomy 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 229960003515 bendroflumethiazide Drugs 0.000 description 3
- HAVZTGSQJIEKPI-UHFFFAOYSA-N benzothiadiazine Chemical compound C1=CC=C2C=NNSC2=C1 HAVZTGSQJIEKPI-UHFFFAOYSA-N 0.000 description 3
- 239000003613 bile acid Substances 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 238000009395 breeding Methods 0.000 description 3
- 230000001488 breeding effect Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 210000004413 cardiac myocyte Anatomy 0.000 description 3
- 230000022131 cell cycle Effects 0.000 description 3
- 230000024245 cell differentiation Effects 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 230000036461 convulsion Effects 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 239000012531 culture fluid Substances 0.000 description 3
- ZGFASEKBKWVCGP-UHFFFAOYSA-N cyclocoumarol Chemical compound C12=CC=CC=C2OC(=O)C2=C1OC(OC)(C)CC2C1=CC=CC=C1 ZGFASEKBKWVCGP-UHFFFAOYSA-N 0.000 description 3
- 239000000551 dentifrice Substances 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 229960001912 dicoumarol Drugs 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 239000000890 drug combination Substances 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- 238000002592 echocardiography Methods 0.000 description 3
- 235000013399 edible fruits Nutrition 0.000 description 3
- PJWPNDMDCLXCOM-UHFFFAOYSA-N encainide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=CC=C1CCC1N(C)CCCC1 PJWPNDMDCLXCOM-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 239000002532 enzyme inhibitor Substances 0.000 description 3
- 229940125532 enzyme inhibitor Drugs 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 229960003745 esmolol Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000013613 expression plasmid Substances 0.000 description 3
- 210000002744 extracellular matrix Anatomy 0.000 description 3
- 230000003480 fibrinolytic effect Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 3
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 150000002357 guanidines Chemical class 0.000 description 3
- 229940083094 guanine derivative acting on arteriolar smooth muscle Drugs 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 230000010247 heart contraction Effects 0.000 description 3
- 230000006801 homologous recombination Effects 0.000 description 3
- 238000002744 homologous recombination Methods 0.000 description 3
- 238000009396 hybridization Methods 0.000 description 3
- 229960002003 hydrochlorothiazide Drugs 0.000 description 3
- 229960003313 hydroflumethiazide Drugs 0.000 description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 3
- 238000001114 immunoprecipitation Methods 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 208000014861 isolated congenital hepatic fibrosis Diseases 0.000 description 3
- 229960000201 isosorbide dinitrate Drugs 0.000 description 3
- 238000011813 knockout mouse model Methods 0.000 description 3
- 150000003951 lactams Chemical class 0.000 description 3
- 229940063699 lanoxin Drugs 0.000 description 3
- 108091023663 let-7 stem-loop Proteins 0.000 description 3
- 108091063478 let-7-1 stem-loop Proteins 0.000 description 3
- 108091049777 let-7-2 stem-loop Proteins 0.000 description 3
- 229960001941 lidoflazine Drugs 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 108091053735 lin-4 stem-loop Proteins 0.000 description 3
- 108091032363 lin-4-1 stem-loop Proteins 0.000 description 3
- 108091028008 lin-4-2 stem-loop Proteins 0.000 description 3
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 108091029162 miR-29 stem-loop Proteins 0.000 description 3
- 238000002493 microarray Methods 0.000 description 3
- 230000005486 microgravity Effects 0.000 description 3
- 238000010369 molecular cloning Methods 0.000 description 3
- 229950006549 moveltipril Drugs 0.000 description 3
- 230000005405 multipole Effects 0.000 description 3
- 208000017445 musculoskeletal system disease Diseases 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 229960003512 nicotinic acid Drugs 0.000 description 3
- 238000011457 non-pharmacological treatment Methods 0.000 description 3
- 229960002748 norepinephrine Drugs 0.000 description 3
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000002831 pharmacologic agent Substances 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 3
- 201000006038 polycystic kidney disease 4 Diseases 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 229960003912 probucol Drugs 0.000 description 3
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 3
- REQCZEXYDRLIBE-UHFFFAOYSA-N procainamide Chemical compound CCN(CC)CCNC(=O)C1=CC=C(N)C=C1 REQCZEXYDRLIBE-UHFFFAOYSA-N 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 230000002685 pulmonary effect Effects 0.000 description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 description 3
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 230000029058 respiratory gaseous exchange Effects 0.000 description 3
- 238000010839 reverse transcription Methods 0.000 description 3
- 210000005241 right ventricle Anatomy 0.000 description 3
- 238000004904 shortening Methods 0.000 description 3
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229940126121 sodium channel inhibitor Drugs 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 229950008275 sufosfamide Drugs 0.000 description 3
- GUTZRTRUIMWMJZ-UHFFFAOYSA-N teclothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)(Cl)Cl)NS2(=O)=O GUTZRTRUIMWMJZ-UHFFFAOYSA-N 0.000 description 3
- 229950009303 teclothiazide Drugs 0.000 description 3
- 230000008719 thickening Effects 0.000 description 3
- 229960000356 tienilic acid Drugs 0.000 description 3
- AGHANLSBXUWXTB-UHFFFAOYSA-N tienilic acid Chemical compound ClC1=C(Cl)C(OCC(=O)O)=CC=C1C(=O)C1=CC=CS1 AGHANLSBXUWXTB-UHFFFAOYSA-N 0.000 description 3
- 229940035742 trimethaphan Drugs 0.000 description 3
- CHQOEHPMXSHGCL-UHFFFAOYSA-N trimethaphan Chemical compound C12C[S+]3CCCC3C2N(CC=2C=CC=CC=2)C(=O)N1CC1=CC=CC=C1 CHQOEHPMXSHGCL-UHFFFAOYSA-N 0.000 description 3
- HALWUDBBYKMYPW-STOWLHSFSA-M trimethaphan camsylate Chemical compound C1C[C@@]2(CS([O-])(=O)=O)C(=O)C[C@@H]1C2(C)C.C12C[S+]3CCCC3C2N(CC=2C=CC=CC=2)C(=O)N1CC1=CC=CC=C1 HALWUDBBYKMYPW-STOWLHSFSA-M 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 229960005080 warfarin Drugs 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 2
- APUDBKTWDCXQJA-XQBPLPMBSA-N (1R)-4-[(2S,6R)-2,6-dimethylpiperidin-1-yl]-1-phenyl-1-pyridin-2-ylbutan-1-ol Chemical compound C[C@H]1CCC[C@@H](C)N1CCC[C@](O)(C=1N=CC=CC=1)C1=CC=CC=C1 APUDBKTWDCXQJA-XQBPLPMBSA-N 0.000 description 2
- WFTSRDISOMSAQC-ZNFOTRSXSA-N (1R,15S,17R,18R,19S,20S)-3-[2-(diethylamino)ethyl]-6,18-dimethoxy-17-[oxo-(3,4,5-trimethoxyphenyl)methoxy]-11,12,14,15,16,17,18,19,20,21-decahydro-1H-yohimban-19-carboxylic acid methyl ester Chemical compound O([C@@H]1C[C@H]2[C@@H]([C@@H]([C@H]1OC)C(=O)OC)C[C@@H]1C=3N(C4=CC(OC)=CC=C4C=3CCN1C2)CCN(CC)CC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 WFTSRDISOMSAQC-ZNFOTRSXSA-N 0.000 description 2
- APSWDBKJUOEMOA-MTEWDWANSA-N (2S)-4-amino-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S,3S)-2-[(2-aminoacetyl)amino]-3-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]-4-oxobutanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)CN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O APSWDBKJUOEMOA-MTEWDWANSA-N 0.000 description 2
- VLPIATFUUWWMKC-SNVBAGLBSA-N (2r)-1-(2,6-dimethylphenoxy)propan-2-amine Chemical compound C[C@@H](N)COC1=C(C)C=CC=C1C VLPIATFUUWWMKC-SNVBAGLBSA-N 0.000 description 2
- LIEMBEWXEZJEEZ-INEUFUBQSA-N (2r,3r)-4-(6-aminopurin-9-yl)-2,3-dihydroxybutanoic acid Chemical compound NC1=NC=NC2=C1N=CN2C[C@@H](O)[C@@H](O)C(O)=O LIEMBEWXEZJEEZ-INEUFUBQSA-N 0.000 description 2
- UQIPVSBPFZSWGD-ILYVXUQDSA-N (8r,9s,13s,14s,16r)-16-chloro-3-methoxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-17-one Chemical compound C1C[C@]2(C)C(=O)[C@H](Cl)C[C@H]2[C@@H]2CCC3=CC(OC)=CC=C3[C@H]21 UQIPVSBPFZSWGD-ILYVXUQDSA-N 0.000 description 2
- PHIQHXFUZVPYII-ZCFIWIBFSA-O (R)-carnitinium Chemical compound C[N+](C)(C)C[C@H](O)CC(O)=O PHIQHXFUZVPYII-ZCFIWIBFSA-O 0.000 description 2
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 2
- HVAKUYCEWDPRCA-IZZDOVSWSA-N (e)-1-(2,4-dimethoxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1\C=C\C(=O)C1=CC=C(OC)C=C1OC HVAKUYCEWDPRCA-IZZDOVSWSA-N 0.000 description 2
- LJOQGZACKSYWCH-LHHVKLHASA-N (s)-[(2r,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol Chemical compound C1=C(OC)C=C2C([C@H](O)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 LJOQGZACKSYWCH-LHHVKLHASA-N 0.000 description 2
- XULIXFLCVXWHRF-UHFFFAOYSA-N 1,2,2,6,6-pentamethylpiperidine Chemical compound CN1C(C)(C)CCCC1(C)C XULIXFLCVXWHRF-UHFFFAOYSA-N 0.000 description 2
- SSMSBSWKLKKXGG-UHFFFAOYSA-N 1-(2-chlorophenyl)-2-isopropylaminoethanol Chemical compound CC(C)NCC(O)C1=CC=CC=C1Cl SSMSBSWKLKKXGG-UHFFFAOYSA-N 0.000 description 2
- KJBSVTAYVZKMDM-UHFFFAOYSA-N 1-(2-nitrophenyl)cyclopropane-1-carboxylic acid Chemical compound C=1C=CC=C([N+]([O-])=O)C=1C1(C(=O)O)CC1 KJBSVTAYVZKMDM-UHFFFAOYSA-N 0.000 description 2
- LUKOGYUKYPZBFP-UHFFFAOYSA-N 1-(4-fluorophenyl)-4-piperidin-1-ylbutan-1-one Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCCCC1 LUKOGYUKYPZBFP-UHFFFAOYSA-N 0.000 description 2
- IVVNZDGDKPTYHK-JTQLQIEISA-N 1-cyano-2-[(2s)-3,3-dimethylbutan-2-yl]-3-pyridin-4-ylguanidine Chemical compound CC(C)(C)[C@H](C)N=C(NC#N)NC1=CC=NC=C1 IVVNZDGDKPTYHK-JTQLQIEISA-N 0.000 description 2
- GJHKWLSRHNWTAN-UHFFFAOYSA-N 1-ethoxy-4-(4-pentylcyclohexyl)benzene Chemical compound C1CC(CCCCC)CCC1C1=CC=C(OCC)C=C1 GJHKWLSRHNWTAN-UHFFFAOYSA-N 0.000 description 2
- SZLZWPPUNLXJEA-UHFFFAOYSA-N 11,17-dimethoxy-18-[3-(3,4,5-trimethoxy-phenyl)-acryloyloxy]-yohimbane-16-carboxylic acid methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(OC)C1OC(=O)C=CC1=CC(OC)=C(OC)C(OC)=C1 SZLZWPPUNLXJEA-UHFFFAOYSA-N 0.000 description 2
- KWVJHCQQUFDPLU-YEUCEMRASA-N 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KWVJHCQQUFDPLU-YEUCEMRASA-N 0.000 description 2
- 239000003315 2-(4-chlorophenoxy)-2-methylpropanoic acid Substances 0.000 description 2
- YYRYCTNXXHOENE-UHFFFAOYSA-N 2-(morpholin-4-ylmethyl)-2-phenylindene-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)C1(C=1C=CC=CC=1)CN1CCOCC1 YYRYCTNXXHOENE-UHFFFAOYSA-N 0.000 description 2
- YREYLAVBNPACJM-UHFFFAOYSA-N 2-(tert-butylamino)-1-(2-chlorophenyl)ethanol Chemical compound CC(C)(C)NCC(O)C1=CC=CC=C1Cl YREYLAVBNPACJM-UHFFFAOYSA-N 0.000 description 2
- IULOBWFWYDMECP-UHFFFAOYSA-N 2-[4-[2-[(4-chlorophenyl)sulfonylamino]ethyl]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1CCNS(=O)(=O)C1=CC=C(Cl)C=C1 IULOBWFWYDMECP-UHFFFAOYSA-N 0.000 description 2
- RMWVZGDJPAKBDE-UHFFFAOYSA-N 2-acetyloxy-4-(trifluoromethyl)benzoic acid Chemical compound CC(=O)OC1=CC(C(F)(F)F)=CC=C1C(O)=O RMWVZGDJPAKBDE-UHFFFAOYSA-N 0.000 description 2
- ATOTUUBRFJHZQG-UHFFFAOYSA-N 2-amino-2-methylpropan-1-ol;8-bromo-1,3-dimethyl-7h-purine-2,6-dione Chemical compound CC(C)(N)CO.O=C1N(C)C(=O)N(C)C2=C1NC(Br)=N2 ATOTUUBRFJHZQG-UHFFFAOYSA-N 0.000 description 2
- PTKSEFOSCHHMPD-SNVBAGLBSA-N 2-amino-n-[(2s)-2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide Chemical compound COC1=CC=C(OC)C([C@H](O)CNC(=O)CN)=C1 PTKSEFOSCHHMPD-SNVBAGLBSA-N 0.000 description 2
- JIVPVXMEBJLZRO-CQSZACIVSA-N 2-chloro-5-[(1r)-1-hydroxy-3-oxo-2h-isoindol-1-yl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC([C@@]2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-CQSZACIVSA-N 0.000 description 2
- HGAVKWUHBLHFNP-UHFFFAOYSA-N 2-hydroxy-5-(4-methylphenyl)sulfonyloxybenzenesulfonic acid;piperazine Chemical compound C1CNCCN1.C1=CC(C)=CC=C1S(=O)(=O)OC1=CC=C(O)C(S(O)(=O)=O)=C1 HGAVKWUHBLHFNP-UHFFFAOYSA-N 0.000 description 2
- UNFGQCCHVMMMRF-UHFFFAOYSA-N 2-phenylbutanamide Chemical compound CCC(C(N)=O)C1=CC=CC=C1 UNFGQCCHVMMMRF-UHFFFAOYSA-N 0.000 description 2
- HPMZBILYSWLILX-UMDUKNJSSA-N 3'''-O-acetyldigitoxin Chemical compound C1[C@H](OC(C)=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)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O HPMZBILYSWLILX-UMDUKNJSSA-N 0.000 description 2
- JXZZEXZZKAWDSP-UHFFFAOYSA-N 3-(2-(4-Benzamidopiperid-1-yl)ethyl)indole Chemical compound C1CN(CCC=2C3=CC=CC=C3NC=2)CCC1NC(=O)C1=CC=CC=C1 JXZZEXZZKAWDSP-UHFFFAOYSA-N 0.000 description 2
- SQVIAVUSQAWMKL-UHFFFAOYSA-N 3-[2-(ethylamino)-1-hydroxyethyl]phenol Chemical compound CCNCC(O)C1=CC=CC(O)=C1 SQVIAVUSQAWMKL-UHFFFAOYSA-N 0.000 description 2
- NPOAOTPXWNWTSH-UHFFFAOYSA-N 3-hydroxy-3-methylglutaric acid Chemical compound OC(=O)CC(O)(C)CC(O)=O NPOAOTPXWNWTSH-UHFFFAOYSA-N 0.000 description 2
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 2
- CANLULJYEHSQFU-UHFFFAOYSA-N 4-(1-aminoethyl)benzonitrile Chemical compound CC(N)C1=CC=C(C#N)C=C1 CANLULJYEHSQFU-UHFFFAOYSA-N 0.000 description 2
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 description 2
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 2
- HCNBCFYKPSFHLH-UHFFFAOYSA-N 6-(furan-2-yl)pteridine-2,4,7-triamine Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CO1 HCNBCFYKPSFHLH-UHFFFAOYSA-N 0.000 description 2
- LREQLEBVOXIEOM-UHFFFAOYSA-N 6-amino-2-methyl-2-heptanol Chemical compound CC(N)CCCC(C)(C)O LREQLEBVOXIEOM-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- FVNFBBAOMBJTST-UHFFFAOYSA-N 8-(2-phenylethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound O1C(=O)NCC11CCN(CCC=2C=CC=CC=2)CC1 FVNFBBAOMBJTST-UHFFFAOYSA-N 0.000 description 2
- HPMZBILYSWLILX-UHFFFAOYSA-N Acetyl-digitoxine Natural products C1C(OC(C)=O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O HPMZBILYSWLILX-UHFFFAOYSA-N 0.000 description 2
- 108010013043 Acetylesterase Proteins 0.000 description 2
- LPMXVESGRSUGHW-UHFFFAOYSA-N Acolongiflorosid K Natural products OC1C(O)C(O)C(C)OC1OC1CC2(O)CCC3C4(O)CCC(C=5COC(=O)C=5)C4(C)CC(O)C3C2(CO)C(O)C1 LPMXVESGRSUGHW-UHFFFAOYSA-N 0.000 description 2
- JBMKAUGHUNFTOL-UHFFFAOYSA-N Aldoclor Chemical class C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC=NS2(=O)=O JBMKAUGHUNFTOL-UHFFFAOYSA-N 0.000 description 2
- 108010001779 Ancrod Proteins 0.000 description 2
- 108010072661 Angiotensin Amide Proteins 0.000 description 2
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 2
- 108010064733 Angiotensins Proteins 0.000 description 2
- 102000015427 Angiotensins Human genes 0.000 description 2
- 102100034613 Annexin A2 Human genes 0.000 description 2
- 108090000668 Annexin A2 Proteins 0.000 description 2
- 206010003062 Apraxia Diseases 0.000 description 2
- 208000010061 Autosomal Dominant Polycystic Kidney Diseases 0.000 description 2
- 208000002814 Autosomal Recessive Polycystic Kidney Diseases 0.000 description 2
- 208000017354 Autosomal recessive polycystic kidney disease Diseases 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- 102000018720 Basic Helix-Loop-Helix Transcription Factors Human genes 0.000 description 2
- 108010027344 Basic Helix-Loop-Helix Transcription Factors Proteins 0.000 description 2
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 description 2
- QVZCXCJXTMIDME-UHFFFAOYSA-N Biopropazepan Trimethoxybenzoate Chemical compound COC1=C(OC)C(OC)=CC(C(=O)OCCCN2CCN(CCCOC(=O)C=3C=C(OC)C(OC)=C(OC)C=3)CCC2)=C1 QVZCXCJXTMIDME-UHFFFAOYSA-N 0.000 description 2
- RHLJLALHBZGAFM-UHFFFAOYSA-N Bunazosinum Chemical compound C1CN(C(=O)CCC)CCCN1C1=NC(N)=C(C=C(OC)C(OC)=C2)C2=N1 RHLJLALHBZGAFM-UHFFFAOYSA-N 0.000 description 2
- 239000002083 C09CA01 - Losartan Substances 0.000 description 2
- 239000002080 C09CA02 - Eprosartan Substances 0.000 description 2
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 2
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- VMNRZYKMPOZISX-UHFFFAOYSA-M COC(C[Hg]O)Cc1cccc2cc(C(O)=O)c(=O)oc12 Chemical compound COC(C[Hg]O)Cc1cccc2cc(C(O)=O)c(=O)oc12 VMNRZYKMPOZISX-UHFFFAOYSA-M 0.000 description 2
- QLTVVOATEHFXLT-UHFFFAOYSA-N Cadralazine Chemical compound CCOC(=O)NNC1=CC=C(N(CC)CC(C)O)N=N1 QLTVVOATEHFXLT-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 102100027992 Casein kinase II subunit beta Human genes 0.000 description 2
- 101710158100 Casein kinase II subunit beta Proteins 0.000 description 2
- GZVMBXDQUQRICT-BRTRNLDHSA-N Cerberoside Natural products O(C[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@H](O[C@@H]2[C@H](OC)[C@@H](O)[C@@H](O[C@@H]3C[C@@H]4[C@@](C)([C@@H]5[C@H]([C@]6(O)[C@@](C)([C@H](C7=CC(=O)OC7)CC6)CC5)CC4)CC3)O[C@@H]2C)O1)[C@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](CO)O1 GZVMBXDQUQRICT-BRTRNLDHSA-N 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 101000936911 Chionoecetes opilio Sarcoplasmic/endoplasmic reticulum calcium ATPase Proteins 0.000 description 2
- 101000986346 Chironomus tentans High mobility group protein I Proteins 0.000 description 2
- 229920001287 Chondroitin sulfate Polymers 0.000 description 2
- IPOBOOXFSRWSHL-UHFFFAOYSA-N Cibenzoline Chemical compound C=1C=CC=CC=1C1(C=2C=CC=CC=2)CC1C1=NCCN1 IPOBOOXFSRWSHL-UHFFFAOYSA-N 0.000 description 2
- KPSRODZRAIWAKH-JTQLQIEISA-N Ciprofibrate Natural products C1=CC(OC(C)(C)C(O)=O)=CC=C1[C@H]1C(Cl)(Cl)C1 KPSRODZRAIWAKH-JTQLQIEISA-N 0.000 description 2
- BMOVQUBVGICXQN-UHFFFAOYSA-N Clinofibrate Chemical compound C1=CC(OC(C)(CC)C(O)=O)=CC=C1C1(C=2C=CC(OC(C)(CC)C(O)=O)=CC=2)CCCCC1 BMOVQUBVGICXQN-UHFFFAOYSA-N 0.000 description 2
- NENBAISIHCWPKP-UHFFFAOYSA-N Clofenamide Chemical compound NS(=O)(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NENBAISIHCWPKP-UHFFFAOYSA-N 0.000 description 2
- VPMWFZKOWULPGT-UHFFFAOYSA-N Clorexolone Chemical compound C1C=2C=C(Cl)C(S(=O)(=O)N)=CC=2C(=O)N1C1CCCCC1 VPMWFZKOWULPGT-UHFFFAOYSA-N 0.000 description 2
- 102000029816 Collagenase Human genes 0.000 description 2
- 108060005980 Collagenase Proteins 0.000 description 2
- OPHYOSQDKQYDCM-UHFFFAOYSA-N Convallatoxin Natural products CC1OC(OC2CCC3(C=O)C4CCC5(C)C(CCC5(O)C4CCC3(O)C2)C6=CCC(=O)O6)C(O)C(O)C1O OPHYOSQDKQYDCM-UHFFFAOYSA-N 0.000 description 2
- XQCGNURMLWFQJR-ZNDDOCHDSA-N Cymarin Chemical compound O1[C@H](C)[C@@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)CC[C@@H]3[C@@]2(C=O)CC1 XQCGNURMLWFQJR-ZNDDOCHDSA-N 0.000 description 2
- XQCGNURMLWFQJR-UESCRGIISA-N Cymarin Natural products O=C[C@@]12[C@@](O)(C[C@@H](O[C@H]3O[C@@H](C)[C@@H](O)[C@@H](OC)C3)CC1)CC[C@H]1[C@]3(O)[C@@](C)([C@H](C4=CC(=O)OC4)CC3)CC[C@H]21 XQCGNURMLWFQJR-UESCRGIISA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- LIEMBEWXEZJEEZ-UHFFFAOYSA-N D-threo-Leutysin Natural products NC1=NC=NC2=C1N=CN2CC(O)C(O)C(O)=O LIEMBEWXEZJEEZ-UHFFFAOYSA-N 0.000 description 2
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 2
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 2
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 2
- 241000252212 Danio rerio Species 0.000 description 2
- QEEBRPGZBVVINN-UHFFFAOYSA-N Desacetyl-bufotalin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C1(O)CCC2C=1C=CC(=O)OC=1 QEEBRPGZBVVINN-UHFFFAOYSA-N 0.000 description 2
- CVBMAZKKCSYWQR-BPJCFPRXSA-N Deserpidine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cccc3 CVBMAZKKCSYWQR-BPJCFPRXSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CKNOLMVLQUPVMU-XOMFLMSUSA-N Digitalin Natural products O(C)[C@H]1[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](CO)O2)[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]([C@H](O)C5)C5=CC(=O)OC5)CC4)CC3)CC2)[C@@H]1O CKNOLMVLQUPVMU-XOMFLMSUSA-N 0.000 description 2
- JYGLAHSAISAEAL-UHFFFAOYSA-N Diphenadione Chemical compound O=C1C2=CC=CC=C2C(=O)C1C(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1 JYGLAHSAISAEAL-UHFFFAOYSA-N 0.000 description 2
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 2
- ZVXBAHLOGZCFTP-UHFFFAOYSA-N Efloxate Chemical compound C=1C(OCC(=O)OCC)=CC=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1 ZVXBAHLOGZCFTP-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- RGLLOUBXMOGLDQ-IVEVATEUSA-N Furazabol Chemical compound C([C@@H]1CC2)C3=NON=C3C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@](C)(O)[C@@]2(C)CC1 RGLLOUBXMOGLDQ-IVEVATEUSA-N 0.000 description 2
- XQLWNAFCTODIRK-UHFFFAOYSA-N Gallopamil Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC(OC)=C(OC)C(OC)=C1 XQLWNAFCTODIRK-UHFFFAOYSA-N 0.000 description 2
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 108090000288 Glycoproteins 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
- 208000032843 Hemorrhage Diseases 0.000 description 2
- VZJFGSRCJCXDSG-UHFFFAOYSA-N Hexamethonium Chemical compound C[N+](C)(C)CCCCCC[N+](C)(C)C VZJFGSRCJCXDSG-UHFFFAOYSA-N 0.000 description 2
- 102000007625 Hirudins Human genes 0.000 description 2
- 108010007267 Hirudins Proteins 0.000 description 2
- 101000614095 Homo sapiens Proton-activated chloride channel Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010020850 Hyperthyroidism Diseases 0.000 description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II 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)N[C@@H](CC=1C=CC=CC=1)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 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- HUYWAWARQUIQLE-UHFFFAOYSA-N Isoetharine Chemical compound CC(C)NC(CC)C(O)C1=CC=C(O)C(O)=C1 HUYWAWARQUIQLE-UHFFFAOYSA-N 0.000 description 2
- SXFPNMRWIWIAGS-UHFFFAOYSA-N Khellin Natural products COC1C2CCOC2C(OC)C3OC(C)CC(=O)C13 SXFPNMRWIWIAGS-UHFFFAOYSA-N 0.000 description 2
- WXFIGDLSSYIKKV-RCOVLWMOSA-N L-Metaraminol Chemical compound C[C@H](N)[C@H](O)C1=CC=CC(O)=C1 WXFIGDLSSYIKKV-RCOVLWMOSA-N 0.000 description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 2
- 229930188389 Lanatoside Natural products 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 108010081805 Malonyl-CoA decarboxylase Proteins 0.000 description 2
- 102100029461 Malonyl-CoA decarboxylase, mitochondrial Human genes 0.000 description 2
- LEROTMJVBFSIMP-UHFFFAOYSA-N Mebutamate Chemical compound NC(=O)OCC(C)(C(C)CC)COC(N)=O LEROTMJVBFSIMP-UHFFFAOYSA-N 0.000 description 2
- SMNOERSLNYGGOU-UHFFFAOYSA-N Mefruside Chemical compound C=1C=C(Cl)C(S(N)(=O)=O)=CC=1S(=O)(=O)N(C)CC1(C)CCCO1 SMNOERSLNYGGOU-UHFFFAOYSA-N 0.000 description 2
- HBNPJJILLOYFJU-VMPREFPWSA-N Mibefradil Chemical compound C1CC2=CC(F)=CC=C2[C@H](C(C)C)[C@@]1(OC(=O)COC)CCN(C)CCCC1=NC2=CC=CC=C2N1 HBNPJJILLOYFJU-VMPREFPWSA-N 0.000 description 2
- 108091028066 Mir-126 Proteins 0.000 description 2
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 2
- 208000009525 Myocarditis Diseases 0.000 description 2
- 108010067385 Myosin Light Chains Proteins 0.000 description 2
- 102000016349 Myosin Light Chains Human genes 0.000 description 2
- WGZDBVOTUVNQFP-UHFFFAOYSA-N N-(1-phthalazinylamino)carbamic acid ethyl ester Chemical compound C1=CC=C2C(NNC(=O)OCC)=NN=CC2=C1 WGZDBVOTUVNQFP-UHFFFAOYSA-N 0.000 description 2
- KEECCEWTUVWFCV-UHFFFAOYSA-N N-acetylprocainamide Chemical compound CCN(CC)CCNC(=O)C1=CC=C(NC(C)=O)C=C1 KEECCEWTUVWFCV-UHFFFAOYSA-N 0.000 description 2
- 108020001621 Natriuretic Peptide Proteins 0.000 description 2
- 102000004571 Natriuretic peptide Human genes 0.000 description 2
- YSEXMKHXIOCEJA-FVFQAYNVSA-N Nicergoline Chemical compound C([C@@H]1C[C@]2([C@H](N(C)C1)CC=1C3=C2C=CC=C3N(C)C=1)OC)OC(=O)C1=CN=CC(Br)=C1 YSEXMKHXIOCEJA-FVFQAYNVSA-N 0.000 description 2
- KUEUWHJGRZKESU-UHFFFAOYSA-N Niceritrol Chemical compound C=1C=CN=CC=1C(=O)OCC(COC(=O)C=1C=NC=CC=1)(COC(=O)C=1C=NC=CC=1)COC(=O)C1=CC=CN=C1 KUEUWHJGRZKESU-UHFFFAOYSA-N 0.000 description 2
- VRAHPESAMYMDQI-UHFFFAOYSA-N Nicomol Chemical compound C1CCC(COC(=O)C=2C=NC=CC=2)(COC(=O)C=2C=NC=CC=2)C(O)C1(COC(=O)C=1C=NC=CC=1)COC(=O)C1=CC=CN=C1 VRAHPESAMYMDQI-UHFFFAOYSA-N 0.000 description 2
- FAIIFDPAEUKBEP-UHFFFAOYSA-N Nilvadipine Chemical compound COC(=O)C1=C(C#N)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 FAIIFDPAEUKBEP-UHFFFAOYSA-N 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- JLPDBLFIVFSOCC-UHFFFAOYSA-N Oleandrin Natural products O1C(C)C(O)C(OC)CC1OC1CC(CCC2C3(CC(C(C3(C)CCC32)C=2COC(=O)C=2)OC(C)=O)O)C3(C)CC1 JLPDBLFIVFSOCC-UHFFFAOYSA-N 0.000 description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 2
- LPMXVESGRSUGHW-GHYGWZAOSA-N Ouabain Natural products O([C@@H]1[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1)[C@H]1C[C@@H](O)[C@@]2(CO)[C@@](O)(C1)CC[C@H]1[C@]3(O)[C@@](C)([C@H](C4=CC(=O)OC4)CC3)C[C@@H](O)[C@H]21 LPMXVESGRSUGHW-GHYGWZAOSA-N 0.000 description 2
- 238000012408 PCR amplification Methods 0.000 description 2
- DJWYOLJPSHDSAL-UHFFFAOYSA-N Pantethine Natural products OCC(C)(C)C(O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)C(O)C(C)(C)CO DJWYOLJPSHDSAL-UHFFFAOYSA-N 0.000 description 2
- DPWPWRLQFGFJFI-UHFFFAOYSA-N Pargyline Chemical compound C#CCN(C)CC1=CC=CC=C1 DPWPWRLQFGFJFI-UHFFFAOYSA-N 0.000 description 2
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VQDBNKDJNJQRDG-UHFFFAOYSA-N Pirbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=N1 VQDBNKDJNJQRDG-UHFFFAOYSA-N 0.000 description 2
- UJEWTUDSLQGTOA-UHFFFAOYSA-N Piretanide Chemical compound C=1C=CC=CC=1OC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1N1CCCC1 UJEWTUDSLQGTOA-UHFFFAOYSA-N 0.000 description 2
- CYLWJCABXYDINA-UHFFFAOYSA-N Polythiazide Polymers ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CSCC(F)(F)F)NC2=C1 CYLWJCABXYDINA-UHFFFAOYSA-N 0.000 description 2
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 2
- ADUKCCWBEDSMEB-NSHDSACASA-N Prenalterol Chemical compound CC(C)NC[C@H](O)COC1=CC=C(O)C=C1 ADUKCCWBEDSMEB-NSHDSACASA-N 0.000 description 2
- IFFPICMESYHZPQ-UHFFFAOYSA-N Prenylamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)CCNC(C)CC1=CC=CC=C1 IFFPICMESYHZPQ-UHFFFAOYSA-N 0.000 description 2
- MYEJFUXQJGHEQK-ALRJYLEOSA-N Proscillaridin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C=C2CC[C@H]3[C@@]4(O)CC[C@H](C5=COC(=O)C=C5)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1 MYEJFUXQJGHEQK-ALRJYLEOSA-N 0.000 description 2
- 102000007327 Protamines Human genes 0.000 description 2
- 108010007568 Protamines Proteins 0.000 description 2
- 102100040631 Proton-activated chloride channel Human genes 0.000 description 2
- 229930189630 Protoveratrine Natural products 0.000 description 2
- HYTGGNIMZXFORS-MGYKWWNKSA-N Protoveratrine A Chemical compound O1[C@@]([C@H](CC[C@]23C)OC(=O)[C@@](C)(O)CC)(O)[C@H]3[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]3[C@@]12C[C@H]1[C@H](CN2[C@@H](CC[C@H](C)C2)[C@@]2(C)O)[C@@H]2[C@@H](O)[C@H](OC(=O)[C@H](C)CC)[C@@]31O HYTGGNIMZXFORS-MGYKWWNKSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 108091034057 RNA (poly(A)) Proteins 0.000 description 2
- 108700005075 Regulator Genes Proteins 0.000 description 2
- MMUMZMIKZXSFSD-ADSVITMPSA-N Rescimetol Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)\C=C\C1=CC=C(O)C(OC)=C1 MMUMZMIKZXSFSD-ADSVITMPSA-N 0.000 description 2
- SZLZWPPUNLXJEA-FMCDHCOASA-N Rescinnamine Natural products O=C(O[C@H]1[C@@H](OC)[C@@H](C(=O)OC)[C@@H]2[C@H](C1)CN1[C@@H](c3[nH]c4c(c3CC1)ccc(OC)c4)C2)/C=C/c1cc(OC)c(OC)c(OC)c1 SZLZWPPUNLXJEA-FMCDHCOASA-N 0.000 description 2
- CQXADFVORZEARL-UHFFFAOYSA-N Rilmenidine Chemical compound C1CC1C(C1CC1)NC1=NCCO1 CQXADFVORZEARL-UHFFFAOYSA-N 0.000 description 2
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 2
- 108010083387 Saralasin Proteins 0.000 description 2
- 229930187443 Scillaren Natural products 0.000 description 2
- JLRNKCZRCMIVKA-UHFFFAOYSA-N Simfibrate Chemical compound C=1C=C(Cl)C=CC=1OC(C)(C)C(=O)OCCCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 JLRNKCZRCMIVKA-UHFFFAOYSA-N 0.000 description 2
- 108010023197 Streptokinase Proteins 0.000 description 2
- 244000166550 Strophanthus gratus Species 0.000 description 2
- CPFNIKYEDJFRAT-UHFFFAOYSA-N Strospasid Natural products OC1C(OC)C(O)C(C)OC1OC1CC(CCC2C3(CC(O)C(C3(C)CCC32)C=2COC(=O)C=2)O)C3(C)CC1 CPFNIKYEDJFRAT-UHFFFAOYSA-N 0.000 description 2
- 206010042434 Sudden death Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- ZCDNRPPFBQDQHR-SSYATKPKSA-N Syrosingopine Chemical compound C1=C(OC)C(OC(=O)OCC)=C(OC)C=C1C(=O)O[C@H]1[C@H](OC)[C@@H](C(=O)OC)[C@H]2C[C@@H]3C(NC=4C5=CC=C(OC)C=4)=C5CCN3C[C@H]2C1 ZCDNRPPFBQDQHR-SSYATKPKSA-N 0.000 description 2
- 108700026226 TATA Box Proteins 0.000 description 2
- 241000054452 Takifugu ocellatus Species 0.000 description 2
- 229920002253 Tannate Polymers 0.000 description 2
- 102000006601 Thymidine Kinase Human genes 0.000 description 2
- 108020004440 Thymidine kinase Proteins 0.000 description 2
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 2
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 2
- NGBFQHCMQULJNZ-UHFFFAOYSA-N Torsemide Chemical compound CC(C)NC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 NGBFQHCMQULJNZ-UHFFFAOYSA-N 0.000 description 2
- 101001023030 Toxoplasma gondii Myosin-D Proteins 0.000 description 2
- GSNOZLZNQMLSKJ-UHFFFAOYSA-N Trapidil Chemical compound CCN(CC)C1=CC(C)=NC2=NC=NN12 GSNOZLZNQMLSKJ-UHFFFAOYSA-N 0.000 description 2
- UHWVSEOVJBQKBE-UHFFFAOYSA-N Trimetazidine Chemical compound COC1=C(OC)C(OC)=CC=C1CN1CCNCC1 UHWVSEOVJBQKBE-UHFFFAOYSA-N 0.000 description 2
- 102000004903 Troponin Human genes 0.000 description 2
- 108090001027 Troponin Proteins 0.000 description 2
- CKNOLMVLQUPVMU-UHFFFAOYSA-N UNPD183315 Natural products O1C(C)C(OC2C(C(O)C(O)C(CO)O2)O)C(OC)C(O)C1OC(C1)CCC2(C)C1CCC(C1(CC3O)O)C2CCC1(C)C3C1=CC(=O)OC1 CKNOLMVLQUPVMU-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- ICMGLRUYEQNHPF-UHFFFAOYSA-N Uraprene Chemical compound COC1=CC=CC=C1N1CCN(CCCNC=2N(C(=O)N(C)C(=O)C=2)C)CC1 ICMGLRUYEQNHPF-UHFFFAOYSA-N 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- BLGXFZZNTVWLAY-CCZXDCJGSA-N Yohimbine Natural products C1=CC=C2C(CCN3C[C@@H]4CC[C@@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-CCZXDCJGSA-N 0.000 description 2
- YFGQJKBUXPKSAW-ZUDKKNPISA-N [(2r,3r,4s)-6-[(2r,3s,4s)-4-hydroxy-6-[(2r,3s,4s)-4-hydroxy-6-[[(3s,9s,10s,13r,17r)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2h-furan-3-yl)-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-yl]oxy]-2-methyloxan-3-yl]oxy-2-methyloxan-3-y Chemical compound O([C@H]1[C@@H](OC(C)=O)CC(O[C@@H]1C)O[C@H]1[C@@H](O)CC(O[C@@H]1C)O[C@H]1[C@@H](O)CC(O[C@@H]1C)O[C@@H]1CC2[C@]([C@@H]3C(C4(CC[C@@H]([C@@]4(C)CC3)C=3COC(=O)C=3)O)CC2)(C)CC1)C1O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]1O YFGQJKBUXPKSAW-ZUDKKNPISA-N 0.000 description 2
- SRHWTZAMPFLHAX-WDZFZDKYSA-N [(z)-1-pyridin-4-ylethylideneamino]thiourea Chemical compound NC(=S)N/N=C(/C)C1=CC=NC=C1 SRHWTZAMPFLHAX-WDZFZDKYSA-N 0.000 description 2
- YOKPRDAUBGOISU-UHFFFAOYSA-N [1-(3-methylbutoxy)-3-morpholin-4-ylpropan-2-yl] 3,4,5-trimethoxybenzoate Chemical compound COC1=C(OC)C(OC)=CC(C(=O)OC(COCCC(C)C)CN2CCOCC2)=C1 YOKPRDAUBGOISU-UHFFFAOYSA-N 0.000 description 2
- GRALFSQRIBJAHX-UHFFFAOYSA-N [4-(diethylamino)-3-methylbutan-2-yl] 4-(2-methylpropoxy)benzoate Chemical compound CCN(CC)CC(C)C(C)OC(=O)C1=CC=C(OCC(C)C)C=C1 GRALFSQRIBJAHX-UHFFFAOYSA-N 0.000 description 2
- JNWFIPVDEINBAI-UHFFFAOYSA-N [5-hydroxy-4-[4-(1-methylindol-5-yl)-5-oxo-1H-1,2,4-triazol-3-yl]-2-propan-2-ylphenyl] dihydrogen phosphate Chemical compound C1=C(OP(O)(O)=O)C(C(C)C)=CC(C=2N(C(=O)NN=2)C=2C=C3C=CN(C)C3=CC=2)=C1O JNWFIPVDEINBAI-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 229950005879 acecainide Drugs 0.000 description 2
- 229960002054 acenocoumarol Drugs 0.000 description 2
- VABCILAOYCMVPS-UHFFFAOYSA-N acenocoumarol Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=C([N+]([O-])=O)C=C1 VABCILAOYCMVPS-UHFFFAOYSA-N 0.000 description 2
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 2
- 229960000571 acetazolamide Drugs 0.000 description 2
- 229960003635 acetyldigitoxin Drugs 0.000 description 2
- DFDGRKNOFOJBAJ-UHFFFAOYSA-N acifran Chemical compound C=1C=CC=CC=1C1(C)OC(C(O)=O)=CC1=O DFDGRKNOFOJBAJ-UHFFFAOYSA-N 0.000 description 2
- 229950000146 acifran Drugs 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000000951 adrenergic alpha-1 receptor antagonist Substances 0.000 description 2
- 239000000808 adrenergic beta-agonist Substances 0.000 description 2
- 239000003043 adrenergic neuron blocking agent Substances 0.000 description 2
- 230000008484 agonism Effects 0.000 description 2
- GRTOGORTSDXSFK-XJTZBENFSA-N ajmalicine Chemical compound C1=CC=C2C(CCN3C[C@@H]4[C@H](C)OC=C([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 GRTOGORTSDXSFK-XJTZBENFSA-N 0.000 description 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 2
- WNMJYKCGWZFFKR-UHFFFAOYSA-N alfuzosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(C)CCCNC(=O)C1CCCO1 WNMJYKCGWZFFKR-UHFFFAOYSA-N 0.000 description 2
- 229960004607 alfuzosin Drugs 0.000 description 2
- 101150099105 alien gene Proteins 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- 229960002266 amezinium metilsulfate Drugs 0.000 description 2
- ZEASXVYVFFXULL-UHFFFAOYSA-N amezinium metilsulfate Chemical compound COS([O-])(=O)=O.COC1=CC(N)=CN=[N+]1C1=CC=CC=C1 ZEASXVYVFFXULL-UHFFFAOYSA-N 0.000 description 2
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 2
- 229960002576 amiloride Drugs 0.000 description 2
- NGXUUAFYUCOICP-UHFFFAOYSA-N aminometradine Chemical compound CCN1C(=O)C=C(N)N(CC=C)C1=O NGXUUAFYUCOICP-UHFFFAOYSA-N 0.000 description 2
- 229960001887 aminometradine Drugs 0.000 description 2
- 229960005260 amiodarone Drugs 0.000 description 2
- FXNYSZHYMGWWEZ-UHFFFAOYSA-N amisometradine Chemical compound CC(=C)CN1C(N)=CC(=O)N(C)C1=O FXNYSZHYMGWWEZ-UHFFFAOYSA-N 0.000 description 2
- 229950008305 amisometradine Drugs 0.000 description 2
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 2
- 229960000528 amlodipine Drugs 0.000 description 2
- 229960003173 amoproxan Drugs 0.000 description 2
- 229940025084 amphetamine Drugs 0.000 description 2
- HSNWZBCBUUSSQD-UHFFFAOYSA-N amyl nitrate Chemical compound CCCCCO[N+]([O-])=O HSNWZBCBUUSSQD-UHFFFAOYSA-N 0.000 description 2
- OTBXOEAOVRKTNQ-UHFFFAOYSA-N anagrelide Chemical compound N1=C2NC(=O)CN2CC2=C(Cl)C(Cl)=CC=C21 OTBXOEAOVRKTNQ-UHFFFAOYSA-N 0.000 description 2
- 229960001694 anagrelide Drugs 0.000 description 2
- 229960004233 ancrod Drugs 0.000 description 2
- XRCFXMGQEVUZFC-UHFFFAOYSA-N anisindione Chemical compound C1=CC(OC)=CC=C1C1C(=O)C2=CC=CC=C2C1=O XRCFXMGQEVUZFC-UHFFFAOYSA-N 0.000 description 2
- 229960002138 anisindione Drugs 0.000 description 2
- 229960000983 anistreplase Drugs 0.000 description 2
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 229960004957 aprindine Drugs 0.000 description 2
- NZLBHDRPUJLHCE-UHFFFAOYSA-N aprindine Chemical compound C1C2=CC=CC=C2CC1N(CCCN(CC)CC)C1=CC=CC=C1 NZLBHDRPUJLHCE-UHFFFAOYSA-N 0.000 description 2
- 229960000271 arbutin Drugs 0.000 description 2
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 description 2
- 229960003856 argatroban Drugs 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 230000006793 arrhythmia Effects 0.000 description 2
- 230000004872 arterial blood pressure Effects 0.000 description 2
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 2
- MOTJMGVDPWRKOC-QPVYNBJUSA-N atrasentan Chemical compound C1([C@H]2[C@@H]([C@H](CN2CC(=O)N(CCCC)CCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1 MOTJMGVDPWRKOC-QPVYNBJUSA-N 0.000 description 2
- 229950010993 atrasentan Drugs 0.000 description 2
- 208000022185 autosomal dominant polycystic kidney disease Diseases 0.000 description 2
- FMTFZYKYVZBISL-HUVRVWIJSA-N azacosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](N(C)CCCN(C)C)[C@@]1(C)CC2 FMTFZYKYVZBISL-HUVRVWIJSA-N 0.000 description 2
- 229950005866 azacosterol Drugs 0.000 description 2
- 229950009336 azamethonium bromide Drugs 0.000 description 2
- YEESUBCSWGVPCE-UHFFFAOYSA-N azanylidyneoxidanium iron(2+) pentacyanide Chemical compound [Fe++].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.N#[O+] YEESUBCSWGVPCE-UHFFFAOYSA-N 0.000 description 2
- IIOPLILENRZKRV-UHFFFAOYSA-N azosemide Chemical compound C=1C=CSC=1CNC=1C=C(Cl)C(S(=O)(=O)N)=CC=1C1=NN=N[N]1 IIOPLILENRZKRV-UHFFFAOYSA-N 0.000 description 2
- 229960004988 azosemide Drugs 0.000 description 2
- 229960003060 bambuterol Drugs 0.000 description 2
- ANZXOIAKUNOVQU-UHFFFAOYSA-N bambuterol Chemical compound CN(C)C(=O)OC1=CC(OC(=O)N(C)C)=CC(C(O)CNC(C)(C)C)=C1 ANZXOIAKUNOVQU-UHFFFAOYSA-N 0.000 description 2
- YWQGBCXVCXMSLJ-UHFFFAOYSA-N beclobrate Chemical compound C1=CC(OC(C)(CC)C(=O)OCC)=CC=C1CC1=CC=C(Cl)C=C1 YWQGBCXVCXMSLJ-UHFFFAOYSA-N 0.000 description 2
- 229950009252 beclobrate Drugs 0.000 description 2
- 229960004374 befunolol Drugs 0.000 description 2
- ZPQPDBIHYCBNIG-UHFFFAOYSA-N befunolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1OC(C(C)=O)=C2 ZPQPDBIHYCBNIG-UHFFFAOYSA-N 0.000 description 2
- 229960004530 benazepril Drugs 0.000 description 2
- 229960000945 bencyclane Drugs 0.000 description 2
- FYJJXENSONZJRG-UHFFFAOYSA-N bencyclane Chemical compound C=1C=CC=CC=1CC1(OCCCN(C)C)CCCCCC1 FYJJXENSONZJRG-UHFFFAOYSA-N 0.000 description 2
- YTLQFZVCLXFFRK-UHFFFAOYSA-N bendazol Chemical compound N=1C2=CC=CC=C2NC=1CC1=CC=CC=C1 YTLQFZVCLXFFRK-UHFFFAOYSA-N 0.000 description 2
- 229950000900 bendazol Drugs 0.000 description 2
- 229960001264 benfluorex Drugs 0.000 description 2
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 2
- CJAVTWRYCDNHSM-UHFFFAOYSA-N benzoic acid 2-[1-[3-(trifluoromethyl)phenyl]propan-2-ylamino]ethyl ester Chemical compound C=1C=CC=CC=1C(=O)OCCNC(C)CC1=CC=CC(C(F)(F)F)=C1 CJAVTWRYCDNHSM-UHFFFAOYSA-N 0.000 description 2
- BLGXFZZNTVWLAY-UHFFFAOYSA-N beta-Yohimbin Natural products C1=CC=C2C(CCN3CC4CCC(O)C(C4CC33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-UHFFFAOYSA-N 0.000 description 2
- 229960004980 betanidine Drugs 0.000 description 2
- 229940099231 betapace Drugs 0.000 description 2
- NIVZHWNOUVJHKV-UHFFFAOYSA-N bethanidine Chemical compound CN\C(=N/C)NCC1=CC=CC=C1 NIVZHWNOUVJHKV-UHFFFAOYSA-N 0.000 description 2
- 229960004383 bietaserpine Drugs 0.000 description 2
- BFYRHDVAEJIBON-UHFFFAOYSA-N binifibrate Chemical compound C=1C=CN=CC=1C(=O)OCC(COC(=O)C=1C=NC=CC=1)OC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 BFYRHDVAEJIBON-UHFFFAOYSA-N 0.000 description 2
- 229950004495 binifibrate Drugs 0.000 description 2
- 229960004620 bitolterol Drugs 0.000 description 2
- FZGVEKPRDOIXJY-UHFFFAOYSA-N bitolterol Chemical compound C1=CC(C)=CC=C1C(=O)OC1=CC=C(C(O)CNC(C)(C)C)C=C1OC(=O)C1=CC=C(C)C=C1 FZGVEKPRDOIXJY-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229960003065 bosentan Drugs 0.000 description 2
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- KVWNWTZZBKCOPM-UHFFFAOYSA-M bretylium tosylate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.CC[N+](C)(C)CC1=CC=CC=C1Br KVWNWTZZBKCOPM-UHFFFAOYSA-M 0.000 description 2
- NPUZIGSOEWMFKK-UHFFFAOYSA-N bromindione Chemical compound C1=CC(Br)=CC=C1C1C(=O)C2=CC=CC=C2C1=O NPUZIGSOEWMFKK-UHFFFAOYSA-N 0.000 description 2
- 229950004502 bromindione Drugs 0.000 description 2
- CJGYSWNGNKCJSB-YVLZZHOMSA-N bucladesine Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](OC(=O)CCC)[C@@H]2N1C(N=CN=C2NC(=O)CCC)=C2N=C1 CJGYSWNGNKCJSB-YVLZZHOMSA-N 0.000 description 2
- 229960005263 bucladesine Drugs 0.000 description 2
- CIJVBYRUFLGDHY-UHFFFAOYSA-N bucumolol Chemical compound O1C(=O)C=CC2=C1C(OCC(O)CNC(C)(C)C)=CC=C2C CIJVBYRUFLGDHY-UHFFFAOYSA-N 0.000 description 2
- 229950002568 bucumolol Drugs 0.000 description 2
- DQGFCLJXYFXXIJ-LFIBNONCSA-N budralazine Chemical compound C1=CC=C2C(N/N=C(C)/C=C(C)C)=NN=CC2=C1 DQGFCLJXYFXXIJ-LFIBNONCSA-N 0.000 description 2
- 229950001730 budralazine Drugs 0.000 description 2
- RFIXURDMUINBMD-UHFFFAOYSA-N bufeniode Chemical compound C=1C(I)=C(O)C(I)=CC=1C(O)C(C)NC(C)CCC1=CC=CC=C1 RFIXURDMUINBMD-UHFFFAOYSA-N 0.000 description 2
- 229950003250 bufeniode Drugs 0.000 description 2
- ATLJNLYIJOCWJE-CWMZOUAVSA-N bufogenin Chemical compound C=1([C@H]2C[C@H]3O[C@@]43[C@H]3[C@@H]([C@]5(CC[C@H](O)C[C@H]5CC3)C)CC[C@@]42C)C=CC(=O)OC=1 ATLJNLYIJOCWJE-CWMZOUAVSA-N 0.000 description 2
- 229950006858 bufogenin Drugs 0.000 description 2
- 229960004064 bumetanide Drugs 0.000 description 2
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 2
- 229960005458 bunaftine Drugs 0.000 description 2
- WWGZXRYELYWJBD-UHFFFAOYSA-N bunaftine Chemical compound C1=CC=C2C(C(=O)N(CCN(CC)CC)CCCC)=CC=CC2=C1 WWGZXRYELYWJBD-UHFFFAOYSA-N 0.000 description 2
- 229960002467 bunazosin Drugs 0.000 description 2
- 229960000330 bupranolol Drugs 0.000 description 2
- HQIRNZOQPUAHHV-UHFFFAOYSA-N bupranolol Chemical compound CC1=CC=C(Cl)C(OCC(O)CNC(C)(C)C)=C1 HQIRNZOQPUAHHV-UHFFFAOYSA-N 0.000 description 2
- HZIYHIRJHYIRQO-UHFFFAOYSA-N butazolamide Chemical compound CCCC(=O)NC1=NN=C(S(N)(=O)=O)S1 HZIYHIRJHYIRQO-UHFFFAOYSA-N 0.000 description 2
- 229950000426 butazolamide Drugs 0.000 description 2
- GVNYSERWAKVROD-UHFFFAOYSA-N butidrine Chemical compound C1CCCC2=CC(C(O)CNC(C)CC)=CC=C21 GVNYSERWAKVROD-UHFFFAOYSA-N 0.000 description 2
- 229950003097 butidrine Drugs 0.000 description 2
- ZKSIPEYIAHUPNM-ZEQRLZLVSA-N butobendine Chemical compound C([C@H](CC)N(C)CCN(C)[C@@H](CC)COC(=O)C=1C=C(OC)C(OC)=C(OC)C=1)OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 ZKSIPEYIAHUPNM-ZEQRLZLVSA-N 0.000 description 2
- 229950001141 butobendine Drugs 0.000 description 2
- 229960005211 cadralazine Drugs 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 108010051489 calin Proteins 0.000 description 2
- 229950008603 camphotamide Drugs 0.000 description 2
- 229960005057 canrenone Drugs 0.000 description 2
- UJVLDDZCTMKXJK-WNHSNXHDSA-N canrenone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CCC(=O)C=C3C=C2)C)CC[C@@]11C)C[C@@]11CCC(=O)O1 UJVLDDZCTMKXJK-WNHSNXHDSA-N 0.000 description 2
- 229950007443 capobenic acid Drugs 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 229960001386 carbuterol Drugs 0.000 description 2
- KEMXXQOFIRIICG-UHFFFAOYSA-N carbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(NC(N)=O)=C1 KEMXXQOFIRIICG-UHFFFAOYSA-N 0.000 description 2
- 229940097217 cardiac glycoside Drugs 0.000 description 2
- 239000002368 cardiac glycoside Substances 0.000 description 2
- 229960004203 carnitine Drugs 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000013153 catheter ablation Methods 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 description 2
- 150000005829 chemical entities Chemical class 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 210000000038 chest Anatomy 0.000 description 2
- IHJCXVZDYSXXFT-UHFFFAOYSA-N chloraminophenamide Chemical compound NC1=CC(Cl)=C(S(N)(=O)=O)C=C1S(N)(=O)=O IHJCXVZDYSXXFT-UHFFFAOYSA-N 0.000 description 2
- YRZQHIVOIFJEEE-UHFFFAOYSA-N chlorazanil Chemical compound NC1=NC=NC(NC=2C=CC(Cl)=CC=2)=N1 YRZQHIVOIFJEEE-UHFFFAOYSA-N 0.000 description 2
- 229950002325 chlorazanil Drugs 0.000 description 2
- IXWDUZLHWJKVPX-UHFFFAOYSA-N chlorisondamine Chemical compound ClC1=C(Cl)C(Cl)=C(Cl)C2=C1C[N+](CC[N+](C)(C)C)(C)C2 IXWDUZLHWJKVPX-UHFFFAOYSA-N 0.000 description 2
- 229950002565 chlorisondamine Drugs 0.000 description 2
- BJFGVYCULWBXKF-UHFFFAOYSA-M chlormerodrin Chemical compound Cl[Hg]CC(OC)CNC(N)=O BJFGVYCULWBXKF-UHFFFAOYSA-M 0.000 description 2
- 229950002901 chlormerodrin Drugs 0.000 description 2
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 2
- JIVPVXMEBJLZRO-UHFFFAOYSA-N chlorthalidone Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-UHFFFAOYSA-N 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 229940059329 chondroitin sulfate Drugs 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 229960004757 cibenzoline Drugs 0.000 description 2
- AJPLPOWGYORUIF-UHFFFAOYSA-N ciclosidomine Chemical compound C1CCCCC1C(/[O-])=N/C(ON=1)=C[N+]=1N1CCOCC1 AJPLPOWGYORUIF-UHFFFAOYSA-N 0.000 description 2
- 229950008471 ciclosidomine Drugs 0.000 description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
- DERZBLKQOCDDDZ-JLHYYAGUSA-N cinnarizine Chemical compound C1CN(C(C=2C=CC=CC=2)C=2C=CC=CC=2)CCN1C\C=C\C1=CC=CC=C1 DERZBLKQOCDDDZ-JLHYYAGUSA-N 0.000 description 2
- 229960000876 cinnarizine Drugs 0.000 description 2
- 229960002174 ciprofibrate Drugs 0.000 description 2
- KPSRODZRAIWAKH-UHFFFAOYSA-N ciprofibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1C1C(Cl)(Cl)C1 KPSRODZRAIWAKH-UHFFFAOYSA-N 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 229960001117 clenbuterol Drugs 0.000 description 2
- STJMRWALKKWQGH-UHFFFAOYSA-N clenbuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 STJMRWALKKWQGH-UHFFFAOYSA-N 0.000 description 2
- 229950003072 clinofibrate Drugs 0.000 description 2
- 229960002883 clofenamide Drugs 0.000 description 2
- 229960001214 clofibrate Drugs 0.000 description 2
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 2
- TXCGAZHTZHNUAI-UHFFFAOYSA-N clofibric acid Chemical compound OC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 TXCGAZHTZHNUAI-UHFFFAOYSA-N 0.000 description 2
- 229950008441 clofibric acid Drugs 0.000 description 2
- SUAJWTBTMNHVBZ-UHFFFAOYSA-N clonitrate Chemical compound [O-][N+](=O)OCC(CCl)O[N+]([O-])=O SUAJWTBTMNHVBZ-UHFFFAOYSA-N 0.000 description 2
- 229950004347 clonitrate Drugs 0.000 description 2
- 229960004893 cloranolol Drugs 0.000 description 2
- XYCMOTOFHFTUIU-UHFFFAOYSA-N cloranolol Chemical compound CC(C)(C)NCC(O)COC1=CC(Cl)=CC=C1Cl XYCMOTOFHFTUIU-UHFFFAOYSA-N 0.000 description 2
- 229960005315 clorexolone Drugs 0.000 description 2
- 229960001261 cloridarol Drugs 0.000 description 2
- KBFBRIPYVVGWRS-UHFFFAOYSA-N cloridarol Chemical compound C=1C2=CC=CC=C2OC=1C(O)C1=CC=C(Cl)C=C1 KBFBRIPYVVGWRS-UHFFFAOYSA-N 0.000 description 2
- 229960001307 clorindione Drugs 0.000 description 2
- NJDUWAXIURWWLN-UHFFFAOYSA-N clorindione Chemical compound C1=CC(Cl)=CC=C1C1C(=O)C2=CC=CC=C2C1=O NJDUWAXIURWWLN-UHFFFAOYSA-N 0.000 description 2
- 229950011462 clorprenaline Drugs 0.000 description 2
- 239000000701 coagulant Substances 0.000 description 2
- GMRWGQCZJGVHKL-UHFFFAOYSA-N colestipol Chemical compound ClCC1CO1.NCCNCCNCCNCCN GMRWGQCZJGVHKL-UHFFFAOYSA-N 0.000 description 2
- 229960002604 colestipol Drugs 0.000 description 2
- 229960002424 collagenase Drugs 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- HULMNSIAKWANQO-JQKSAQOKSA-N convallatoxin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)CC[C@@H]3[C@@]2(C=O)CC1 HULMNSIAKWANQO-JQKSAQOKSA-N 0.000 description 2
- 230000027326 copulation Effects 0.000 description 2
- BUCJFFQZPGTGPX-UHFFFAOYSA-N coumetarol Chemical compound C1=CC=C2OC(=O)C(C(C=3C(OC4=CC=CC=C4C=3O)=O)COC)=C(O)C2=C1 BUCJFFQZPGTGPX-UHFFFAOYSA-N 0.000 description 2
- 229950001111 coumetarol Drugs 0.000 description 2
- 238000011262 co‐therapy Methods 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 229950002423 cyclocoumarol Drugs 0.000 description 2
- 229960003176 cyclothiazide Drugs 0.000 description 2
- BOCUKUHCLICSIY-QJWLJZLASA-N cyclothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2C1[C@H](C=C2)C[C@H]2C1 BOCUKUHCLICSIY-QJWLJZLASA-N 0.000 description 2
- 229960003083 cymarin Drugs 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- DKRSEIPLAZTSFD-UHFFFAOYSA-N d-quinotoxine Natural products C12=CC(OC)=CC=C2N=CC=C1C(=O)CCC1CCNCC1C=C DKRSEIPLAZTSFD-UHFFFAOYSA-N 0.000 description 2
- 229950008150 daltroban Drugs 0.000 description 2
- RFWZESUMWJKKRN-UHFFFAOYSA-N dapiprazole Chemical compound CC1=CC=CC=C1N1CCN(CCC=2N3CCCCC3=NN=2)CC1 RFWZESUMWJKKRN-UHFFFAOYSA-N 0.000 description 2
- 229960002947 dapiprazole Drugs 0.000 description 2
- FEJVSJIALLTFRP-LJQANCHMSA-N darusentan Chemical compound COC1=CC(OC)=NC(O[C@H](C(O)=O)C(OC)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 FEJVSJIALLTFRP-LJQANCHMSA-N 0.000 description 2
- 229950008833 darusentan Drugs 0.000 description 2
- OBATZBGFDSVCJD-UHFFFAOYSA-N de-O-acetyl-lanatoside C Natural products CC1OC(OC2CC3C(C4C(C5(CCC(C5(C)C(O)C4)C=4COC(=O)C=4)O)CC3)(C)CC2)CC(O)C1OC(OC1C)CC(O)C1OC(OC1C)CC(O)C1OC1OC(CO)C(O)C(O)C1O OBATZBGFDSVCJD-UHFFFAOYSA-N 0.000 description 2
- JWPGJSVJDAJRLW-UHFFFAOYSA-N debrisoquin Chemical compound C1=CC=C2CN(C(=N)N)CCC2=C1 JWPGJSVJDAJRLW-UHFFFAOYSA-N 0.000 description 2
- 229960004096 debrisoquine Drugs 0.000 description 2
- 229960004120 defibrotide Drugs 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 229960001993 deserpidine Drugs 0.000 description 2
- ISMCNVNDWFIXLM-WCGOZPBSSA-N deserpidine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 ISMCNVNDWFIXLM-WCGOZPBSSA-N 0.000 description 2
- 229960001324 deslanoside Drugs 0.000 description 2
- OBATZBGFDSVCJD-LALPQLPRSA-N deslanoside Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@@H]1C)O[C@H]1[C@@H](O)C[C@@H](O[C@@H]1C)O[C@H]1[C@@H](O)C[C@@H](O[C@@H]1C)O[C@@H]1C[C@@H]2[C@]([C@@H]3[C@H]([C@]4(CC[C@@H]([C@@]4(C)[C@H](O)C3)C=3COC(=O)C=3)O)CC2)(C)CC1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O OBATZBGFDSVCJD-LALPQLPRSA-N 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 230000035487 diastolic blood pressure Effects 0.000 description 2
- DOBMPNYZJYQDGZ-UHFFFAOYSA-N dicoumarol Chemical compound C1=CC=CC2=C1OC(=O)C(CC=1C(OC3=CC=CC=C3C=1O)=O)=C2O DOBMPNYZJYQDGZ-UHFFFAOYSA-N 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- CKNOLMVLQUPVMU-YMMLYESFSA-N digitalin Chemical compound C1([C@@H]2[C@@]3(C)CC[C@H]4[C@H]([C@]3(C[C@@H]2O)O)CC[C@H]2[C@]4(C)CC[C@@H](C2)O[C@H]2[C@H](O)[C@H]([C@H]([C@@H](C)O2)O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)OC)=CC(=O)OC1 CKNOLMVLQUPVMU-YMMLYESFSA-N 0.000 description 2
- 229950004590 digitalin Drugs 0.000 description 2
- 229960002877 dihydralazine Drugs 0.000 description 2
- VQKLRVZQQYVIJW-UHFFFAOYSA-N dihydralazine Chemical compound C1=CC=C2C(NN)=NN=C(NN)C2=C1 VQKLRVZQQYVIJW-UHFFFAOYSA-N 0.000 description 2
- 229960001079 dilazep Drugs 0.000 description 2
- 229960004166 diltiazem Drugs 0.000 description 2
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- ZOMNIUBKTOKEHS-UHFFFAOYSA-L dimercury dichloride Chemical compound Cl[Hg][Hg]Cl ZOMNIUBKTOKEHS-UHFFFAOYSA-L 0.000 description 2
- 229960002547 dimetofrine Drugs 0.000 description 2
- ZKGDBJAHIIXDDW-UHFFFAOYSA-N dimetofrine Chemical compound CNCC(O)C1=CC(OC)=C(O)C(OC)=C1 ZKGDBJAHIIXDDW-UHFFFAOYSA-N 0.000 description 2
- OHDICGSRVLBVLC-UHFFFAOYSA-N dioxethedrin Chemical compound CCNC(C)C(O)C1=CC=C(O)C(O)=C1 OHDICGSRVLBVLC-UHFFFAOYSA-N 0.000 description 2
- 229950005373 dioxethedrin Drugs 0.000 description 2
- 229960000267 diphenadione Drugs 0.000 description 2
- RQXWFEXQGWCOGQ-UHFFFAOYSA-K disodium;carboxylatomethylsulfanyl-[3-[(3-carboxylato-2,2,3-trimethylcyclopentanecarbonyl)amino]-2-methoxypropyl]mercury Chemical compound [Na+].[Na+].[O-]C(=O)CS[Hg]CC(OC)CNC(=O)C1CCC(C)(C([O-])=O)C1(C)C RQXWFEXQGWCOGQ-UHFFFAOYSA-K 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- RCFKEIREOSXLET-UHFFFAOYSA-N disulfamide Chemical compound CC1=CC(Cl)=C(S(N)(=O)=O)C=C1S(N)(=O)=O RCFKEIREOSXLET-UHFFFAOYSA-N 0.000 description 2
- 229950008177 disulfamide Drugs 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- HTAFVGKAHGNWQO-UHFFFAOYSA-N droprenilamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)CCNC(C)CC1CCCCC1 HTAFVGKAHGNWQO-UHFFFAOYSA-N 0.000 description 2
- 229950011072 droprenilamine Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 229960003859 efloxate Drugs 0.000 description 2
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 229960002680 enalaprilat Drugs 0.000 description 2
- LZFZMUMEGBBDTC-QEJZJMRPSA-N enalaprilat (anhydrous) Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 LZFZMUMEGBBDTC-QEJZJMRPSA-N 0.000 description 2
- 229960001142 encainide Drugs 0.000 description 2
- 230000002124 endocrine Effects 0.000 description 2
- 229960002029 endralazine Drugs 0.000 description 2
- ALAXZYHFVBSJKZ-UHFFFAOYSA-N endralazine Chemical compound C1CC=2N=NC(NN)=CC=2CN1C(=O)C1=CC=CC=C1 ALAXZYHFVBSJKZ-UHFFFAOYSA-N 0.000 description 2
- 229960000610 enoxaparin Drugs 0.000 description 2
- 229960000972 enoximone Drugs 0.000 description 2
- ZJKNESGOIKRXQY-UHFFFAOYSA-N enoximone Chemical compound C1=CC(SC)=CC=C1C(=O)C1=C(C)NC(=O)N1 ZJKNESGOIKRXQY-UHFFFAOYSA-N 0.000 description 2
- GLCKXJLCYIJMRB-UPRLRBBYSA-N enrasentan Chemical compound C1([C@H]2[C@@H]([C@H](C3=CC=C(C=C32)OCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1OCCO GLCKXJLCYIJMRB-UPRLRBBYSA-N 0.000 description 2
- 229950006561 enrasentan Drugs 0.000 description 2
- 229960002179 ephedrine Drugs 0.000 description 2
- RINBGYCKMGDWPY-UHFFFAOYSA-N epitizide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(CSCC(F)(F)F)NS2(=O)=O RINBGYCKMGDWPY-UHFFFAOYSA-N 0.000 description 2
- 229960004563 eprosartan Drugs 0.000 description 2
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 description 2
- 229960003199 etacrynic acid Drugs 0.000 description 2
- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 description 2
- IRVLBORJKFZWMI-JQWIXIFHSA-N etafedrine Chemical compound CCN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 IRVLBORJKFZWMI-JQWIXIFHSA-N 0.000 description 2
- 229950002456 etafedrine Drugs 0.000 description 2
- 238000012869 ethanol precipitation Methods 0.000 description 2
- OUZWUKMCLIBBOG-UHFFFAOYSA-N ethoxzolamide Chemical compound CCOC1=CC=C2N=C(S(N)(=O)=O)SC2=C1 OUZWUKMCLIBBOG-UHFFFAOYSA-N 0.000 description 2
- 229950005098 ethoxzolamide Drugs 0.000 description 2
- UPCIBFUJJLCOQG-UHFFFAOYSA-L ethyl-[2-[2-[ethyl(dimethyl)azaniumyl]ethyl-methylamino]ethyl]-dimethylazanium;dibromide Chemical compound [Br-].[Br-].CC[N+](C)(C)CCN(C)CC[N+](C)(C)CC UPCIBFUJJLCOQG-UHFFFAOYSA-L 0.000 description 2
- WNKCJOWTKXGERE-UHFFFAOYSA-N etifelmine Chemical compound C=1C=CC=CC=1C(=C(CN)CC)C1=CC=CC=C1 WNKCJOWTKXGERE-UHFFFAOYSA-N 0.000 description 2
- 229950005475 etifelmine Drugs 0.000 description 2
- 229960004695 etilefrine Drugs 0.000 description 2
- 229960003501 etofibrate Drugs 0.000 description 2
- XXRVYAFBUDSLJX-UHFFFAOYSA-N etofibrate Chemical compound C=1C=CN=CC=1C(=O)OCCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 XXRVYAFBUDSLJX-UHFFFAOYSA-N 0.000 description 2
- KYAKGJDISSNVPZ-UHFFFAOYSA-N etofylline clofibrate Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KYAKGJDISSNVPZ-UHFFFAOYSA-N 0.000 description 2
- 229950009036 etofylline clofibrate Drugs 0.000 description 2
- 229960004514 etozolin Drugs 0.000 description 2
- ZCKKHYXUQFTBIK-KTKRTIGZSA-N etozoline Chemical compound O=C1N(C)C(=C/C(=O)OCC)/SC1N1CCCCC1 ZCKKHYXUQFTBIK-KTKRTIGZSA-N 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- DOBLSWXRNYSVDC-UHFFFAOYSA-N fenalcomine Chemical compound C1=CC(C(O)CC)=CC=C1OCCNC(C)CC1=CC=CC=C1 DOBLSWXRNYSVDC-UHFFFAOYSA-N 0.000 description 2
- 229950009129 fenalcomine Drugs 0.000 description 2
- 229960002297 fenofibrate Drugs 0.000 description 2
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 2
- 229960002724 fenoldopam Drugs 0.000 description 2
- TVURRHSHRRELCG-UHFFFAOYSA-N fenoldopam Chemical compound C1=CC(O)=CC=C1C1C2=CC(O)=C(O)C(Cl)=C2CCNC1 TVURRHSHRRELCG-UHFFFAOYSA-N 0.000 description 2
- 229960001022 fenoterol Drugs 0.000 description 2
- 229960002912 fenspiride Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229960000449 flecainide Drugs 0.000 description 2
- MXVLJFCCQMXEEE-UHFFFAOYSA-N floredil Chemical compound CCOC1=CC(OCC)=CC(OCCN2CCOCC2)=C1 MXVLJFCCQMXEEE-UHFFFAOYSA-N 0.000 description 2
- 229950011336 floredil Drugs 0.000 description 2
- 229960001606 flosequinan Drugs 0.000 description 2
- UYGONJYYUKVHDD-UHFFFAOYSA-N flosequinan Chemical compound C1=C(F)C=C2N(C)C=C(S(C)=O)C(=O)C2=C1 UYGONJYYUKVHDD-UHFFFAOYSA-N 0.000 description 2
- 229960005298 fluindione Drugs 0.000 description 2
- NASXCEITKQITLD-UHFFFAOYSA-N fluindione Chemical compound C1=CC(F)=CC=C1C1C(=O)C2=CC=CC=C2C1=O NASXCEITKQITLD-UHFFFAOYSA-N 0.000 description 2
- SMANXXCATUTDDT-QPJJXVBHSA-N flunarizine Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)N1CCN(C\C=C\C=2C=CC=CC=2)CC1 SMANXXCATUTDDT-QPJJXVBHSA-N 0.000 description 2
- 229960000326 flunarizine Drugs 0.000 description 2
- 229960002848 formoterol Drugs 0.000 description 2
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 2
- 229950010710 furazabol Drugs 0.000 description 2
- 229950001523 furterene Drugs 0.000 description 2
- 229960000457 gallopamil Drugs 0.000 description 2
- 229950008114 ganglefene Drugs 0.000 description 2
- 230000000574 ganglionic effect Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 229960003627 gemfibrozil Drugs 0.000 description 2
- 238000001476 gene delivery Methods 0.000 description 2
- 229960005059 gepefrine Drugs 0.000 description 2
- WTDGMHYYGNJEKQ-ZETCQYMHSA-N gepefrine Chemical compound C[C@H](N)CC1=CC=CC(O)=C1 WTDGMHYYGNJEKQ-ZETCQYMHSA-N 0.000 description 2
- 210000004602 germ cell Anatomy 0.000 description 2
- 229940118313 gitalin Drugs 0.000 description 2
- LKRDZKPBAOKJBT-CNPIRKNPSA-N gitoxin 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(C[C@H](O)[C@@H]([C@@]6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LKRDZKPBAOKJBT-CNPIRKNPSA-N 0.000 description 2
- 229950000974 gitoxin Drugs 0.000 description 2
- WQVAYGCXSJMPRT-UHFFFAOYSA-N guanacline Chemical compound CC1=CCN(CCN=C(N)N)CC1 WQVAYGCXSJMPRT-UHFFFAOYSA-N 0.000 description 2
- 229950006795 guanacline Drugs 0.000 description 2
- HPBNRIOWIXYZFK-UHFFFAOYSA-N guanadrel Chemical compound O1C(CNC(=N)N)COC11CCCCC1 HPBNRIOWIXYZFK-UHFFFAOYSA-N 0.000 description 2
- 229960003845 guanadrel Drugs 0.000 description 2
- 229960004614 guanazodine Drugs 0.000 description 2
- ZCVAIGPGEINFCX-UHFFFAOYSA-N guanazodine Chemical compound NC(=N)NCC1CCCCCCN1 ZCVAIGPGEINFCX-UHFFFAOYSA-N 0.000 description 2
- XIHXRRMCNSMUET-UHFFFAOYSA-N guanoclor Chemical compound NC(=N)NNCCOC1=C(Cl)C=CC=C1Cl XIHXRRMCNSMUET-UHFFFAOYSA-N 0.000 description 2
- 229960001016 guanoxabenz Drugs 0.000 description 2
- QKIQJNNDIWGVEH-UUILKARUSA-N guanoxabenz Chemical compound ONC(/N)=N/N=C/C1=C(Cl)C=CC=C1Cl QKIQJNNDIWGVEH-UUILKARUSA-N 0.000 description 2
- 229960000760 guanoxan Drugs 0.000 description 2
- HIUVKVDQFXDZHU-UHFFFAOYSA-N guanoxan Chemical compound C1=CC=C2OC(CNC(=N)N)COC2=C1 HIUVKVDQFXDZHU-UHFFFAOYSA-N 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 229960005402 heptaminol Drugs 0.000 description 2
- 229950002932 hexamethonium Drugs 0.000 description 2
- 229960002212 hexobendine Drugs 0.000 description 2
- KRQAMFQCSAJCRH-UHFFFAOYSA-N hexobendine Chemical compound COC1=C(OC)C(OC)=CC(C(=O)OCCCN(C)CCN(C)CCCOC(=O)C=2C=C(OC)C(OC)=C(OC)C=2)=C1 KRQAMFQCSAJCRH-UHFFFAOYSA-N 0.000 description 2
- 229960000708 hexoprenaline Drugs 0.000 description 2
- OXLZNBCNGJWPRV-UHFFFAOYSA-N hexoprenaline Chemical compound C=1C=C(O)C(O)=CC=1C(O)CNCCCCCCNCC(O)C1=CC=C(O)C(O)=C1 OXLZNBCNGJWPRV-UHFFFAOYSA-N 0.000 description 2
- 239000012145 high-salt buffer Substances 0.000 description 2
- 229940006607 hirudin Drugs 0.000 description 2
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 2
- 238000010231 histologic analysis Methods 0.000 description 2
- YOJQZPVUNUQTDF-UHFFFAOYSA-N hydrastinine Chemical compound C1=C2C(O)N(C)CCC2=CC2=C1OCO2 YOJQZPVUNUQTDF-UHFFFAOYSA-N 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 238000007901 in situ hybridization Methods 0.000 description 2
- UCEWGESNIULAGX-UHFFFAOYSA-N indecainide Chemical compound C1=CC=C2C(CCCNC(C)C)(C(N)=O)C3=CC=CC=C3C2=C1 UCEWGESNIULAGX-UHFFFAOYSA-N 0.000 description 2
- 229950004448 indecainide Drugs 0.000 description 2
- 229940095990 inderal Drugs 0.000 description 2
- 230000000053 inderal effect Effects 0.000 description 2
- 229960002056 indoramin Drugs 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 230000000297 inotrophic effect Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229960002198 irbesartan Drugs 0.000 description 2
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- 229940039009 isoproterenol Drugs 0.000 description 2
- 229940093268 isordil Drugs 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 229940072289 kerlone Drugs 0.000 description 2
- FPCCSQOGAWCVBH-UHFFFAOYSA-N ketanserin Chemical compound C1=CC(F)=CC=C1C(=O)C1CCN(CCN2C(C3=CC=CC=C3NC2=O)=O)CC1 FPCCSQOGAWCVBH-UHFFFAOYSA-N 0.000 description 2
- 229960005417 ketanserin Drugs 0.000 description 2
- HSMPDPBYAYSOBC-UHFFFAOYSA-N khellin Chemical compound O1C(C)=CC(=O)C2=C1C(OC)=C1OC=CC1=C2OC HSMPDPBYAYSOBC-UHFFFAOYSA-N 0.000 description 2
- 229960002801 khellin Drugs 0.000 description 2
- 210000003292 kidney cell Anatomy 0.000 description 2
- 230000003907 kidney function Effects 0.000 description 2
- 101150066555 lacZ gene Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229960000831 levobunolol Drugs 0.000 description 2
- IXHBTMCLRNMKHZ-LBPRGKRZSA-N levobunolol Chemical compound O=C1CCCC2=C1C=CC=C2OC[C@@H](O)CNC(C)(C)C IXHBTMCLRNMKHZ-LBPRGKRZSA-N 0.000 description 2
- 230000037356 lipid metabolism Effects 0.000 description 2
- 239000006193 liquid solution Substances 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- KSMAGQUYOIHWFS-UHFFFAOYSA-N lofexidine Chemical compound N=1CCNC=1C(C)OC1=C(Cl)C=CC=C1Cl KSMAGQUYOIHWFS-UHFFFAOYSA-N 0.000 description 2
- 229960005209 lofexidine Drugs 0.000 description 2
- 229960001725 lorajmine Drugs 0.000 description 2
- LAHDERDHXJFFJU-ZWNKPRIXSA-N lorajmine Chemical compound CN([C@H]1[C@@H]2C3)C4=CC=CC=C4[C@]11C[C@@H]4N2[C@H](O)[C@@H](CC)[C@H]3[C@@H]4[C@H]1OC(=O)CCl LAHDERDHXJFFJU-ZWNKPRIXSA-N 0.000 description 2
- 229960001074 lorcainide Drugs 0.000 description 2
- XHOJAWVAWFHGHL-UHFFFAOYSA-N lorcainide Chemical compound C1CN(C(C)C)CCC1N(C=1C=CC(Cl)=CC=1)C(=O)CC1=CC=CC=C1 XHOJAWVAWFHGHL-UHFFFAOYSA-N 0.000 description 2
- 229960004773 losartan Drugs 0.000 description 2
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 2
- 229960004844 lovastatin Drugs 0.000 description 2
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 2
- JSJCTEKTBOKRST-UHFFFAOYSA-N mabuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(C(F)(F)F)=C1 JSJCTEKTBOKRST-UHFFFAOYSA-N 0.000 description 2
- 229950004407 mabuterol Drugs 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 206010025482 malaise Diseases 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229960004119 mebutamate Drugs 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- ORAUEDBBTFLQSK-UHFFFAOYSA-N medibazine Chemical compound C=1C=C2OCOC2=CC=1CN(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 ORAUEDBBTFLQSK-UHFFFAOYSA-N 0.000 description 2
- 229950000437 medibazine Drugs 0.000 description 2
- 229960004678 mefruside Drugs 0.000 description 2
- 229960001961 meglutol Drugs 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- SPLVKBMIQSSFFN-UHFFFAOYSA-N meobentine Chemical compound CNC(=NC)NCC1=CC=C(OC)C=C1 SPLVKBMIQSSFFN-UHFFFAOYSA-N 0.000 description 2
- 229950009531 meobentine Drugs 0.000 description 2
- HXYLKKGRIDSMFL-UHFFFAOYSA-N meralluride Chemical compound O.COC(C[Hg])CNC(=O)NC(=O)CCC(O)=O HXYLKKGRIDSMFL-UHFFFAOYSA-N 0.000 description 2
- 229950005795 meralluride Drugs 0.000 description 2
- 229960000224 mersalyl Drugs 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- LMOINURANNBYCM-UHFFFAOYSA-N metaproterenol Chemical compound CC(C)NCC(O)C1=CC(O)=CC(O)=C1 LMOINURANNBYCM-UHFFFAOYSA-N 0.000 description 2
- 229960003663 metaraminol Drugs 0.000 description 2
- FLOSMHQXBMRNHR-DAXSKMNVSA-N methazolamide Chemical compound CC(=O)\N=C1/SC(S(N)(=O)=O)=NN1C FLOSMHQXBMRNHR-DAXSKMNVSA-N 0.000 description 2
- 229960004083 methazolamide Drugs 0.000 description 2
- OEHAYUOVELTAPG-UHFFFAOYSA-N methoxyphenamine Chemical compound CNC(C)CC1=CC=CC=C1OC OEHAYUOVELTAPG-UHFFFAOYSA-N 0.000 description 2
- 229960005405 methoxyphenamine Drugs 0.000 description 2
- COAPCKUZMKOWBC-ZEJGPHSTSA-N methyl (1s,4ar,4bs,7e,8r,8as,9s,10ar)-9-hydroxy-1,4a,8-trimethyl-7-[2-[2-(methylamino)ethoxy]-2-oxoethylidene]-3,4,4b,5,6,8,8a,9,10,10a-decahydro-2h-phenanthrene-1-carboxylate Chemical compound [C@H]1([C@@](CCC2)(C)C(=O)OC)[C@@]2(C)[C@H]2CC\C(=C/C(=O)OCCNC)[C@H](C)[C@@H]2[C@@H](O)C1 COAPCKUZMKOWBC-ZEJGPHSTSA-N 0.000 description 2
- ZOSQTCOGKFRDET-UHFFFAOYSA-L methyl sulfate;trimethyl-[3-(3,5,8,8-tetramethyl-3-azoniabicyclo[3.2.1]octan-3-yl)propyl]azanium Chemical compound COS([O-])(=O)=O.COS([O-])(=O)=O.C1[N+](C)(CCC[N+](C)(C)C)CC2(C)CCC1C2(C)C ZOSQTCOGKFRDET-UHFFFAOYSA-L 0.000 description 2
- 229950005579 metochalcone Drugs 0.000 description 2
- VLPIATFUUWWMKC-UHFFFAOYSA-N mexiletine Chemical compound CC(N)COC1=C(C)C=CC=C1C VLPIATFUUWWMKC-UHFFFAOYSA-N 0.000 description 2
- 229960003404 mexiletine Drugs 0.000 description 2
- 108091049773 miR-14 stem-loop Proteins 0.000 description 2
- 229960004438 mibefradil Drugs 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 239000004531 microgranule Substances 0.000 description 2
- 229960001094 midodrine Drugs 0.000 description 2
- 229960003574 milrinone Drugs 0.000 description 2
- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 description 2
- 238000007479 molecular analysis Methods 0.000 description 2
- 229960002608 moracizine Drugs 0.000 description 2
- 230000002969 morbid Effects 0.000 description 2
- FUBVWMNBEHXPSU-UHFFFAOYSA-N moricizine Chemical compound C12=CC(NC(=O)OCC)=CC=C2SC2=CC=CC=C2N1C(=O)CCN1CCOCC1 FUBVWMNBEHXPSU-UHFFFAOYSA-N 0.000 description 2
- 210000000107 myocyte Anatomy 0.000 description 2
- OOVXZFCPCSVSEM-NADOGSGZSA-N mytatrienediol Chemical compound C1C[C@]2(C)[C@@H](O)[C@@](C)(O)C[C@H]2[C@@H]2CCC3=CC(OC)=CC=C3[C@H]21 OOVXZFCPCSVSEM-NADOGSGZSA-N 0.000 description 2
- QPHACUMLBDXKIF-UHFFFAOYSA-M n,n-diethyl-1-methylpyridin-1-ium-3-carboxamide;4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptane-2-sulfonate Chemical compound CCN(CC)C(=O)C1=CC=C[N+](C)=C1.C1CC2(C)C(=O)C(S([O-])(=O)=O)C1C2(C)C QPHACUMLBDXKIF-UHFFFAOYSA-M 0.000 description 2
- HHRNQOGXBRYCHF-UHFFFAOYSA-N n-[2-hydroxy-5-[1-hydroxy-2-(propan-2-ylamino)ethyl]phenyl]methanesulfonamide Chemical compound CC(C)NCC(O)C1=CC=C(O)C(NS(C)(=O)=O)=C1 HHRNQOGXBRYCHF-UHFFFAOYSA-N 0.000 description 2
- TUYWTLTWNJOZNY-UHFFFAOYSA-N n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(2h-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]-5-propan-2-ylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C2=NNN=N2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 TUYWTLTWNJOZNY-UHFFFAOYSA-N 0.000 description 2
- UPZVYDSBLFNMLK-UHFFFAOYSA-N nadoxolol Chemical compound C1=CC=C2C(OCC(O)CC(/N)=N/O)=CC=CC2=C1 UPZVYDSBLFNMLK-UHFFFAOYSA-N 0.000 description 2
- 229960004501 nadoxolol Drugs 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 239000000692 natriuretic peptide Substances 0.000 description 2
- 229960003642 nicergoline Drugs 0.000 description 2
- 229960000827 niceritrol Drugs 0.000 description 2
- XPPXHQUWVYMTDM-UHFFFAOYSA-N nicoclonate Chemical compound C=1C=C(Cl)C=CC=1C(C(C)C)OC(=O)C1=CC=CN=C1 XPPXHQUWVYMTDM-UHFFFAOYSA-N 0.000 description 2
- 229950011138 nicoclonate Drugs 0.000 description 2
- RARQHAFNGNPQCZ-UHFFFAOYSA-N nicofibrate Chemical compound C=1C=CN=CC=1COC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 RARQHAFNGNPQCZ-UHFFFAOYSA-N 0.000 description 2
- 229950005171 nicofibrate Drugs 0.000 description 2
- 229950001071 nicomol Drugs 0.000 description 2
- UAORFCGRZIGNCI-UHFFFAOYSA-N nifenalol Chemical compound CC(C)NCC(O)C1=CC=C([N+]([O-])=O)C=C1 UAORFCGRZIGNCI-UHFFFAOYSA-N 0.000 description 2
- 229950000096 nifenalol Drugs 0.000 description 2
- 229960005366 nilvadipine Drugs 0.000 description 2
- 229960000715 nimodipine Drugs 0.000 description 2
- 229960002460 nitroprusside Drugs 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 229960002657 orciprenaline Drugs 0.000 description 2
- 229940082615 organic nitrates used in cardiac disease Drugs 0.000 description 2
- 229960003104 ornithine Drugs 0.000 description 2
- 229960003343 ouabain Drugs 0.000 description 2
- 229950001773 oxazidione Drugs 0.000 description 2
- 229960003684 oxedrine Drugs 0.000 description 2
- FJCFFCXMEXZEIM-UHFFFAOYSA-N oxiniacic acid Chemical compound OC(=O)C1=CC=C[N+]([O-])=C1 FJCFFCXMEXZEIM-UHFFFAOYSA-N 0.000 description 2
- 229950005065 oxiniacic acid Drugs 0.000 description 2
- SHZKQBHERIJWAO-AATRIKPKSA-N ozagrel Chemical compound C1=CC(/C=C/C(=O)O)=CC=C1CN1C=NC=C1 SHZKQBHERIJWAO-AATRIKPKSA-N 0.000 description 2
- 229950003837 ozagrel Drugs 0.000 description 2
- BJRNKVDFDLYUGJ-UHFFFAOYSA-N p-hydroxyphenyl beta-D-alloside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-UHFFFAOYSA-N 0.000 description 2
- 229960003357 pamabrom Drugs 0.000 description 2
- DJWYOLJPSHDSAL-ROUUACIJSA-N pantethine Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO DJWYOLJPSHDSAL-ROUUACIJSA-N 0.000 description 2
- 229960000903 pantethine Drugs 0.000 description 2
- 235000008975 pantethine Nutrition 0.000 description 2
- 239000011581 pantethine Substances 0.000 description 2
- 229960001779 pargyline Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229950009414 pempidine Drugs 0.000 description 2
- 229960004321 pentaerithrityl tetranitrate Drugs 0.000 description 2
- XUSPWDAHGXSTHS-UHFFFAOYSA-N pentamethonium Chemical compound C[N+](C)(C)CCCCC[N+](C)(C)C XUSPWDAHGXSTHS-UHFFFAOYSA-N 0.000 description 2
- 229950000494 pentamethonium bromide Drugs 0.000 description 2
- HSMKTIKKPMTUQH-WBPXWQEISA-L pentolinium tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C([O-])=O.OC(=O)[C@H](O)[C@@H](O)C([O-])=O.C1CCC[N+]1(C)CCCCC[N+]1(C)CCCC1 HSMKTIKKPMTUQH-WBPXWQEISA-L 0.000 description 2
- 229950008637 pentolonium Drugs 0.000 description 2
- BRBAEHHXGZRCBK-UHFFFAOYSA-N pentrinitrol Chemical compound [O-][N+](=O)OCC(CO)(CO[N+]([O-])=O)CO[N+]([O-])=O BRBAEHHXGZRCBK-UHFFFAOYSA-N 0.000 description 2
- 229950006286 pentrinitrol Drugs 0.000 description 2
- 235000020030 perry Nutrition 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 229950001512 phenactropinium chloride Drugs 0.000 description 2
- 229960000280 phenindione Drugs 0.000 description 2
- NFBAXHOPROOJAW-UHFFFAOYSA-N phenindione Chemical compound O=C1C2=CC=CC=C2C(=O)C1C1=CC=CC=C1 NFBAXHOPROOJAW-UHFFFAOYSA-N 0.000 description 2
- VXTWEDPZMSVFEF-UHFFFAOYSA-N pheniprazine Chemical compound NNC(C)CC1=CC=CC=C1 VXTWEDPZMSVFEF-UHFFFAOYSA-N 0.000 description 2
- 229950005573 pheniprazine Drugs 0.000 description 2
- 229960001999 phentolamine Drugs 0.000 description 2
- MRBDMNSDAVCSSF-UHFFFAOYSA-N phentolamine Chemical compound C1=CC(C)=CC=C1N(C=1C=C(O)C=CC=1)CC1=NCCN1 MRBDMNSDAVCSSF-UHFFFAOYSA-N 0.000 description 2
- SBUQZKJEOOQSBV-UHFFFAOYSA-N pholedrine Chemical compound CNC(C)CC1=CC=C(O)C=C1 SBUQZKJEOOQSBV-UHFFFAOYSA-N 0.000 description 2
- 229960001029 pholedrine Drugs 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 2
- 229960001006 picotamide Drugs 0.000 description 2
- KYIAWOXNPBANEW-UHFFFAOYSA-N pildralazine Chemical compound CC(O)CN(C)C1=CC=C(NN)N=N1 KYIAWOXNPBANEW-UHFFFAOYSA-N 0.000 description 2
- 229950007220 pildralazine Drugs 0.000 description 2
- CDHVRXOLGDSJGX-UHFFFAOYSA-N pimefylline Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCNCC1=CC=CN=C1 CDHVRXOLGDSJGX-UHFFFAOYSA-N 0.000 description 2
- 229950010919 pimefylline Drugs 0.000 description 2
- 229960002310 pinacidil Drugs 0.000 description 2
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical compound C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 2
- 229950007976 piperoxan Drugs 0.000 description 2
- 229960005414 pirbuterol Drugs 0.000 description 2
- 229960001085 piretanide Drugs 0.000 description 2
- YJBIJSVYPHRVCI-UHFFFAOYSA-N pirifibrate Chemical compound C=1C=CC(CO)=NC=1COC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 YJBIJSVYPHRVCI-UHFFFAOYSA-N 0.000 description 2
- 229950000957 pirifibrate Drugs 0.000 description 2
- 229950008066 pirmenol Drugs 0.000 description 2
- DIIBXMIIOQXTHW-UHFFFAOYSA-N pirozadil Chemical compound COC1=C(OC)C(OC)=CC(C(=O)OCC=2N=C(COC(=O)C=3C=C(OC)C(OC)=C(OC)C=3)C=CC=2)=C1 DIIBXMIIOQXTHW-UHFFFAOYSA-N 0.000 description 2
- 229950008646 pirozadil Drugs 0.000 description 2
- DDDQVDIPBFGVIG-UHFFFAOYSA-N plafibride Chemical compound C1COCCN1CNC(=O)NC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 DDDQVDIPBFGVIG-UHFFFAOYSA-N 0.000 description 2
- 229950010439 plafibride Drugs 0.000 description 2
- 229960005483 polythiazide Drugs 0.000 description 2
- 229920000046 polythiazide Polymers 0.000 description 2
- 229960001749 practolol Drugs 0.000 description 2
- DURULFYMVIFBIR-UHFFFAOYSA-N practolol Chemical compound CC(C)NCC(O)COC1=CC=C(NC(C)=O)C=C1 DURULFYMVIFBIR-UHFFFAOYSA-N 0.000 description 2
- 229960002965 pravastatin Drugs 0.000 description 2
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 2
- 229960004358 prenalterol Drugs 0.000 description 2
- 229960001989 prenylamine Drugs 0.000 description 2
- 229950002277 primaperone Drugs 0.000 description 2
- 229960000244 procainamide Drugs 0.000 description 2
- 229960002288 procaterol Drugs 0.000 description 2
- FKNXQNWAXFXVNW-BLLLJJGKSA-N procaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)[C@@H](NC(C)C)CC FKNXQNWAXFXVNW-BLLLJJGKSA-N 0.000 description 2
- 229960000203 propafenone Drugs 0.000 description 2
- JWHAUXFOSRPERK-UHFFFAOYSA-N propafenone Chemical compound CCCNCC(O)COC1=CC=CC=C1C(=O)CCC1=CC=CC=C1 JWHAUXFOSRPERK-UHFFFAOYSA-N 0.000 description 2
- 229940048914 protamine Drugs 0.000 description 2
- MXRGZXBFSKSZPH-UHFFFAOYSA-N protheobromine Chemical compound O=C1N(CC(O)C)C(=O)N(C)C2=C1N(C)C=N2 MXRGZXBFSKSZPH-UHFFFAOYSA-N 0.000 description 2
- 229950001920 protheobromine Drugs 0.000 description 2
- LUMAEVHDZXIGEP-UHFFFAOYSA-N protokylol Chemical compound C=1C=C2OCOC2=CC=1CC(C)NCC(O)C1=CC=C(O)C(O)=C1 LUMAEVHDZXIGEP-UHFFFAOYSA-N 0.000 description 2
- 229950009066 protokylol Drugs 0.000 description 2
- 210000001147 pulmonary artery Anatomy 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- NCZXKYCNHGRFHE-UHFFFAOYSA-N pyrinoline Chemical compound C=1C=CC=NC=1C(C=1N=CC=CC=1)(O)C(C=C1)=CC1=C(C=1N=CC=CC=1)C1=CC=CC=N1 NCZXKYCNHGRFHE-UHFFFAOYSA-N 0.000 description 2
- 229950006756 pyrinoline Drugs 0.000 description 2
- 239000002510 pyrogen Substances 0.000 description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 2
- 229960001404 quinidine Drugs 0.000 description 2
- 229960004482 quinidine sulfate Drugs 0.000 description 2
- 230000001869 rapid Effects 0.000 description 2
- ZLQMRLSBXKQKMG-UHFFFAOYSA-N rauniticine Natural products COC(=O)C1=CC2CC3N(CCc4c3[nH]c5ccccc45)CC2C(C)O1 ZLQMRLSBXKQKMG-UHFFFAOYSA-N 0.000 description 2
- 238000010223 real-time analysis Methods 0.000 description 2
- 230000002040 relaxant effect Effects 0.000 description 2
- 230000008521 reorganization Effects 0.000 description 2
- 229960002720 reproterol Drugs 0.000 description 2
- WVLAAKXASPCBGT-UHFFFAOYSA-N reproterol Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCCNCC(O)C1=CC(O)=CC(O)=C1 WVLAAKXASPCBGT-UHFFFAOYSA-N 0.000 description 2
- 229950002609 rescimetol Drugs 0.000 description 2
- 229960001965 rescinnamine Drugs 0.000 description 2
- SMSAPZICLFYVJS-QEGASFHISA-N rescinnamine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)\C=C\C1=CC(OC)=C(OC)C(OC)=C1 SMSAPZICLFYVJS-QEGASFHISA-N 0.000 description 2
- ATLJNLYIJOCWJE-UHFFFAOYSA-N resibufogenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C=1C=CC(=O)OC=1 ATLJNLYIJOCWJE-UHFFFAOYSA-N 0.000 description 2
- 108091092562 ribozyme Proteins 0.000 description 2
- 229960000764 rilmenidine Drugs 0.000 description 2
- 229960001457 rimiterol Drugs 0.000 description 2
- IYMMESGOJVNCKV-SKDRFNHKSA-N rimiterol Chemical compound C([C@@H]1[C@@H](O)C=2C=C(O)C(O)=CC=2)CCCN1 IYMMESGOJVNCKV-SKDRFNHKSA-N 0.000 description 2
- IOVGROKTTNBUGK-SJCJKPOMSA-N ritodrine Chemical compound N([C@@H](C)[C@H](O)C=1C=CC(O)=CC=1)CCC1=CC=C(O)C=C1 IOVGROKTTNBUGK-SJCJKPOMSA-N 0.000 description 2
- 229960001634 ritodrine Drugs 0.000 description 2
- 229960000804 ronifibrate Drugs 0.000 description 2
- AYJVGKWCGIYEAK-UHFFFAOYSA-N ronifibrate Chemical compound C=1C=CN=CC=1C(=O)OCCCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 AYJVGKWCGIYEAK-UHFFFAOYSA-N 0.000 description 2
- 229960002052 salbutamol Drugs 0.000 description 2
- PFGWGEPQIUAZME-NXSMLHPHSA-N saralasin Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CNC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)C1=CC=C(O)C=C1 PFGWGEPQIUAZME-NXSMLHPHSA-N 0.000 description 2
- 229960004785 saralasin Drugs 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- NXJOCELNFPGKIV-ARHXXGKOSA-N scillaren A Chemical compound C=1([C@@H]2[C@@]3(C)CC[C@@H]4[C@@]5(C)CC[C@@H](C=C5CC[C@H]4[C@@]3(O)CC2)O[C@@H]2O[C@H]([C@@H]([C@@H](O)[C@H]2O)O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C)C=CC(=O)OC=1 NXJOCELNFPGKIV-ARHXXGKOSA-N 0.000 description 2
- OVUOVMIMOCJILI-KFZANIOBSA-N scillarenin Chemical compound C=1([C@H]2CC[C@]3(O)[C@H]4[C@@H]([C@]5(CC[C@H](O)C=C5CC4)C)CC[C@@]32C)C=CC(=O)OC=1 OVUOVMIMOCJILI-KFZANIOBSA-N 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 229940082552 sectral Drugs 0.000 description 2
- 238000002864 sequence alignment Methods 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 229960004058 simfibrate Drugs 0.000 description 2
- 229960002855 simvastatin Drugs 0.000 description 2
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 2
- 229920002351 sodium apolate Polymers 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- QGGPRJRKWYRGKR-UHFFFAOYSA-M sodium;[3-[[2-(carboxylatomethoxy)benzoyl]amino]-2-methoxypropyl]mercury;hydrate Chemical group O.[Na+].COC(C[Hg])CNC(=O)C1=CC=CC=C1OCC([O-])=O QGGPRJRKWYRGKR-UHFFFAOYSA-M 0.000 description 2
- 229940093252 sorbitrate Drugs 0.000 description 2
- 229950010289 soterenol Drugs 0.000 description 2
- 229960002256 spironolactone Drugs 0.000 description 2
- 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 2
- 238000010561 standard procedure Methods 0.000 description 2
- 229930002534 steroid glycoside Natural products 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 description 2
- XMFCOYRWYYXZMY-UHFFFAOYSA-N sulmazole Chemical compound COC1=CC(S(C)=O)=CC=C1C1=NC2=NC=CC=C2N1 XMFCOYRWYYXZMY-UHFFFAOYSA-N 0.000 description 2
- 229950006153 sulmazole Drugs 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000011477 surgical intervention Methods 0.000 description 2
- 229950006534 syrosingopine Drugs 0.000 description 2
- 229940108485 tenormin Drugs 0.000 description 2
- 229960000195 terbutaline Drugs 0.000 description 2
- UISARWKNNNHPGI-UHFFFAOYSA-N terodiline Chemical compound C=1C=CC=CC=1C(CC(C)NC(C)(C)C)C1=CC=CC=C1 UISARWKNNNHPGI-UHFFFAOYSA-N 0.000 description 2
- 229960005383 terodiline Drugs 0.000 description 2
- 229950000584 tezosentan Drugs 0.000 description 2
- 229960004559 theobromine Drugs 0.000 description 2
- 239000003451 thiazide diuretic agent Substances 0.000 description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 2
- 229940033663 thimerosal Drugs 0.000 description 2
- VRORTNGXAKZJML-UHFFFAOYSA-N thyropropic acid Chemical compound IC1=CC(CCC(=O)O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 VRORTNGXAKZJML-UHFFFAOYSA-N 0.000 description 2
- 229950000464 thyropropic acid Drugs 0.000 description 2
- 229940034208 thyroxine Drugs 0.000 description 2
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 2
- 229960000822 tiadenol Drugs 0.000 description 2
- WRCITXQNXAIKLR-UHFFFAOYSA-N tiadenol Chemical compound OCCSCCCCCCCCCCSCCO WRCITXQNXAIKLR-UHFFFAOYSA-N 0.000 description 2
- CVWILQHZFWRYPB-UHFFFAOYSA-N tiamenidine Chemical compound CC1=CSC(Cl)=C1NC1=NCCN1 CVWILQHZFWRYPB-UHFFFAOYSA-N 0.000 description 2
- 229950000164 tiamenidine Drugs 0.000 description 2
- 229960001060 tioclomarol Drugs 0.000 description 2
- WRGOVNKNTPWHLZ-UHFFFAOYSA-N tioclomarol Chemical compound C=1C=C(Cl)C=CC=1C(O)CC(C=1C(OC2=CC=CC=C2C=1O)=O)C1=CC=C(Cl)S1 WRGOVNKNTPWHLZ-UHFFFAOYSA-N 0.000 description 2
- 229960002872 tocainide Drugs 0.000 description 2
- 229950001089 todralazine Drugs 0.000 description 2
- 229960002312 tolazoline Drugs 0.000 description 2
- JIVZKJJQOZQXQB-UHFFFAOYSA-N tolazoline Chemical compound C=1C=CC=CC=1CC1=NCCN1 JIVZKJJQOZQXQB-UHFFFAOYSA-N 0.000 description 2
- 229960001580 tolonidine Drugs 0.000 description 2
- KWBTZIFLQYYPTH-UHFFFAOYSA-N tolonidine Chemical compound ClC1=CC(C)=CC=C1NC1=NCCN1 KWBTZIFLQYYPTH-UHFFFAOYSA-N 0.000 description 2
- 230000001256 tonic effect Effects 0.000 description 2
- 229960005461 torasemide Drugs 0.000 description 2
- 229940108522 trandate Drugs 0.000 description 2
- 229960000363 trapidil Drugs 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 229960005204 tretoquinol Drugs 0.000 description 2
- RGVPOXRFEPSFGH-AWEZNQCLSA-N tretoquinol Chemical compound COC1=C(OC)C(OC)=CC(C[C@H]2C3=CC(O)=C(O)C=C3CCN2)=C1 RGVPOXRFEPSFGH-AWEZNQCLSA-N 0.000 description 2
- YFDSDPIBEUFTMI-UHFFFAOYSA-N tribromoethanol Chemical compound OCC(Br)(Br)Br YFDSDPIBEUFTMI-UHFFFAOYSA-N 0.000 description 2
- 229950004616 tribromoethanol Drugs 0.000 description 2
- 229960002268 triflusal Drugs 0.000 description 2
- 229960001177 trimetazidine Drugs 0.000 description 2
- 229950005894 trimethidinium methosulfate Drugs 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- SYHDSBBKRLVLFF-UHFFFAOYSA-N triparanol Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(O)(C=1C=CC(C)=CC=1)CC1=CC=C(Cl)C=C1 SYHDSBBKRLVLFF-UHFFFAOYSA-N 0.000 description 2
- 229950005498 triparanol Drugs 0.000 description 2
- 229960000859 tulobuterol Drugs 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 229960001130 urapidil Drugs 0.000 description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 2
- 229960004699 valsartan Drugs 0.000 description 2
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- DKRSEIPLAZTSFD-LSDHHAIUSA-N viquidil Chemical compound C12=CC(OC)=CC=C2N=CC=C1C(=O)CC[C@@H]1CCNC[C@@H]1C=C DKRSEIPLAZTSFD-LSDHHAIUSA-N 0.000 description 2
- 229960003353 viquidil Drugs 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- 239000013603 viral vector Substances 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- IYEPZNKOJZOGJG-UHFFFAOYSA-N xenbucin Chemical compound C1=CC(C(C(O)=O)CC)=CC=C1C1=CC=CC=C1 IYEPZNKOJZOGJG-UHFFFAOYSA-N 0.000 description 2
- 229950005298 xenbucin Drugs 0.000 description 2
- 229940072358 xylocaine Drugs 0.000 description 2
- BLGXFZZNTVWLAY-SCYLSFHTSA-N yohimbine Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-SCYLSFHTSA-N 0.000 description 2
- 229960000317 yohimbine Drugs 0.000 description 2
- AADVZSXPNRLYLV-UHFFFAOYSA-N yohimbine carboxylic acid Natural products C1=CC=C2C(CCN3CC4CCC(C(C4CC33)C(O)=O)O)=C3NC2=C1 AADVZSXPNRLYLV-UHFFFAOYSA-N 0.000 description 2
- CJDRUOGAGYHKKD-XMTJACRCSA-N (+)-Ajmaline Natural products O[C@H]1[C@@H](CC)[C@@H]2[C@@H]3[C@H](O)[C@@]45[C@@H](N(C)c6c4cccc6)[C@@H](N1[C@H]3C5)C2 CJDRUOGAGYHKKD-XMTJACRCSA-N 0.000 description 1
- MXYUKLILVYORSK-UHFFFAOYSA-N (+/-)-allo-lobeline Natural products C1CCC(CC(=O)C=2C=CC=CC=2)N(C)C1CC(O)C1=CC=CC=C1 MXYUKLILVYORSK-UHFFFAOYSA-N 0.000 description 1
- KZJWDPNRJALLNS-VPUBHVLGSA-N (-)-beta-Sitosterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@@H](C(C)C)CC)C)CC4)CC3)CC=2)CC1 KZJWDPNRJALLNS-VPUBHVLGSA-N 0.000 description 1
- MXYUKLILVYORSK-HBMCJLEFSA-N (-)-lobeline Chemical compound C1([C@@H](O)C[C@H]2N([C@H](CCC2)CC(=O)C=2C=CC=CC=2)C)=CC=CC=C1 MXYUKLILVYORSK-HBMCJLEFSA-N 0.000 description 1
- TWUSDDMONZULSC-HZMBPMFUSA-N (1r,2s)-2-(tert-butylamino)-1-(2,5-dimethoxyphenyl)propan-1-ol Chemical compound COC1=CC=C(OC)C([C@@H](O)[C@H](C)NC(C)(C)C)=C1 TWUSDDMONZULSC-HZMBPMFUSA-N 0.000 description 1
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 1
- CSVWWLUMXNHWSU-UHFFFAOYSA-N (22E)-(24xi)-24-ethyl-5alpha-cholest-22-en-3beta-ol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(CC)C(C)C)C1(C)CC2 CSVWWLUMXNHWSU-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- CTNPHHZPAJYPFO-PDXBGNJTSA-N (3s,5s,8r,9s,10s,13r,14s,17r)-3-[(2r,4s,5r,6r)-5-[(2r,3s,4s,5r,6s)-3,4-dihydroxy-6-(hydroxymethyl)-5-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-4-methoxy-6-methyloxan-2-yl]oxy-5,14-dihydroxy-13-methyl-17-(5-oxo-2h-furan Chemical compound C1([C@@H]2[C@@]3(C)CC[C@@H]4[C@@]5(C=O)CC[C@@H](C[C@@]5(O)CC[C@H]4[C@@]3(O)CC2)O[C@H]2C[C@@H]([C@@H]([C@@H](C)O2)O[C@@H]2[C@H]([C@H](O)[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)[C@H](CO)O2)O)OC)=CC(=O)OC1 CTNPHHZPAJYPFO-PDXBGNJTSA-N 0.000 description 1
- STTOCSZNTPWKMI-UHFFFAOYSA-L (5-cyano-5,5-diphenylpentyl)-dimethyl-[2-(4-methylmorpholin-4-ium-4-yl)ethyl]azanium;methyl sulfate Chemical compound COS([O-])(=O)=O.COS([O-])(=O)=O.C1COCC[N+]1(C)CC[N+](C)(C)CCCCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 STTOCSZNTPWKMI-UHFFFAOYSA-L 0.000 description 1
- RWIUTHWKQHRQNP-ZDVGBALWSA-N (9e,12e)-n-(1-phenylethyl)octadeca-9,12-dienamide Chemical compound CCCCC\C=C\C\C=C\CCCCCCCC(=O)NC(C)C1=CC=CC=C1 RWIUTHWKQHRQNP-ZDVGBALWSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- WLRMANUAADYWEA-NWASOUNVSA-N (S)-timolol maleate Chemical compound OC(=O)\C=C/C(O)=O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 WLRMANUAADYWEA-NWASOUNVSA-N 0.000 description 1
- KAJZGRFYZKWYDX-VQHVLOKHSA-N (e)-3-methyl-4-phenylbut-3-enamide Chemical compound NC(=O)CC(/C)=C/C1=CC=CC=C1 KAJZGRFYZKWYDX-VQHVLOKHSA-N 0.000 description 1
- BRIPGNJWPCKDQZ-WXXKFALUSA-N (e)-but-2-enedioic acid;1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol Chemical compound OC(=O)\C=C\C(O)=O.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 BRIPGNJWPCKDQZ-WXXKFALUSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- ZHNFLHYOFXQIOW-AHSOWCEXSA-N (s)-[(2r,4s,5r)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol;sulfuric acid;dihydrate Chemical compound O.O.OS(O)(=O)=O.C([C@H]([C@H](C1)C=C)C2)CN1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21.C([C@H]([C@H](C1)C=C)C2)CN1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 ZHNFLHYOFXQIOW-AHSOWCEXSA-N 0.000 description 1
- KUTGSSTVCUKONV-JWVVETNKSA-N (s)-[(2r,5r)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol;(2s,3r,4s,5r)-2,3,4,5-tetrahydroxy-6-oxohexanoic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O.C1C([C@H](C2)C=C)CCN2[C@H]1[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 KUTGSSTVCUKONV-JWVVETNKSA-N 0.000 description 1
- HGLLQAPXHCAZBP-UHFFFAOYSA-N 1,3-dimethyl-7-(morpholin-4-ylmethyl)purine-2,6-dione Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CN1CCOCC1 HGLLQAPXHCAZBP-UHFFFAOYSA-N 0.000 description 1
- PGHBYDVOOPRPQW-UHFFFAOYSA-N 1,3-dinitrooxypropan-2-yl nitrate Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O.[O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O PGHBYDVOOPRPQW-UHFFFAOYSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- ZZKWNLZUYAGVOT-UHFFFAOYSA-N 1-(2-chlorophenothiazin-10-yl)-3-(diethylamino)propan-1-one Chemical compound C1=C(Cl)C=C2N(C(=O)CCN(CC)CC)C3=CC=CC=C3SC2=C1 ZZKWNLZUYAGVOT-UHFFFAOYSA-N 0.000 description 1
- VVJYUAYZJAKGRQ-BGZDPUMWSA-N 1-[(2r,4r,5s,6r)-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)C1 VVJYUAYZJAKGRQ-BGZDPUMWSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- KZILRTFVGWVPLE-UHFFFAOYSA-N 2,3,3-tris(4-methoxyphenyl)-n,n-dimethylprop-2-en-1-amine;hydrochloride Chemical compound Cl.C1=CC(OC)=CC=C1C(CN(C)C)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 KZILRTFVGWVPLE-UHFFFAOYSA-N 0.000 description 1
- LDGWQMRUWMSZIU-LQDDAWAPSA-M 2,3-bis[(z)-octadec-9-enoxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC LDGWQMRUWMSZIU-LQDDAWAPSA-M 0.000 description 1
- JJFSSNDOOJCPLD-UHFFFAOYSA-N 2-[(2-cyclopropyl-5-methylphenoxy)methyl]-4,5-dihydro-1h-imidazole Chemical compound N=1CCNC=1COC1=CC(C)=CC=C1C1CC1 JJFSSNDOOJCPLD-UHFFFAOYSA-N 0.000 description 1
- MELCWEWUZODSIS-UHFFFAOYSA-N 2-[2-(diethylamino)ethoxy]-n,n-diethylethanamine Chemical compound CCN(CC)CCOCCN(CC)CC MELCWEWUZODSIS-UHFFFAOYSA-N 0.000 description 1
- XQJLGXMAEVIFDR-UHFFFAOYSA-N 2-benzylidenebutanamide Chemical compound CCC(C(N)=O)=CC1=CC=CC=C1 XQJLGXMAEVIFDR-UHFFFAOYSA-N 0.000 description 1
- ILPUOPPYSQEBNJ-UHFFFAOYSA-N 2-methyl-2-phenoxypropanoic acid Chemical compound OC(=O)C(C)(C)OC1=CC=CC=C1 ILPUOPPYSQEBNJ-UHFFFAOYSA-N 0.000 description 1
- KLEXDBGYSOIREE-UHFFFAOYSA-N 24xi-n-propylcholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CCC)C(C)C)C1(C)CC2 KLEXDBGYSOIREE-UHFFFAOYSA-N 0.000 description 1
- 238000011265 2D-echocardiography Methods 0.000 description 1
- OSDHQBPYWITTKO-UHFFFAOYSA-N 2H-1,2,3-benzothiadiazine Chemical compound S1NN=CC2=C1C=CC=C2.S2NN=CC1=C2C=CC=C1 OSDHQBPYWITTKO-UHFFFAOYSA-N 0.000 description 1
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 1
- MGUBQPRSQWCLCX-UHFFFAOYSA-N 3,7-dimethylpurine-2,6-dione Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C.CN1C(=O)NC(=O)C2=C1N=CN2C MGUBQPRSQWCLCX-UHFFFAOYSA-N 0.000 description 1
- VPUNMTHWNSJUOG-XOMUPIDMSA-N 3-[(3s,5r,10s,13r,14s)-3-[(2r,3s,4r,5s,6s)-3,5-dihydroxy-4-methoxy-6-methyloxan-2-yl]oxy-14-hydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]-2h-furan-5-one Chemical compound O[C@H]1[C@H](OC)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@H](CCC2[C@]3(CCC([C@@]3(C)CCC32)C=2COC(=O)C=2)O)[C@]3(C)CC1 VPUNMTHWNSJUOG-XOMUPIDMSA-N 0.000 description 1
- OVUOVMIMOCJILI-UHFFFAOYSA-N 3alpha-Scillarenin Natural products CC12CCC(C3(CCC(O)C=C3CC3)C)C3C1(O)CCC2C=1C=CC(=O)OC=1 OVUOVMIMOCJILI-UHFFFAOYSA-N 0.000 description 1
- PBBGSZCBWVPOOL-HDICACEKSA-N 4-[(1r,2s)-1-ethyl-2-(4-hydroxyphenyl)butyl]phenol Chemical compound C1([C@H](CC)[C@H](CC)C=2C=CC(O)=CC=2)=CC=C(O)C=C1 PBBGSZCBWVPOOL-HDICACEKSA-N 0.000 description 1
- YYAMOMYEENPVSP-UHFFFAOYSA-N 4-[(4-sulfamoylphenyl)methyl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)N)=CC=C1CC1=CC=C(S(N)(=O)=O)C=C1 YYAMOMYEENPVSP-UHFFFAOYSA-N 0.000 description 1
- CPDOMNNHJSTWKL-UHFFFAOYSA-N 4-hydroxy-3-[1-(4-hydroxy-2-oxochromen-3-yl)ethyl]chromen-2-one Chemical compound C1=CC=C2OC(=O)C(C(C=3C(OC4=CC=CC=C4C=3O)=O)C)=C(O)C2=C1 CPDOMNNHJSTWKL-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- 108020005029 5' Flanking Region Proteins 0.000 description 1
- JKOCGAMDKVAHCI-UHFFFAOYSA-N 6,7-Benzocoumarin Chemical compound C1=CC=C2C=C(OC(=O)C=C3)C3=CC2=C1 JKOCGAMDKVAHCI-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- DJQOOSBJCLSSEY-UHFFFAOYSA-N Acipimox Chemical compound CC1=CN=C(C(O)=O)C=[N+]1[O-] DJQOOSBJCLSSEY-UHFFFAOYSA-N 0.000 description 1
- 102000010825 Actinin Human genes 0.000 description 1
- 108010063503 Actinin Proteins 0.000 description 1
- 208000010370 Adenoviridae Infections Diseases 0.000 description 1
- 206010060931 Adenovirus infection Diseases 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- 241000352333 Amegilla alpha Species 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 102100022987 Angiogenin Human genes 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 229940123073 Angiotensin antagonist Drugs 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 102400000345 Angiotensin-2 Human genes 0.000 description 1
- 102000008682 Argonaute Proteins Human genes 0.000 description 1
- 108010088141 Argonaute Proteins Proteins 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 102000005427 Asialoglycoprotein Receptor Human genes 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000000412 Avitaminosis Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000829192 Bos taurus polyomavirus 1 Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000701822 Bovine papillomavirus Species 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 102400000967 Bradykinin Human genes 0.000 description 1
- 241000197194 Bulla Species 0.000 description 1
- 241001260012 Bursa Species 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 1
- OXKVSIKENKOOMZ-UHFFFAOYSA-N CC1=CC=NC(N)=C1.CC1=CC=NC(N)=C1 Chemical compound CC1=CC=NC(N)=C1.CC1=CC=NC(N)=C1 OXKVSIKENKOOMZ-UHFFFAOYSA-N 0.000 description 1
- 102100025238 CD302 antigen Human genes 0.000 description 1
- RFVOIBFBFJXBMP-VGMFFHCQSA-N CN[C@H](C(=O)O)CC1=CC=C(O)C(O)=C1.CN[C@H](C(=O)O)CC1=CC=C(O)C(O)=C1 Chemical compound CN[C@H](C(=O)O)CC1=CC=C(O)C(O)=C1.CN[C@H](C(=O)O)CC1=CC=C(O)C(O)=C1 RFVOIBFBFJXBMP-VGMFFHCQSA-N 0.000 description 1
- 102000004631 Calcineurin Human genes 0.000 description 1
- 108010042955 Calcineurin Proteins 0.000 description 1
- 102000004612 Calcium-Transporting ATPases Human genes 0.000 description 1
- 108010017954 Calcium-Transporting ATPases Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 108090000565 Capsid Proteins Proteins 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 241000490499 Cardamine Species 0.000 description 1
- 206010062746 Carditis Diseases 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 102100023321 Ceruloplasmin Human genes 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000011022 Chorionic Gonadotropin Human genes 0.000 description 1
- 108010062540 Chorionic Gonadotropin Proteins 0.000 description 1
- CVKNDPRBJVBDSS-UHFFFAOYSA-N Cicletanine Chemical compound O1CC2=C(O)C(C)=NC=C2C1C1=CC=C(Cl)C=C1 CVKNDPRBJVBDSS-UHFFFAOYSA-N 0.000 description 1
- LPZCCMIISIBREI-MTFRKTCUSA-N Citrostadienol Natural products CC=C(CC[C@@H](C)[C@H]1CC[C@H]2C3=CC[C@H]4[C@H](C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C LPZCCMIISIBREI-MTFRKTCUSA-N 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 208000001778 Coronary Occlusion Diseases 0.000 description 1
- 206010011086 Coronary artery occlusion Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 238000007399 DNA isolation Methods 0.000 description 1
- 108010008286 DNA nucleotidylexotransferase Proteins 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- ARVGMISWLZPBCH-UHFFFAOYSA-N Dehydro-beta-sitosterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)CCC(CC)C(C)C)CCC33)C)C3=CC=C21 ARVGMISWLZPBCH-UHFFFAOYSA-N 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000032781 Diabetic cardiomyopathy Diseases 0.000 description 1
- 241000208011 Digitalis Species 0.000 description 1
- 240000001879 Digitalis lutea Species 0.000 description 1
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 229940097420 Diuretic Drugs 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- 206010013974 Dyspnoea paroxysmal nocturnal Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 102000001039 Dystrophin Human genes 0.000 description 1
- 108010069091 Dystrophin Proteins 0.000 description 1
- 108700011215 E-Box Elements Proteins 0.000 description 1
- 108091035710 E-box Proteins 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 102100027723 Endogenous retrovirus group K member 6 Rec protein Human genes 0.000 description 1
- 102000048186 Endothelin-converting enzyme 1 Human genes 0.000 description 1
- 108030001679 Endothelin-converting enzyme 1 Proteins 0.000 description 1
- 101710091045 Envelope protein Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010088842 Fibrinolysin Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- OCEDEAQHBIGPTE-UHFFFAOYSA-N Gitoxin Natural products CC1OC(CC(O)C1O)OC2C(O)CC(OC3C(O)CC(OC4CCC5(C)C(CCC6C5CCC7(C)C(C(O)CC67O)C8=CCOC8=O)C4)OC3C)OC2C OCEDEAQHBIGPTE-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000058061 Glucose Transporter Type 4 Human genes 0.000 description 1
- MCSPBPXATWBACD-GAYQJXMFSA-N Guanabenz acetate Chemical compound CC(O)=O.NC(N)=N\N=C\C1=C(Cl)C=CC=C1Cl MCSPBPXATWBACD-GAYQJXMFSA-N 0.000 description 1
- 108020005004 Guide RNA Proteins 0.000 description 1
- 208000035211 Heart Murmurs Diseases 0.000 description 1
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 1
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 206010019842 Hepatomegaly Diseases 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 102100022130 High mobility group protein B3 Human genes 0.000 description 1
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 1
- 101100273718 Homo sapiens CD302 gene Proteins 0.000 description 1
- 101001006375 Homo sapiens High mobility group nucleosome-binding domain-containing protein 4 Proteins 0.000 description 1
- 101001045794 Homo sapiens High mobility group protein B3 Proteins 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 101100344903 Homo sapiens MED13 gene Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 102000002265 Human Growth Hormone Human genes 0.000 description 1
- 108010000521 Human Growth Hormone Proteins 0.000 description 1
- 239000000854 Human Growth Hormone Substances 0.000 description 1
- 241000598436 Human T-cell lymphotropic virus Species 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- LJOQGZACKSYWCH-AFHBHXEDSA-N Hydroquinidine Natural products C1=C(OC)C=C2C([C@@H](O)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 LJOQGZACKSYWCH-AFHBHXEDSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 241000282620 Hylobates sp. Species 0.000 description 1
- 206010020565 Hyperaemia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021135 Hypovitaminosis Diseases 0.000 description 1
- 108700002232 Immediate-Early Genes Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- KLDXJTOLSGUMSJ-JGWLITMVSA-N Isosorbide Chemical compound O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 KLDXJTOLSGUMSJ-JGWLITMVSA-N 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- FHIREUBIEIPPMC-UHFFFAOYSA-N K-Strophanthin-beta Natural products O1C(C)C(OC2C(C(O)C(O)C(CO)O2)O)C(OC)CC1OC(CC1(O)CCC2C3(O)CC4)CCC1(C=O)C2CCC3(C)C4C1=CC(=O)OC1 FHIREUBIEIPPMC-UHFFFAOYSA-N 0.000 description 1
- ZQISRDCJNBUVMM-UHFFFAOYSA-N L-Histidinol Natural products OCC(N)CC1=CN=CN1 ZQISRDCJNBUVMM-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- ZQISRDCJNBUVMM-YFKPBYRVSA-N L-histidinol Chemical compound OC[C@@H](N)CC1=CNC=N1 ZQISRDCJNBUVMM-YFKPBYRVSA-N 0.000 description 1
- 108091026898 Leader sequence (mRNA) Proteins 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 241001625930 Luria Species 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 101150043413 MYH7 gene Proteins 0.000 description 1
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- 108010031099 Mannose Receptor Proteins 0.000 description 1
- PKVZBNCYEICAQP-UHFFFAOYSA-N Mecamylamine hydrochloride Chemical compound Cl.C1CC2C(C)(C)C(NC)(C)C1C2 PKVZBNCYEICAQP-UHFFFAOYSA-N 0.000 description 1
- 102100026161 Mediator of RNA polymerase II transcription subunit 13 Human genes 0.000 description 1
- ABSPRNADVQNDOU-UHFFFAOYSA-N Menaquinone 1 Natural products C1=CC=C2C(=O)C(CC=C(C)C)=C(C)C(=O)C2=C1 ABSPRNADVQNDOU-UHFFFAOYSA-N 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 108091026807 MiR-214 Proteins 0.000 description 1
- 101100496109 Mus musculus Clec2i gene Proteins 0.000 description 1
- 108010074084 Muscle Proteins Proteins 0.000 description 1
- 206010028289 Muscle atrophy Diseases 0.000 description 1
- 206010049565 Muscle fatigue Diseases 0.000 description 1
- 102000036675 Myoglobin Human genes 0.000 description 1
- 108010062374 Myoglobin Proteins 0.000 description 1
- 102100026925 Myosin regulatory light chain 2, ventricular/cardiac muscle isoform Human genes 0.000 description 1
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 1
- 101000783356 Naja sputatrix Cytotoxin Proteins 0.000 description 1
- 108091061960 Naked DNA Proteins 0.000 description 1
- 206010029120 Nephritis allergic Diseases 0.000 description 1
- 102400000064 Neuropeptide Y Human genes 0.000 description 1
- 101800003845 Neuropeptide Y Proteins 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 206010031123 Orthopnoea Diseases 0.000 description 1
- 241001504519 Papio ursinus Species 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000004327 Paroxysmal Dyspnea Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 239000000026 Pentaerythritol tetranitrate Substances 0.000 description 1
- 102000005877 Peptide Initiation Factors Human genes 0.000 description 1
- 108010044843 Peptide Initiation Factors Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 208000000474 Poliomyelitis Diseases 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940123359 Potassium antagonist Drugs 0.000 description 1
- 101710188315 Protein X Proteins 0.000 description 1
- 102000007620 Pulmonary Surfactant-Associated Protein C Human genes 0.000 description 1
- 108010007125 Pulmonary Surfactant-Associated Protein C Proteins 0.000 description 1
- 206010037368 Pulmonary congestion Diseases 0.000 description 1
- YEKQSSHBERGOJK-UHFFFAOYSA-N Pyricarbate Chemical compound CNC(=O)OCC1=CC=CC(COC(=O)NC)=N1 YEKQSSHBERGOJK-UHFFFAOYSA-N 0.000 description 1
- 239000013614 RNA sample Substances 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 208000004531 Renal Artery Obstruction Diseases 0.000 description 1
- 206010038378 Renal artery stenosis Diseases 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- 241001068263 Replication competent viruses Species 0.000 description 1
- 102000009661 Repressor Proteins Human genes 0.000 description 1
- 108010034634 Repressor Proteins Proteins 0.000 description 1
- 208000037656 Respiratory Sounds Diseases 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 239000012722 SDS sample buffer Substances 0.000 description 1
- 108091006300 SLC2A4 Proteins 0.000 description 1
- 241000555745 Sciuridae Species 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 101001081186 Tetrahymena pyriformis High mobility group protein Proteins 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 208000024799 Thyroid disease Diseases 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- GYDJEQRTZSCIOI-UHFFFAOYSA-N Tranexamic acid Chemical compound NCC1CCC(C(O)=O)CC1 GYDJEQRTZSCIOI-UHFFFAOYSA-N 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 102000005937 Tropomyosin Human genes 0.000 description 1
- 108010030743 Tropomyosin Proteins 0.000 description 1
- 102100036859 Troponin I, cardiac muscle Human genes 0.000 description 1
- 101710128251 Troponin I, cardiac muscle Proteins 0.000 description 1
- 102000004987 Troponin T Human genes 0.000 description 1
- 108090001108 Troponin T Proteins 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 1
- 102100039094 Tyrosinase Human genes 0.000 description 1
- 108060008724 Tyrosinase Proteins 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 208000009982 Ventricular Dysfunction Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 description 1
- GVBNSPFBYXGREE-CXWAGAITSA-N Visnadin Chemical compound C1=CC(=O)OC2=C1C=CC1=C2[C@@H](OC(C)=O)[C@@H](OC(=O)[C@H](C)CC)C(C)(C)O1 GVBNSPFBYXGREE-CXWAGAITSA-N 0.000 description 1
- GVBNSPFBYXGREE-UHFFFAOYSA-N Visnadine Natural products C1=CC(=O)OC2=C1C=CC1=C2C(OC(C)=O)C(OC(=O)C(C)CC)C(C)(C)O1 GVBNSPFBYXGREE-UHFFFAOYSA-N 0.000 description 1
- 108010084455 Zeocin Proteins 0.000 description 1
- OEXHQOGQTVQTAT-BZQJJPTISA-N [(1s,5r)-8-methyl-8-propan-2-yl-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate Chemical compound C([C@H]1CC[C@@H](C2)[N+]1(C)C(C)C)C2OC(=O)C(CO)C1=CC=CC=C1 OEXHQOGQTVQTAT-BZQJJPTISA-N 0.000 description 1
- MJOQJPYNENPSSS-XQHKEYJVSA-N [(3r,4s,5r,6s)-4,5,6-triacetyloxyoxan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1CO[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O MJOQJPYNENPSSS-XQHKEYJVSA-N 0.000 description 1
- HNOMCFWTCNOVHP-UHFFFAOYSA-M [3-[(3-carboxy-2,2,3-trimethylcyclopentanecarbonyl)amino]-2-methoxypropyl]mercury(1+) hydroxide Chemical compound COC(CNC(=O)C1CCC(C)(C(O)=O)C1(C)C)C[Hg]O HNOMCFWTCNOVHP-UHFFFAOYSA-M 0.000 description 1
- HMNZFMSWFCAGGW-XPWSMXQVSA-N [3-[hydroxy(2-hydroxyethoxy)phosphoryl]oxy-2-[(e)-octadec-9-enoyl]oxypropyl] (e)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(COP(O)(=O)OCCO)OC(=O)CCCCCCC\C=C\CCCCCCCC HMNZFMSWFCAGGW-XPWSMXQVSA-N 0.000 description 1
- OUHCZCFQVONTOC-UHFFFAOYSA-N [3-acetyloxy-2,2-bis(acetyloxymethyl)propyl] acetate Chemical compound CC(=O)OCC(COC(C)=O)(COC(C)=O)COC(C)=O OUHCZCFQVONTOC-UHFFFAOYSA-N 0.000 description 1
- KNDHRUPPBXRELB-UHFFFAOYSA-M [4-[3-(4-ethylphenyl)butyl]phenyl]-trimethylazanium;chloride Chemical compound [Cl-].C1=CC(CC)=CC=C1C(C)CCC1=CC=C([N+](C)(C)C)C=C1 KNDHRUPPBXRELB-UHFFFAOYSA-M 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 229960003526 acipimox Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940099983 activase Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 201000005180 acute myocarditis Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 208000011589 adenoviridae infectious disease Diseases 0.000 description 1
- 239000000923 adrenergic beta-3 receptor antagonist Substances 0.000 description 1
- 208000019269 advanced heart failure Diseases 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960002414 ambrisentan Drugs 0.000 description 1
- OUJTZYPIHDYQMC-LJQANCHMSA-N ambrisentan Chemical compound O([C@@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-LJQANCHMSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- FRQGJOFRWIILCX-UHFFFAOYSA-N aminoxytriphene Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 FRQGJOFRWIILCX-UHFFFAOYSA-N 0.000 description 1
- 229950009931 aminoxytriphene Drugs 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I 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)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 229960001119 angiotensinamide Drugs 0.000 description 1
- JYPVVOOBQVVUQV-CGHBYZBKSA-N angiotensinamide Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(N)=O)C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 JYPVVOOBQVVUQV-CGHBYZBKSA-N 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000002959 anti-hypotensive effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 150000003975 aryl alkyl amines Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 108010006523 asialoglycoprotein receptor Proteins 0.000 description 1
- 108010084541 asialoorosomucoid Proteins 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229950011524 avosentan Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229950008586 benzalamide Drugs 0.000 description 1
- ZAENXHXQWSDUOG-UHFFFAOYSA-N benzene;iodine Chemical compound [I].C1=CC=CC=C1 ZAENXHXQWSDUOG-UHFFFAOYSA-N 0.000 description 1
- 229960004411 benziodarone Drugs 0.000 description 1
- CZCHIEJNWPNBDE-UHFFFAOYSA-N benziodarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(O)C(I)=C1 CZCHIEJNWPNBDE-UHFFFAOYSA-N 0.000 description 1
- JCSJTDYCNQHPRJ-MMDFAQQLSA-N beta-D-Xylp-(1->4)-beta-D-Xylp-(1->4)-beta-D-Xylp Chemical compound O[C@@H]1[C@@H](O)[C@H](O)CO[C@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)OC2)O)OC1 JCSJTDYCNQHPRJ-MMDFAQQLSA-N 0.000 description 1
- WPIHMWBQRSAMDE-YCZTVTEBSA-N beta-D-galactosyl-(1->4)-beta-D-galactosyl-N-(pentacosanoyl)sphingosine Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO[C@@H]1O[C@H](CO)[C@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O)[C@H](O)\C=C\CCCCCCCCCCCCC WPIHMWBQRSAMDE-YCZTVTEBSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 108010051210 beta-Fructofuranosidase Proteins 0.000 description 1
- MJVXAPPOFPTTCA-UHFFFAOYSA-N beta-Sistosterol Natural products CCC(CCC(C)C1CCC2C3CC=C4C(C)C(O)CCC4(C)C3CCC12C)C(C)C MJVXAPPOFPTTCA-UHFFFAOYSA-N 0.000 description 1
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 1
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 210000002459 blastocyst Anatomy 0.000 description 1
- 208000002352 blister Diseases 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 229960002624 bretylium tosilate Drugs 0.000 description 1
- 229960004895 bretylium tosylate Drugs 0.000 description 1
- 229940097683 brevibloc Drugs 0.000 description 1
- AKLNLVOZXMQGSI-UHFFFAOYSA-N bufetolol Chemical compound CC(C)(C)NCC(O)COC1=CC=CC=C1OCC1OCCC1 AKLNLVOZXMQGSI-UHFFFAOYSA-N 0.000 description 1
- 229950009385 bufetolol Drugs 0.000 description 1
- 229950009770 butaxamine Drugs 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 229940075397 calomel Drugs 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960005003 carbocromen Drugs 0.000 description 1
- KLOIYEQEVSIOOO-UHFFFAOYSA-N carbocromen Chemical compound CC1=C(CCN(CC)CC)C(=O)OC2=CC(OCC(=O)OCC)=CC=C21 KLOIYEQEVSIOOO-UHFFFAOYSA-N 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 210000005242 cardiac chamber Anatomy 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 239000002340 cardiotoxin Substances 0.000 description 1
- 231100000677 cardiotoxin Toxicity 0.000 description 1
- 229940072282 cardura Drugs 0.000 description 1
- 101150055766 cat gene Proteins 0.000 description 1
- 229940063628 catapres Drugs 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 230000018486 cell cycle phase Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- PBKVEOSEPXMKDN-LZHUFOCISA-N chembl2311030 Chemical class CS(O)(=O)=O.CS(O)(=O)=O.CS(O)(=O)=O.CS(O)(=O)=O.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)C)C(C)C)=C3C2=CNC3=C1.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)CC)C(C)C)=C3C2=CNC3=C1.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)CC(C)C)C(C)C)=C3C2=CNC3=C1.C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](C(N21)=O)(NC(=O)[C@H]1CN(C)[C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C1)C(C)C)C1=CC=CC=C1 PBKVEOSEPXMKDN-LZHUFOCISA-N 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 230000000723 chemosensory effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000003837 chick embryo Anatomy 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 229960001932 cicletanine Drugs 0.000 description 1
- 229950000841 cilutazoline Drugs 0.000 description 1
- 229950007733 clazosentan Drugs 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 229940097479 colestid Drugs 0.000 description 1
- 229960001678 colestyramine Drugs 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000009091 contractile dysfunction Effects 0.000 description 1
- 229940088540 cordarone Drugs 0.000 description 1
- 229940097488 corgard Drugs 0.000 description 1
- 229940072645 coumadin Drugs 0.000 description 1
- 229940009995 cryptenamine Drugs 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 210000001771 cumulus cell Anatomy 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 101150012655 dcl1 gene Proteins 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000003205 diastolic effect Effects 0.000 description 1
- HIZKPJUTKKJDGA-UHFFFAOYSA-N dicumarol Natural products O=C1OC2=CC=CC=C2C(=O)C1CC1C(=O)C2=CC=CC=C2OC1=O HIZKPJUTKKJDGA-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 229940120500 dihydroergotoxine Drugs 0.000 description 1
- 108020001096 dihydrofolate reductase Proteins 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 201000011257 dilated cardiomyopathy 1B Diseases 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 208000017574 dry cough Diseases 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000008143 early embryonic development Effects 0.000 description 1
- 230000005014 ectopic expression Effects 0.000 description 1
- 229950004880 edonentan Drugs 0.000 description 1
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 1
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- OYFJQPXVCSSHAI-QFPUQLAESA-N enalapril maleate Chemical compound OC(=O)\C=C/C(O)=O.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 OYFJQPXVCSSHAI-QFPUQLAESA-N 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 210000003725 endotheliocyte Anatomy 0.000 description 1
- 108700004025 env Genes Proteins 0.000 description 1
- 101150030339 env gene Proteins 0.000 description 1
- 239000003344 environmental pollutant Substances 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
- 229940040520 ergoloid mesylates Drugs 0.000 description 1
- SNFOERUNNSHUGP-ZXZARUISSA-N erythrityl tetranitrate Chemical compound [O-][N+](=O)OC[C@@H](O[N+]([O-])=O)[C@@H](O[N+]([O-])=O)CO[N+]([O-])=O SNFOERUNNSHUGP-ZXZARUISSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- 229960005542 ethidium bromide Drugs 0.000 description 1
- 229960002822 ethyl biscoumacetate Drugs 0.000 description 1
- SEGSDVUVOWIWFX-UHFFFAOYSA-N ethyl biscoumacetate Chemical compound C1=CC=C2C(=O)C(C(C=3C(C4=CC=CC=C4OC=3O)=O)C(=O)OCC)=C(O)OC2=C1 SEGSDVUVOWIWFX-UHFFFAOYSA-N 0.000 description 1
- LENNRXOJHWNHSD-UHFFFAOYSA-N ethylnorepinephrine Chemical compound CCC(N)C(O)C1=CC=C(O)C(O)=C1 LENNRXOJHWNHSD-UHFFFAOYSA-N 0.000 description 1
- 229960002267 ethylnorepinephrine Drugs 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 208000004996 familial dilated cardiomyopathy Diseases 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 229940001501 fibrinolysin Drugs 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 229940087051 fragmin Drugs 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 108700004026 gag Genes Proteins 0.000 description 1
- 101150098622 gag gene Proteins 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- FODTZLFLDFKIQH-FSVGXZBPSA-N gamma-Oryzanol (TN) Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)O[C@@H]2C([C@@H]3CC[C@H]4[C@]5(C)CC[C@@H]([C@@]5(C)CC[C@@]54C[C@@]53CC2)[C@H](C)CCC=C(C)C)(C)C)=C1 FODTZLFLDFKIQH-FSVGXZBPSA-N 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000003209 gene knockout Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 231100000734 genotoxic potential Toxicity 0.000 description 1
- 210000002816 gill Anatomy 0.000 description 1
- 206010061989 glomerulosclerosis Diseases 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 229960002201 guanoclor Drugs 0.000 description 1
- 230000001492 haemagglutinating effect Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 230000009067 heart development Effects 0.000 description 1
- 230000023560 heart growth Effects 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 229950001996 hexestrol Drugs 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000003667 hormone antagonist Substances 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 229940084986 human chorionic gonadotropin Drugs 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 229960000811 hydroquinidine Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 208000015210 hypertensive heart disease Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229960003422 indobufen Drugs 0.000 description 1
- AYDXAULLCROVIT-UHFFFAOYSA-N indobufen Chemical compound C1=CC(C(C(O)=O)CC)=CC=C1N1C(=O)C2=CC=CC=C2C1 AYDXAULLCROVIT-UHFFFAOYSA-N 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 208000021646 inflammation of heart layer Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000001573 invertase Substances 0.000 description 1
- 235000011073 invertase Nutrition 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229960001361 ipratropium bromide Drugs 0.000 description 1
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 description 1
- LDHBWEYLDHLIBQ-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide;hydrate Chemical compound O.[OH-].[O-2].[Fe+3] LDHBWEYLDHLIBQ-UHFFFAOYSA-M 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
- 229960001268 isoetarine Drugs 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 229960002479 isosorbide Drugs 0.000 description 1
- 229960001557 itramin tosilate Drugs 0.000 description 1
- HPPBBWMYZVALRK-UHFFFAOYSA-N itramin tosilate Chemical compound NCCO[N+]([O-])=O.CC1=CC=C(S(O)(=O)=O)C=C1 HPPBBWMYZVALRK-UHFFFAOYSA-N 0.000 description 1
- 230000009916 joint effect Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000001418 larval effect Effects 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940096773 levatol Drugs 0.000 description 1
- 210000000088 lip Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 229960002339 lobeline Drugs 0.000 description 1
- 229930013610 lobeline Natural products 0.000 description 1
- 229940089504 lopressor Drugs 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 108091023436 lsy-6 stem-loop Proteins 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- HWYHZTIRURJOHG-UHFFFAOYSA-N luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229950008446 melinamide Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 229950005826 mercumatilin sodium Drugs 0.000 description 1
- 229950008987 mercurophylline Drugs 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- ABJKIHHNDMEBNA-UHFFFAOYSA-N methylchromone Chemical group C1=CC=C2C(=O)C(C)=COC2=C1 ABJKIHHNDMEBNA-UHFFFAOYSA-N 0.000 description 1
- 229950009263 methylchromone Drugs 0.000 description 1
- 108091055042 miR-181 stem-loop Proteins 0.000 description 1
- 108091062762 miR-21 stem-loop Proteins 0.000 description 1
- 108091041631 miR-21-1 stem-loop Proteins 0.000 description 1
- 108091044442 miR-21-2 stem-loop Proteins 0.000 description 1
- 108091074955 miR-273 stem-loop Proteins 0.000 description 1
- 108091039812 miR-28 stem-loop Proteins 0.000 description 1
- 108091047189 miR-29c stem-loop Proteins 0.000 description 1
- 108091054490 miR-29c-2 stem-loop Proteins 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229940064639 minipress Drugs 0.000 description 1
- 208000019266 moderate heart failure Diseases 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 230000004220 muscle function Effects 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 230000003680 myocardial damage Effects 0.000 description 1
- 108010065781 myosin light chain 2 Proteins 0.000 description 1
- GACQNVJDWUAPFY-UHFFFAOYSA-N n'-[2-[2-(2-aminoethylamino)ethylamino]ethyl]ethane-1,2-diamine;hydrochloride Chemical compound Cl.NCCNCCNCCNCCN GACQNVJDWUAPFY-UHFFFAOYSA-N 0.000 description 1
- IAYNHDZSSDUYHY-UHFFFAOYSA-N n-(2-acetyl-4,6-dimethylphenyl)-3-[(3,4-dimethyl-1,2-oxazol-5-yl)sulfamoyl]thiophene-2-carboxamide Chemical compound CC(=O)C1=CC(C)=CC(C)=C1NC(=O)C1=C(S(=O)(=O)NC2=C(C(C)=NO2)C)C=CS1 IAYNHDZSSDUYHY-UHFFFAOYSA-N 0.000 description 1
- LFWCJABOXHSRGC-UHFFFAOYSA-N n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(2h-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C2=NNN=N2)OCCO)=C1NS(=O)(=O)C1=CC=C(C)C=N1 LFWCJABOXHSRGC-UHFFFAOYSA-N 0.000 description 1
- YBWLTKFZAOSWSM-UHFFFAOYSA-N n-[6-methoxy-5-(2-methoxyphenoxy)-2-pyridin-4-ylpyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=CN=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 YBWLTKFZAOSWSM-UHFFFAOYSA-N 0.000 description 1
- VRUJTPHFVRXEPB-UHFFFAOYSA-N n-[[2-[2-[(4,5-dimethyl-1,2-oxazol-3-yl)sulfamoyl]phenyl]-5-(1,3-oxazol-2-yl)phenyl]methyl]-n,3,3-trimethylbutanamide;hydrate Chemical compound O.CC(C)(C)CC(=O)N(C)CC1=CC(C=2OC=CN=2)=CC=C1C1=CC=CC=C1S(=O)(=O)NC1=NOC(C)=C1C VRUJTPHFVRXEPB-UHFFFAOYSA-N 0.000 description 1
- VZAUGYDMVQSQAO-VOTNWUEESA-M neo-gilurytmal Chemical compound OC(=O)[C@H](O)[C@@H](O)C([O-])=O.CN([C@H]12)C3=CC=CC=C3[C@]11C[C@@H]3[N@@+](CCC)([C@@H]([C@H]4CC)O)[C@H]2C[C@@H]4[C@@H]3[C@H]1O VZAUGYDMVQSQAO-VOTNWUEESA-M 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000000712 neurohormone Substances 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 102000008434 neuropeptide hormone activity proteins Human genes 0.000 description 1
- 108040002669 neuropeptide hormone activity proteins Proteins 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229940072991 nitro-bid Drugs 0.000 description 1
- 229940073015 nitrostat Drugs 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 229940088938 norpace Drugs 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 208000012144 orthopnea Diseases 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000001734 parasympathetic effect Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 238000002161 passivation Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- FEDSNBHHWZEYTP-ZFQYHYQMSA-N penbutolol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NC[C@H](O)COC1=CC=CC=C1C1CCCC1.CC(C)(C)NC[C@H](O)COC1=CC=CC=C1C1CCCC1 FEDSNBHHWZEYTP-ZFQYHYQMSA-N 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- 229940043138 pentosan polysulfate Drugs 0.000 description 1
- 210000003516 pericardium Anatomy 0.000 description 1
- 239000000810 peripheral vasodilating agent Substances 0.000 description 1
- 229960002116 peripheral vasodilator Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 229960004923 phenprocoumon Drugs 0.000 description 1
- DQDAYGNAKTZFIW-UHFFFAOYSA-N phenprocoumon Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC)C1=CC=CC=C1 DQDAYGNAKTZFIW-UHFFFAOYSA-N 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- MBWXNTAXLNYFJB-NKFFZRIASA-N phylloquinone Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-NKFFZRIASA-N 0.000 description 1
- 235000019175 phylloquinone Nutrition 0.000 description 1
- 239000011772 phylloquinone Substances 0.000 description 1
- 230000008288 physiological mechanism Effects 0.000 description 1
- 229960001898 phytomenadione Drugs 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 108700004029 pol Genes Proteins 0.000 description 1
- 101150088264 pol gene Proteins 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 231100000857 poor renal function Toxicity 0.000 description 1
- 208000007232 portal hypertension Diseases 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229960004215 prajmaline Drugs 0.000 description 1
- UAUHEPXILIZYCU-ALHOSYKFSA-N prajmalium Chemical compound CN([C@H]12)C3=CC=CC=C3[C@]11C[C@@H]3[N@@+](CCC)([C@@H]([C@H]4CC)O)[C@H]2C[C@@H]4[C@@H]3[C@H]1O UAUHEPXILIZYCU-ALHOSYKFSA-N 0.000 description 1
- WFXFYZULCQKPIP-UHFFFAOYSA-N prazosin hydrochloride Chemical compound [H+].[Cl-].N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 WFXFYZULCQKPIP-UHFFFAOYSA-N 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229930190098 proscillaridin Natural products 0.000 description 1
- 229960003584 proscillaridin Drugs 0.000 description 1
- MYEJFUXQJGHEQK-UHFFFAOYSA-N proscillaridin A Natural products OC1C(O)C(O)C(C)OC1OC1C=C2CCC3C4(O)CCC(C5=COC(=O)C=C5)C4(C)CCC3C2(C)CC1 MYEJFUXQJGHEQK-UHFFFAOYSA-N 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940070851 pyridinolcarbamate Drugs 0.000 description 1
- 229940073095 questran Drugs 0.000 description 1
- 229960000755 quinidine polygalacturonate Drugs 0.000 description 1
- 239000009847 quinidine polygalacturonate Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 206010037833 rales Diseases 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 210000001908 sarcoplasmic reticulum Anatomy 0.000 description 1
- 108010073863 saruplase Proteins 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000013605 shuttle vector Substances 0.000 description 1
- 108091069025 single-strand RNA Proteins 0.000 description 1
- 229960002578 sitaxentan Drugs 0.000 description 1
- PHWXUGHIIBDVKD-UHFFFAOYSA-N sitaxentan Chemical compound CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC=2C(=CC=3OCOC=3C=2)C)=C1Cl PHWXUGHIIBDVKD-UHFFFAOYSA-N 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- NLQLSVXGSXCXFE-UHFFFAOYSA-N sitosterol Natural products CC=C(/CCC(C)C1CC2C3=CCC4C(C)C(O)CCC4(C)C3CCC2(C)C1)C(C)C NLQLSVXGSXCXFE-UHFFFAOYSA-N 0.000 description 1
- 235000015500 sitosterol Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229960003968 sodium apolate Drugs 0.000 description 1
- 229940083618 sodium nitroprusside Drugs 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- SGLZWZOFNVYMPV-UHFFFAOYSA-M sodium;[3-(3-carboxylato-2-oxochromen-8-yl)-2-methoxypropyl]mercury;1,3-dimethyl-7h-purine-2,6-dione;hydrate Chemical compound O.[Na+].O=C1N(C)C(=O)N(C)C2=C1NC=N2.C1=C(C([O-])=O)C(=O)OC2=C1C=CC=C2CC(C[Hg])OC SGLZWZOFNVYMPV-UHFFFAOYSA-M 0.000 description 1
- BWYYYTVSBPRQCN-UHFFFAOYSA-M sodium;ethenesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C=C BWYYYTVSBPRQCN-UHFFFAOYSA-M 0.000 description 1
- MKTGEYSXQZFWGG-UHFFFAOYSA-L sodium;mercury(2+);3-(2-methoxypropylcarbamoyl)-1,2,2-trimethylcyclopentane-1-carboxylate;hydroxide Chemical compound [OH-].[Na+].[Hg+2].COC([CH2-])CNC(=O)C1CCC(C)(C([O-])=O)C1(C)C MKTGEYSXQZFWGG-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical class NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 229960003329 sulfinpyrazone Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 206010042772 syncope Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 229940106719 tambocor Drugs 0.000 description 1
- 238000010863 targeted diagnosis Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940065385 tenex Drugs 0.000 description 1
- 230000033912 thigmotaxis Effects 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 208000021510 thyroid gland disease Diseases 0.000 description 1
- 229940028869 ticlid Drugs 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229940029774 trimethaphan camsylate Drugs 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 229960002485 trolnitrate Drugs 0.000 description 1
- HWKQNAWCHQMZHK-UHFFFAOYSA-N trolnitrate Chemical compound [O-][N+](=O)OCCN(CCO[N+]([O-])=O)CCO[N+]([O-])=O HWKQNAWCHQMZHK-UHFFFAOYSA-N 0.000 description 1
- UOCLRXFKRLRMKV-UHFFFAOYSA-N trolnitrate phosphate Chemical compound OP(O)(O)=O.OP(O)(O)=O.[O-][N+](=O)OCCN(CCO[N+]([O-])=O)CCO[N+]([O-])=O UOCLRXFKRLRMKV-UHFFFAOYSA-N 0.000 description 1
- 230000010415 tropism Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229940099270 vasotec Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000006815 ventricular dysfunction Effects 0.000 description 1
- 208000003663 ventricular fibrillation Diseases 0.000 description 1
- 206010047302 ventricular tachycardia Diseases 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 229940063670 visken Drugs 0.000 description 1
- 229960000821 visnadine Drugs 0.000 description 1
- 208000030401 vitamin deficiency disease Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- RNRHMQWZFJXKLZ-XUWXXGDYSA-N xibornol Chemical compound C1=C(C)C(C)=CC(O)=C1[C@H]1[C@](C2(C)C)(C)CC[C@@H]2C1 RNRHMQWZFJXKLZ-XUWXXGDYSA-N 0.000 description 1
- 229960001643 xibornol Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
- A01K67/0276—Knock-out vertebrates
-
- 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
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/035—Animal model for multifactorial diseases
- A01K2267/0375—Animal model for cardiovascular diseases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/11—Antisense
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
- C12N2310/141—MicroRNAs, miRNAs
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2330/00—Production
- C12N2330/10—Production naturally occurring
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Cardiology (AREA)
- Environmental Sciences (AREA)
- Analytical Chemistry (AREA)
- Plant Pathology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Animal Husbandry (AREA)
- Biodiversity & Conservation Biology (AREA)
- Pathology (AREA)
- Immunology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Neurology (AREA)
Abstract
本发明涉及诱导β-肌球蛋白重链(β-MHC)表达且遏制快速骨骼肌收缩蛋白质基因的微RNA,miR-208的鉴定。对此功能的抑制被建议作为心脏纤维化、肥大和/或心力衰竭的治疗方法,而且对此功能的提升可用于在肌肉骨骼病症的治疗中遏制慢速纤维基因和激活快速纤维基因。
Description
发明背景
本发明是在来自(美国)国家卫生研究院的经费支持下进行的,经费号HL53351-06。政府具有本发明的某些权利。
本申请要求2006年8月1日提交的美国临时申请流水号60/834,667;2007年7月31日提交的60/952,911;和2007年7月31日提交的60/952,917的优先权,通过提及将其完整内容收入本文。
1.发明领域
一般地,本发明涉及发育生物学和分子生物学领域。更具体地,本发明关注心肌细胞和骨骼肌细胞中的基因调节和细胞生理学。明确地,本发明涉及对miRNA的抑制,导致β-肌球蛋白重链(β-MHC)表达降低,由此治疗心脏肥大和心力衰竭。本发明还涵盖上调此miRNA用于治疗肌肉骨骼疾病。
2.相关技术的描述
应答施加于心脏的工作负荷升高的心脏肥大是一种基础的适应性机制。它是一种特化的过程,反映了由于神经、内分泌或机械刺激中的任一项或组合而发生的细胞大小和质量(mass)(而非细胞数目)的数量增加。高血压,心脏肥大的另一种因素,常常是充血性心力衰竭的前兆。当发生心力衰竭时,左心室常常肥大和扩张,而且收缩功能的指数,诸如射血分数,会降低。显然,心脏肥大应答是一种复杂的综合征,而且阐明导致心脏肥大的机制对于各种刺激所致的心脏病的治疗会是有益的。
病理性心肌肥大的特征在于心肌细胞蛋白质的增加和重现(reminiscentof)早期胚胎发育的基因表达序型。具体地说,β-肌球蛋白重链(β-MHC)、骨骼α-肌动蛋白(sACT)、及心房和脑两种钠尿肽(分别是ANP和BNP)的表达增加,而成年心脏肌肉特异性基因、α-肌球蛋白重链(α-MHC)和肌质网Ca2+-ATP酶(SERCA)的表达降低。更具体地,有令人信服的证据指明MHC同种型(isoform)表达变化在人心力衰竭发病机制中的作用。事实上,α-MHCmRNA和蛋白质水平在衰弱的心脏中显著降低,而且通过β-阻滞剂疗法改善左心室射血分数与α-MHC表达正常化有关。另外,鉴定了人α-MHC基因中的一处突变与肥厚性心肌病有关,这证明了α-MHC表达水平对于正常心脏功能是至关重要的,尽管其丰度低。如此,清楚的是α和β两种MHC在心脏肥大发生中发挥作用,但是这些产物在产生和/或维持病理状态中确切的作用特征仍然未知。
发明概述
如此,依照本发明,在一个实施方案中提供了调节心脏收缩性和重塑(remodeling)的方法,包括给心脏细胞施用miR-208表达或活性的调控剂。在一个实施方案中,提供了调节心脏收缩蛋白质基因表达的方法,包括给心脏细胞施用miR-208表达或活性的调控剂。所述调控剂可以是miR-208表达或活性的激动剂或拮抗剂。在本发明的某些方面,提供了减少心脏细胞中的β-MHC表达的方法,包括给心脏细胞施用miR-208表达或活性的抑制剂。在本发明的其它方面,提供了提高心脏细胞中的β-MHC表达的方法,包括提高内源miR-208表达或活性或给心脏细胞施用外源miR-208。在本发明的一个方面,提供了提高心脏细胞中的快速骨骼肌收缩蛋白质基因的表达的方法,包括给心脏细胞施用miR-208表达或活性的抑制剂。在本发明的另一个方面,提供了降低心脏细胞中的快速骨骼肌收缩蛋白质基因的表达的方法,包括提高内源miR-208表达或活性或给心脏细胞施用外源miR-208。依照本发明的方法可以提高或降低的快速骨骼肌收缩蛋白质基因的例子包括:骨骼肌钙蛋白I、肌钙蛋白T3、肌球蛋白轻链、或α-骨骼肌动蛋白。
在一个实施方案中,本发明提供了治疗病理性心脏肥大或心力衰竭的方法,包括:鉴定具有心脏肥大、心力衰竭、或心肌梗死后重塑的患者;并抑制患者心脏细胞中的miR-208表达或活性。在另一个实施方案中,提供了预防病理性肥大或心力衰竭的方法,包括:鉴定有风险发生病理性心脏肥大或心力衰竭的患者;并抑制患者心脏细胞中的miR-208表达或活性。
在一个实施方案中,本发明提供了治疗心肌梗死的方法,包括抑制所述受试者的心脏细胞中的miR-208表达或活性。在另一个实施方案中,本发明提供了预防心脏肥大和扩张型心肌病的方法,包括抑制受试者心脏细胞中的miR-208表达或活性。在又一个实施方案中,本发明提供了抑制心脏肥大进展的方法,包括抑制受试者心脏细胞中的miR-208表达或活性。在某些实施方案中,本发明提供了在患有心力衰竭或心脏肥大的受试者中提高运动耐量、减少入院治疗、改善生活质量、降低发病率、和/或降低死亡率的方法,包括抑制受试者心脏细胞中的miR-208表达或活性。在本发明的其它方面,提供了在病理条件下通过施用miR-208抑制剂来提高心脏细胞中的α-MHC表达的方法。
在本发明的某些方面,抑制miR-208的表达或活性包括施用miR-208的antagomir。在一个实施方案中,本发明提供了miR-208antagomir。antagomir或miR-208表达或活性的其它调控剂的施用可以通过本领域技术人员知道的适于投递至目标器官、组织、或细胞类型的任何方法来进行。例如,在本发明的某些方面,miR-208的调控剂可以通过静脉内注射、动脉内注射、心包内注射、或直接注射入组织(例如心脏组织、骨骼肌组织)来施用。在一些方面,施用包括口服、经皮、腹膜内、皮下、持续释放、受控释放、延迟释放、栓剂、或舌下施用miR-208。
在本发明的某些方面,在患者中治疗或预防病理性心脏肥大或心力衰竭进一步包括给患者施用第二心脏肥大疗法。所述第二疗法可以是例如β阻滞剂、ionotrope、利尿药、ACE-I、AII拮抗剂、BNP、Ca++-阻滞剂、和ERA、或HDAC抑制剂。所述第二疗法可以在抑制miR-208之前、同时、或之后施用。
病理性心脏肥大或心力衰竭的治疗可以定义为病理性心脏肥大或心力衰竭的一种或多种症状的改善。得到改善的症状可以是例如升高的运动能力(exercise capacity)、升高的心脏射血体积、降低的左心室舒张末期压、降低的肺毛细血管楔压、升高的心排血量或心排血指数、降低的肺动脉压、降低的左心室收缩和舒张末期内径(end systolic and distolic dimensions)、降低的左右心室壁压(wall stress)、降低的壁张力(wall tension)、提高的生活质量、和降低的疾病相关发病率或死亡率。病理性心脏肥大的治疗还可以定义为延迟从心脏肥大到心力衰竭的转变。
在本发明的某些实施方案中,提供了在有风险发生病理性心脏肥大或心力衰竭的患者中预防病理性肥大或心力衰竭的方法。有风险发生病理性心脏肥大或心力衰竭的患者可以展现出一种或多种风险因子,包括例如长期不受控制的高血压、未矫正的瓣膜病、慢性咽峡炎、新近的心肌梗死、心脏病的先天素因或病理性肥大。在某些方面,有风险的患者可以是诊断为具有心脏肥大的遗传素因。在本发明的某些方面,有风险的患者可以具有心脏肥大的家族史。
在一个实施方案中,本发明提供了降低骨骼肌细胞中的快速骨骼肌收缩蛋白质基因表达或活性的方法,包括给骨骼肌细胞施用miR-208。在一个实施方案中,本发明提供了在受试者中治疗或预防肌肉骨骼病症的方法,包括:鉴定具有或有风险发生肌肉骨骼病症的患者;并提高所述患者骨骼肌细胞中的miR-208表达和/或活性。肌肉骨骼病症可以是例如失用性萎缩、应答于微重力的肌肉消耗(muscle-wasting in response to microgravity)、或失神经支配。在本发明的某些方面,治疗或预防肌肉骨骼病症的方法进一步包括施用第二非miR-208疗法。
提高miR-208的表达和/或活性可以包括给受试者施用miR-208或者给受试者施用表达miR-208的表达载体。所述表达载体是病毒表达载体。所述病毒表达载体可以是例如腺病毒或逆转录病毒表达载体。在某些方面,所述表达载体是非病毒表达载体。在本发明的某些方面,miR-208或编码miR-208的表达载体与脂质媒介相结合。或者,可以仅仅提供独立的miR-208,任选地被包括在投递媒介内,诸如脂质体或纳米颗粒。miR-208是心脏特异性的,这一点可防止其它器官中发生不想要的副作用。
在一个实施方案中,本发明提供了鉴定miR-208的调控剂的方法,包括:(a)使细胞接触候选化合物;(b)评估miR-208活性或表达;并(c)比较步骤(b)中的活性或表达与不存在候选化合物时的活性或表达,其中测得的活性或表达之间的差异指示该候选化合物是miR-208的调控剂。在本发明的某些方面,在体外使细胞接触候选化合物。在本发明的其它方面,在体内使细胞接触候选化合物。所述miR-208的调控剂可以是miR-208的激动剂或拮抗剂。可以依照本发明的方法来筛选的候选化合物的非限制性例子是肽、多肽、多核苷酸、或小分子。
评估miR-208活性或表达可以包括评估miR-208的表达水平。本领域技术人员熟悉多种评估RNA表达水平的方法,包括例如Northern印迹或RT-PCR。评估miR-208活性或表达可以包括评估miR-208的活性。在一些实施方案中,评估miR-208的活性包括评估受miR-208调节的基因的表达或活性。受miR-208调节的基因包括例如α和β-肌球蛋白重链和快速骨骼肌蛋白质基因,诸如快速骨骼肌钙蛋白I、肌钙蛋白T3、肌球蛋白轻链、和α骨骼肌动蛋白。在本发明的某些方面,评估miR-208的活性包括评估α-肌球蛋白重链表达水平对β-肌球蛋白重链表达水平的比率。本领域技术人员熟悉多种评估受miR-208调节的基因的活性或表达的方法。此类方法包括例如Northern印迹、RT-PCR、ELISA、或Western印迹。
在一个实施方案中,本发明提供了通过如下方法鉴定的miR-208调控剂,所述方法包括:(a)使细胞接触候选化合物;(b)评估miR-208活性或表达;并(c)比较步骤(b)中的活性或表达与不存在候选化合物时的活性或表达,其中测得的活性或表达之间的差异指示该候选化合物是miR-208的调控剂。miR-208的调控剂可以被包括在药物组合物中,用于依照本发明的方法治疗心脏病症和/或肌肉骨骼病症。
在另一个实施方案中,本发明提供了通过如下方法鉴定的miR-208抑制剂,所述方法包括:(a)使细胞接触候选化合物;(b)评估miR-208活性或表达;并(c)比较步骤(b)中的活性或表达与不存在候选化合物时的活性或表达,其中接触候选化合物的细胞中的活性或表达与不存在候选化合物的细胞中的活性或表达相比的降低指示该候选化合物是miR-208的抑制剂。
在一个实施方案中,本发明提供了治疗病理性心脏肥大或心力衰竭的方法,包括:鉴定具有心脏肥大或心力衰竭的患者;并给患者施用miR-208抑制剂。在本发明的某些方面,所述miR-208抑制剂可以是通过如下方法鉴定的,所述方法包括:(a)使细胞接触候选化合物;(b)评估miR-208活性或表达;并(c)比较步骤(b)中的活性或表达与不存在候选化合物时的活性或表达,其中接触候选化合物的细胞中的miR-208活性或表达与不存在候选化合物的细胞中的活性或表达相比的降低指示该候选化合物是miR-208的抑制剂。
在另一个实施方案中,本发明提供了治疗肌肉骨骼病症的方法,包括:鉴定具有肌肉骨骼病症或有风险发生肌肉骨骼病症的患者;并给患者施用miR-208激动剂。在本发明的某些方面,所述miR-208激动剂可以是通过如下方法鉴定的,所述方法包括:(a)使细胞接触候选化合物;(b)评估miR-208活性或表达;并(c)比较步骤(b)中的活性或表达与不存在候选化合物时的活性或表达,其中接触候选化合物的细胞中的miR-208活性或表达与不存在候选化合物的细胞中的活性或表达相比的升高指示该候选化合物是miR-208的激动剂。
在一个实施方案中,本发明提供了转基因非人哺乳动物,其细胞未能表达功能性miR-208。在另一个实施方案中,本发明提供了转基因非人哺乳动物,其细胞包含在异源启动子控制下的miR-208编码区,所述异源启动子在所述非人哺乳动物的细胞中是有活性的。所述转基因哺乳动物可以是例如小鼠或大鼠。所述启动子可以是组织特异性启动子,诸如例如骨骼肌特异性启动子或心脏肌肉特异性启动子。在某些实施方案中,本发明提供了转基因非人哺乳动物细胞,其缺乏一个或两个天然miR-208等位基因。
词语“一个”或“一种”在权利要求书/说明书中与术语“包含”、“包括”或“含有”一起使用时的使用可以表示“一(个/种)”,但是也与“一(个/种)或多(个/种)”、“至少一(个/种)”、或“一(个/种)或多于一(个/种)”的意思一致。
就本发明的任何方法或组合物而言,可以实施本文中所讨论的任何实施方案,反之亦然。此外,本发明的组合物和试剂盒可用于实现本发明的方法。
在本申请全文中,术语“约”用于表示某数值包括用于测定该数值的装置或方法的标准偏差。术语“或”在权利要求书中的使用用于表示“和/或”,除非明确指出仅指二选一的或者各选项互相排斥,尽管公开内容支持仅指二选一和“和/或”的定义。
在用于本说明书和权利要求书时,词语“包含”(及任何形式的包含,诸如“包括”和“含有”)、“具有”(及任何形式的具有,诸如“有”和“带有”)、“包括”(及任何形式的包括,诸如“包含”和“含有”)、或“含有”(及任何形式的含有,诸如“含”)指包括在内(inclusive)或开放式的(open-ended),而且不排除别的、未叙及的成分或方法步骤。
本发明的其它目的、特征和优点根据以下详述将变得显而易见。然而,应当理解,尽管详述和具体实施例指出了本发明的具体实施方案,但是它们仅是作为例示而提供的,因为本发明精神和范围内的各种变化和改良对于本领域技术人员而言根据此详述将是显而易见的。
附图简述
以下附图构成本说明书的一部分,用以进一步演示本发明的某些方面。通过参照这些附图中的一幅或多幅并结合本文所述具体实施方案的详细描述可以更好地理解本发明。
图1-miR-208包含在心脏α-MHC基因中。miR-208由αMHC基因的内含子27编码。星号指示序列保守性。
图2-miR-208具有与α-MHC相同的表达样式。通过成年小鼠组织的Northern分析进行的miR-208转录物检测。U6mRNA充当加样对照。
图3A-C-甲状腺激素对miR-208表达的调节。(图3A)α-和β-MHC的PTU/T3调节的示意图。(图3B)在有和无T3的情况下将大鼠用PTU处理1周,并通过实时PCR检测αMHC和βMHC mRNA。(图3C)如所示的将大鼠用PTU或PTU+T3处理1周,并通过Northern印迹检测miR-208表达。分析了来自每种条件下4只动物的心脏。
图4A-C-α-MHC表达抑制导致降低的miR-208水平。(图4A-B)第0,3,6,9,12,15,18和21天的α-和β-MHC转录物的相对表达水平。(图4C)PTU处理过程中所示时间点大鼠心脏组织中miR-208的Northern印迹分析。
图5A-B-miR-208基因敲除。(图5A)通过同源重组生成miR-208突变型小鼠的策略。用侧翼为loxP位点的新霉素抗性盒(Neo)替换前miRNA(pre-miRNA)序列。通过杂合小鼠与包含CAG-Cre转基因的转基因小鼠的交配消除小鼠种系中的新霉素盒。DTA,白喉毒素A。(图5B)通过来自野生型(WT)和miR-208突变型(KO)小鼠的心脏的Northern分析进行的miR-208转录物检测。
图6A-B-miR-208删除不改变α-MHC表达。(图6A)通过来自所示基因型的小鼠的心脏的RNA的RT-PCR进行的αMHC转录物分析。显示了引物相对于αMHC外显子的位置,而且引物对显示在每组样品上方。(图6B)所示基因型的新生小鼠的心脏中的aMHC和bMHC蛋白质水平的Western分析。分析了每种基因型的2只小鼠。检测甘油醛-3-磷酸脱氢酶(GAPDH)作为加样对照。
图7-miR-208敲除中快速骨骼基因的上调。
图8-miR-208敲除小鼠中心脏应激应答(stress response)基因的失调。
图9-miR-208在心脏基因调节中的作用的模型。αMHC基因编码miR-208,其负调节THRAP1和骨骼肌基因(及可能别的靶物)的表达。α-和β-MHC基因是连锁的(linked),而且miR-208是应答应激信号传导而发生的βMHC上调和PTU阻断T3信号传导所需要的。α-和β-MHC分别促进快速和慢速收缩。
图10-人心脏样品:未衰竭的-衰竭的(failing)。
图11-THRAP1作为miR-208的预测靶物。THRAP1的3′UTR中推定的miR-208结合位点的序列比对显示了高水平的互补性和序列保守性。
图12-3′UTR THRAP1萤光素酶测定。
图13-miR-208突变型小鼠的心脏中快速骨骼肌基因的上调。
图14A-E-野生型和miR-208 -/- 动物在TAB后的分析。(图14A)假手术或TAB 21天后野生型和miR-208-/-小鼠中通过实时PCR检测αMHC mRNA表达。(图14B)通过来自野生型和miR-208-/-小鼠的心脏组织的Northern印迹检测miR-208。(图14C)超声心动图显象分析指示FS的降低,这是由于miR-208-/-和同窝野生型小鼠二者中应答于TAB的收缩期左心室内径(LV in systole,LVIDs)扩张的增加所导致的。TAB后心缩期(s)或心舒期(d)的前壁和后壁(AW和PW)厚度显示与野生型动物相比,miR-208-/-动物中变钝的(blunted)肥大型应答(n=5-7每组)。*p<0.05,与相应的野生型组相比。(图14D)通过Northern分析检测来自野生型和miR-208转基因小鼠的心脏的miR-208转录物。(图14E)通过来自所示基因型的心脏中的实时PCR检测αMHC、βMHC、ANF和BNP的转录物。数值表述成与野生型小鼠相比的表达增加倍数(±SEM)(n=3)。
图15A-G-miR-208 -/- 小鼠应答于压力过度负荷而显示心脏肥大的降低。(图15A)野生型和miR-208-/-小鼠的心脏的Masson三色染色组织学切片。miR-208的缺失削弱了在进行21天TAB的野生型小鼠中所见的肥大和纤维化。标尺在顶图中等于2mm而在底图中等于20μm。(图15B)通过实时PCR检测假手术或TAB手术后的野生型和miR-208-/-小鼠的心脏中的βMHC、ANF和BNP的转录物。数值表述成与假手术的野生型小鼠相比的表达增加倍数(±SEM)(n=3)。(图15C)假手术和TAB后21天的成年野生型和miR-208突变型小鼠中的αMHC和βMHC蛋白质水平的Western分析。(图15D)表达钙依赖磷酸酶(calcineurin)转基因(CnA-Tg)的6周龄小鼠的心脏和miR-208-/-的心脏的组织学切片;对CnA-Tg进行Masson三色染色。miR-208的缺失削弱了在CnA-Tg小鼠中所见的肥大和纤维化。标尺在顶图中等于2mm而在底图中等于20μm。(图15E)通过实时PCR检测来自所示基因型的心脏中的βMHC、ANF和BNP的转录物。数值表述成与野生型小鼠相比的表达增加倍数(±SEM)(n=3)。(图15F)成年野生型和有和无CnA转基因的miR-208突变型小鼠中αMHC和βMHC蛋白质水平的Western分析。(图15G)成年野生型和miR-208转基因动物中αMHC和βMHC蛋白质水平的Western分析。
图16A-C-PTU处理后的野生型和miR-208 -/- 动物的分析。(图16A)通过Northern印迹检测来自PTU处理后的野生型和miR-208-/-小鼠的心脏组织的miR-208。(图16B)超声心动图显象显示了野生型和miR-208-/-小鼠中相当的应答于PTU的心率(HR)和缩短分数(FS)降低,这是由于心舒期(d)和心缩期(s)二者中左心室扩张(LV dilation)(LVID)的增加和前后左心室壁(AW,PW)的变薄(n=6)导致的。*p<0.05,与相应的野生型组相比。(图16C)通过实时PCR检测来自PTU处理后的野生型和miR-208-/-小鼠的心脏中的ANF和BNP的转录物。数值表述成与接受常规食物的野生型小鼠相比的表达增加倍数(±SEM)(n=3)。
图17A-B-miR-208对βMHC基因的响应性的调节。(图17A)野生型和miR-208突变型小鼠中的基线和PTU处理后2周的αMHC和βMHC表达的Western分析。(图17B)通过实时PCR检测来自PTU处理后的野生型和miR-208-/-小鼠的心脏中的αMHC和βMHC转录物。数值表述成与接受常规食物的野生型小鼠相比的表达增加倍数(±SEM)(n=3)。
图18A-D-miR-208靶向THRAP1。(图18A)THRAP1的3′UTR中推定的miR-208结合位点的序列比对显示了高水平的互补性和序列保守性。(图18B)将COS1细胞用THRAP1 3′UTR萤光素酶构建物以及miR-126和miR-208的表达质粒转染。数值表述成与单独的报道物相比的萤光素酶表达增加倍数(±SD)。(图18)将COS1用HA-MCD-WT UTR或HA-MCD-突变型UTR,以及范围为0.1-2μg的递增剂量的pCMV-miR-208转染。使用免疫印迹检测HA-水平。(图18D)使用THRAP1特异性抗体对被THRAP1免疫沉淀的心脏细胞溶胞物进行的THRAP1 Western印迹,其中使用400μg来自野生型动物或miR-208-/-动物的蛋白质。
图19-THRAP1转录物的RT-PCR分析。通过来自野生型和miR-208-/-小鼠的心脏的RNA的RT-PCR进行的THRAP1转录物分析。显示了引物在mRNA转录物中的位置。
图20-甲状腺激素受体信号传导靶物的实时PCR分析。通过实时PCR检测来自野生型和miR-208-/-小鼠的心脏中的SERCA2a和PLB、及GLUT4的转录物。数值表述成与野生型小鼠相比的表达增加倍数(±SEM)。
图21-显示野生型、miR-208 +/- 和miR-208 -/- 形式的心脏中的miR-499表达 的Northern印迹。野生型和突变型小鼠中miR-208的表达和miR-499,以及Myb7b之间有正相关。
图22-Myh7b基因座的结构和miR-499编码区在其中的位置。
图23-显示心脏和比目鱼肌中miR-499表达的RNA印迹。mir-499在快速骨骼肌纤维诸如腓肠肌/跖肌(GP)、胫骨前肌(TA)或趾长伸肌(EDL)中不表达。
图24-显示具有心脏病的野生型小鼠中miR-499表达的Northern印迹。MI,心肌梗死。CnA Tg,钙依赖磷酸酶转基因小鼠。
图25-心脏肌肉中miR-208调节miR-499的示意图。
图26A-C-心脏肥大过程中的miRNA表达。(图26A)来自假手术和TAB21天后的小鼠和来自CnA Tg小鼠的代表性心脏的H&E染色切片。标尺等于2mm。(图26B)下面显示了显示在每种类型的心脏中表达有变化的微RNA数目的Venn图。(图26C)在肥大过程中表达有变化的微RNA的Northern印迹。检测U6RNA作为加样对照。
图27-miR-29表达应答心脏应激而下调。左边显示了来自野生型小鼠(WT)和具有依赖磷酸酶转基因(CnA)或TAB诱导的肥大和纤维化的小鼠的心脏。右边显示了每种类型的心脏中miR-29的相对表达水平。
图28-与野生型相比来自miR-208敲除小鼠的心脏的微阵列分析。对6周龄时自野生型和miR-208缺失型心脏分离的mRNA进行了微阵列分析。仅次于miR-208的下调最多的miRNA是miR-499。
图29-miR-29家族在miR-208缺失型心脏中显著上调。
图30-miR-29家族靶向编码胶原和细胞外基质中参与纤维化的其它成 分的mRNA。
图31-miR-208和miR-29家族控制心脏纤维化的模型。在正常心脏中,miR-208抑制miR-29的表达。在miR-208缺失的情况中,miR-29表达上调,阻止应答应激而发生的细胞外基质表达和纤维化。miR-208、-499和-29的功能是相互关联的。miR-208的缺失可能具有心脏保护性,这种保护性通过阻止miR-499表达和上调miR-29表达,并因此阻断纤维化来实现。
例示性实施方案的详述
心力衰竭是世界上发病和死亡的主要原因之一。仅在美国,估计有300万人当前正罹患着心肌病,而且每年另有40万人得到诊断。扩张型心肌病(DCM),也称作“充血性心肌病”,是心肌病的最常见形式,而且具有接近每10万人中40例的估计流行程度(Durand等,1995)。虽然DCM有其它的原因,但是有人已经指出家族性扩张型心肌病占“特发性”DCM的大约20%。大约一半的DCM病例是特发性的,其余的则与已知的疾病过程有关。例如,癌症化疗中所使用的某些药物(例如多柔比星(doxorubicin)和柔红霉素(daunoribucin))可导致严重的心肌损伤。另外,许多DCM患者是长期酗酒者。幸运的是,对于这些患者,如果在疾病病程中早期减少或停止饮酒的话,心肌功能障碍的进展可以被停止或逆转。围产期心肌病是DCM的另一种特发性形式,与传染性后遗症相关的疾病也是。总之,心肌病,包括DCM,是重大的公知健康问题。
心脏病及其征候,包括冠心病、心肌梗死、充血性心力衰竭和心脏肥大,显然是今日美国面临的一个主要健康风险。诊断、治疗和维护患有这些疾病的患者的花费高达数十亿美元。两种特别严重的心脏病征候是心肌梗死和心脏肥大。关于心肌梗死,典型地,由于动脉粥样硬化而在冠状动脉中发生急性血小板性冠状动脉闭塞并引起心肌细胞死亡。因为心肌细胞,即心脏肌肉细胞,是终末分化的且一般不能进行细胞分裂,它们在急性心肌梗死过程中死亡后一般被瘢痕组织替换。瘢痕组织没有收缩性,对心脏功能没有帮助,且常常在心脏收缩过程中扩张或者提高心室的大小和有效半径(例如变肥大)而对心脏功能产生有害作用。关于心脏肥大,一种理论将其看作类似异常发育的疾病,因此提出了心脏中的发育信号是否有助于肥大疾病的问题。心脏肥大是对几乎所有形式的心脏病(包括那些源自高血压、机械负荷、心肌梗死、心率失常、内分泌失调、和心脏收缩蛋白质基因中的遗传突变的心脏病)的适应性应答。虽然肥大应答最初是提升心排血量的补偿机制,但是持续的肥大可导致DCM、心力衰竭、和猝死。在美国,每年有大约50万人被诊断有心力衰竭,死亡率大约50%。
关于心脏肥大的原因和结果已经有很多著述,但是其潜在的分子机制尚未阐明。对这些机制的理解是心脏病的预防和诊断中主要关心的问题,而且作为设计特异性靶向心脏肥大和心脏心力衰竭的新药物中的治疗模式,将具有关键意义。因为病理性心脏肥大通常直到心脏损伤严重到足以产生心力衰竭之前都不产生任何症状,所以心肌病的症状是与心力衰竭相关的症状。这些症状包括呼吸急促、筋疲力尽(fatigue with exertion)、不能平躺又不变得呼吸急促(端坐呼吸)、阵发性夜间呼吸困难、心脏尺度扩大、和/或下肢肿胀。患者还常常呈现血压升高、额外心音、心脏杂音、肺和系统性栓塞、胸痛、肺充血、和心悸。另外,DCM引起降低的射血分数(即内在收缩功能和重塑二者的度量)。该疾病进一步表征为心室扩张和心肌收缩性降低引起的收缩功能明显削弱,在许多患者中导致扩张性心力衰竭。作为肌细胞/心肌功能障碍的结果,患病心脏还经历细胞/腔重塑,促使“DCM表型”的形成。随着疾病进展,症状也进展。DCM患者中危及生命的心率失常(包括室性心动过速和心室纤颤)的发生率也大大升高。在这些患者中,晕厥(头晕)事件被视为猝死的前兆。
扩张型心肌病的诊断典型地依赖于心脏腔扩大,特别是心室扩大的表现。扩大通常可以借助胸部X射线观察,但是使用超声心动图进行评估更精确。DCM常常难以与急性心肌炎、瓣膜性心脏病、冠心病、和高血压心脏病区分。一旦作出扩张型心肌病的诊断,则尽力确定和治疗潜在可逆转的病因并预防进一步的心脏损伤。例如,必须排除冠心病和瓣膜性心脏病。贫血、异常的心动过速、营养缺乏、甲状腺疾病和/或其它问题需要加以处置和控制。
如上所述,使用药理学药剂的治疗方法仍然是降低或消除心力衰竭征候的主要机制。利尿剂是轻度到中度心力衰竭的一线治疗方法。不幸的是,许多常用利尿剂(例如噻嗪类)具有许多不良反应。例如,某些利尿剂可能提高血清胆固醇和甘油三酯。此外,利尿剂对于患有重度心力衰竭的患者一般是无效的。
如果利尿剂无效,那么可以使用血管舒张剂(vasodilatory agent);血管紧张素转化(ACE)抑制剂(例如恩诺普利(enalopril)和赖诺普利(lisinopril))不仅提供症状减轻,而且据报道说降低死亡率(Young等,1989)。然而,ACE抑制剂仍然伴随着不良反应,导致它们忌用于具有某些疾病状态(例如肾动脉狭窄)的患者。类似的,肌力药(inotropic agent)疗法(即通过提高心肌肌肉收缩的力量来改善心排血量的药物)伴随着各方面的不良反应,包括胃肠问题和中枢神经系统功能障碍。
由此可见,当前使用的药理学药剂在特定患者群中具有严重的缺点。新的、安全的且有效的药剂毫无疑问将会惠及那些不能使用目前可用的药理学模式或者无法从那些形式获得足够减轻的患者。DCM患者的预后是可变的,而且取决于心室功能障碍的程度,大多数死亡发生在诊断后五年内。
I.本发明
成年心脏中α-与β-MHC同等型的比率是心脏收缩性的主要决定因素。β-MHC是成年心脏中的主要肌球蛋白同等型,它展示相对低的ATP酶活性,而α-MHC具有高ATP酶活性。应答于多种病理性刺激(诸如心肌梗死、高血压、和其它病症时),β-MHC表达升高而α-MHC表达降低,结果是肌纤维ATP酶活性降低和心脏肌纤维的缩短速率降低,导致最终的收缩功能障碍。值得注意的是,心脏α-MHC含量的轻微变化可以对心脏性能具有深刻影响。
微RNA(miR)是小的、约22个核苷酸的RNA,它们衍生自更大的前miR(pre-miR)。miR起靶mRNA阻抑物的作用,这通过促进靶mRNA降解(当它们的序列完全互补时)或抑制靶mRNA翻译(当它们的序列包含错配时)来实现。微RNA-208(miR-208)由α-MHC基因的内含子编码,而且在心脏中特异性表达。本发明人创建了miR-208敲除小鼠并发现了miR-208是在成年心脏中激活β-MHC基因表达以及激活数种其它收缩蛋白质基因表达所必需的。另外,miR-208抑制导致心脏纤维化的剧烈降低。这些发现表明调控miR-208表达的策略对人体中的心脏收缩性会具有深刻影响,例如在心脏损伤后的心脏中抑制miR-208以阻止β-MHC表达并维持α-MHC表达。
本发明的另一个方面是miR-208表达或活性的激动作用用于治疗α-MHC基因中有突变的个体,所述激动作用是通过治疗性激活内源miR-208基因或是通过使用腺病毒载体或其它载体(不需要使用腺病毒系统的异位表达手段来提高β-MHC表达)将外源miR-208导入心脏来实现的。miR-208突变型小鼠心脏中数种快速骨骼肌收缩蛋白质基因的上调也表明miR-208典型地遏制快速骨骼肌基因程序。对心脏中这些基因的激活是调节心脏收缩性的一种潜在手段。
另外,本发明人建议使用miR-208来遏制骨骼肌中的快速纤维基因,由此激活慢速纤维基因的交互性(reciprocal)表达,这些慢速纤维基因与增强的胰岛素敏感性和骨骼肌耐久力关联。骨骼肌中慢速纤维基因的遏制和快速纤维基因的激活与许多肌肉骨骼病症有关,包括失用性萎缩(disuse atrophy)、应答于抗重力的肌肉消耗(musle wasting in response to anti-gravity)、和失神经支配(denervation)。
如此,本发明人发现了miR-208是心脏中β-MHC基因表达的肌肉特异性的、至关重要的调节物,另外还调节心脏纤维化。miR-208调节β-MHC表达和快速骨骼肌基因表达的发现完全是新的,微RNA用于控制心脏收缩性和骨骼肌功能的用途也是如此。
II.miRNA
A.背景
在2001年,数个小组使用一种新的克隆方法自秀丽线虫(C.elegans)、果蝇(Drosophila)、和人类分离和鉴定了一大类“微RNA”(miRNA)(Lagos-Quintana等,2001;Lau等,2001;Lee和Ambros,2001)。在植物和动物(包括似乎不具有内源siRNA的人类)中鉴定了数百种miRNA。如此,尽管与siRNA相似,但是miRNA是截然不同的。
至今观察到的miRNA长大约21-22个核苷酸,而且它们源自更长的前体,这些前体自非蛋白质编码基因转录得到。参见综述Carrington等(2003)。前体形成在自身互补区中彼此背靠背折叠的结构;然后它们受到动物中的Dicer核酸酶或植物中的DCL1的加工。miRNA分子通过与其靶物的精确或不精确的碱基配对来阻断翻译。
miRNA涉及基因调节。有些miRNA,包括lin-4和let-7,通过结合靶mRNA中部分互补的3′非翻译区(3′UTR)来抑制蛋白质合成。其它miRNA,包括在植物中找到的Scarecrow miRNA,像siRNA一样发挥功能,结合完全互补的mRNA序列来破坏靶转录物(Grishok等,2001)。
随着科学家们开始理解微RNA在调节真核基因表达中所发挥的广泛作用,关于这些分子的研究日益增多。了解最多的两种miRNA,即lin-4和let-7,在秀丽线虫中通过调节一个关键mRNA家族的翻译来调节发育时机(综述见Pasquinelli,2002)。已经在秀丽线虫、果蝇、小鼠、和人类中鉴定了数百种miRNA。正如对于调节基因表达的分子而言能想到的,已经显示了miRNA水平在各组织之间和在各发育状态之间有变化。另外,一项研究显示了两种miRNA的降低的表达与慢性淋巴细胞性白血病之间的强相关性,从而提供了miRNA与癌症之间的可能联系(Calin,2002)。虽然该领域仍然年轻,但是人们推测miRNA在高等真核细胞中调节基因表达方面和转录因子具有同样的重要性。
有些例子说明了miRNA在细胞分化、早期发育、和细胞过程像凋亡和脂肪代谢中发挥着至关重要的作用。lin-4和let-7都在秀丽线虫发育过程中调节从一个幼虫状态到另一幼虫状态的过渡(passage)(Ambros,2003)。mir-14和bantam是调节细胞死亡的果蝇miRNA,它们的调节作用表观上是通过调节凋亡相关的基因的表达来实现的(Brennecke等,2003,Xu等,2003)。还有人提示miR14涉及脂肪代谢(Xu等,2003)。Lsy-6和miR-273是秀丽线虫miRNA,它们调节感化性神经元中的不对称性(Chang等,2004)。另一种调节细胞分化的动物miRNA是miR-181,它指导造血细胞分化(Chen等,2004)。这些分子代表了具有已知功能的动物miRNA的整个范围。毫无疑问,对miRNA功能的进一步了解将会揭示有助于正常发育、分化、细胞间和细胞内通讯、细胞周期、血管发生、凋亡、和许多其它细胞过程的调节网络。鉴于miRNA在许多生物学功能中的重要作用,miRNA有可能会对治疗性干预或诊断性分析提供重要的指示。
对生物分子像miRNA的功能的表征常常牵涉将该分子导入细胞或自细胞中消除该分子并测量结果。如果将miRNA导入细胞导致凋亡,那么该miRNA毫无疑问参与凋亡途径。用于将miRNA导入细胞和自细胞中消除miRNA的方法已有记载。两份新近的出版物记载了可用于抑制特定miRNA活性的反义分子(Meister等,2004;Hutvagner等,2004)。另一份出版物记载了在转染入细胞后由内源RNA聚合酶转录并生成特定miRNA的治疗的用途(Zeng等,2002)。这两种试剂组合已经用于评估单一miRNA。
B.miR-208
miR-208是一种内含子miRNA,其位于α-MHC基因的第27个内含子内。图1。人类、小鼠、大鼠、和犬的miR-208的前-miRNA编码序列分别见SEQ IDNO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17。成熟miR-208序列见SEQ ID NO:5。像α-MHC一样,miR-208仅在心脏中表达。图2。
使用PicTar算法来鉴定miRNA靶物(Krek等,2005),本发明人鉴定了甲状腺激素受体相关蛋白1(THRAP1)是miR-208的预测靶物。来自人类、黑猩猩、小鼠、大鼠、犬、鸡、河豚、和斑马鱼的THRAP1 3′UTR序列分别见SEQ IDNO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQID NO:11、SEQ ID NO:12、和SEQ ID NO:13。
C.miR-208的抑制剂
一般而言,miRNA的抑制剂采取“antagomir”的形式,即与miRNA互补、阻断miRNA功能的化学工程化单链短寡核苷酸(Kriitzfeldt等,2005)。其它办法包括用改造成具有某些“药物样”特性(用于稳定性的化学修饰;用于投递的胆固醇偶联)的反义2′-O-甲基(2′-OMe)寡核苷酸和小干扰双链RNA(siRNA)来抑制miRNA(Krutzfeldt等,2005)。
III.治疗心脏肥大的方法
A.治疗方案
当前心血管病症背景下的心脏肥大的医学管理包括使用至少两种类型的药物:凝乳酶-血管紧张素系统的抑制剂和β-肾上腺素能阻滞剂(Bristow,1999)。心力衰竭背景下的治疗病理性肥大的治疗剂包括血管紧张素II转化酶(ACE)抑制剂和β-肾上腺素能受体阻滞剂(Eichhorn和Bristow,1996)。其它已经披露用于治疗心脏肥大的药学药剂包括血管紧张素II受体拮抗剂(美国专利5,604,251)和神经肽Y拮抗剂(WO 98/33791)。尽管有当前可用的药用化合物,对心脏肥大及续起的心力衰竭的预防和治疗仍然是治疗学上的挑战。
非药理学治疗主要用作药理学治疗的辅助手段。非药理学治疗的一种手段包括减少饮食中的钠。另外,非药理学治疗还需要消除某些促发性药物(precipitating drug),包括负性肌力药(negative inotropic agent)(例如某些钙通道阻滞剂和抗心率失常药如丙吡胺(disopyramide))、心脏毒素(例如安非他明(amphetamine))、和血(浆)容量扩充药(例如非类固醇抗炎药和糖皮质激素)。
在本发明的一个实施方案中,提供了利用miR-208的抑制剂来治疗心脏肥大或心力衰竭的方法。为了本申请的目的,治疗包括减少心脏肥大的一种或多种症状,诸如降低的运动能力、降低的射血体积、升高的左心室舒张末期压、升高的肺毛细血管楔压、降低的心排血量、心排血指数、升高的肺动脉压、升高的左心室收缩和舒张末期内径、和升高的左心室壁压、管壁张力和壁厚度——对右心室而言也一样。另外,miR-208的抑制剂的使用可以预防心脏肥大及其相关症状发生。
治疗方案会依临床状况而变化。然而在大多数情况中,长期维持似乎是适当的。可能还希望间歇地用miR-208的抑制剂治疗肥大,诸如在疾病进展过程中的一个短期窗口中进行。
B.联合疗法
在另一个实施方案中,联合其它治疗模式使用miR-208的抑制剂。如此,在上文所述疗法之外,还可以给患者提供更多“标准”药学心脏疗法。其它疗法的例子包括但不限于所谓的“β阻滞剂”、抗高血压药、强心剂、抗血栓药、血管舒张剂、激素拮抗剂、肌力药(iontropes)、利尿剂、内皮缩血管肽受体拮抗剂、钙通道阻滞剂、磷酸二酯酶抑制剂、ACE抑制剂、血管紧张素2型拮抗剂和细胞因子阻滞剂/抑制剂、和HDAC抑制剂。
联合用药可以通过使来心脏细胞接触含有两种药剂的单一组合物或药理学配制剂实现,或者通过使细胞同时接触两种不同的组合物或配制剂,其中一种组合物含有所述表达构建体,而另一种含有所述药剂。或者,使用miR-208抑制剂的疗法可以在其它药剂的施用之前或之后进行,间隔范围为几分钟到几周。在将另一药剂和表达构建体分别应用于细胞的实施方案中,一般会确保在每次投递的时间点之间不会经过一长段时间,以使得所述药剂和表达构建体仍能够对细胞发挥有利的联合效应。在此类情况中,通常会使细胞接触这两种形态的相隔时间在大约12-24小时内,更优选在相隔大约6-12小时内,最优选只有大约12小时的延迟时间。然而,在有些情况中,可能希望显著延长治疗的时间段,其中在各次施用之间相隔数天(2、3、4、5、6或7天)到数周(1、2、3、4、5、6、7或8周)。
还可以想到的是,可能希望施用miR-208抑制剂或者另一药剂多于一次。对此,可以采用各种联合用药。举例而言,基于总共3次和4次施用有下列例示性的排列,其中“A”是miR-208抑制剂,而“B”是另一药剂:A/B/A、B/A/B、B/B/A、A/A/B、B/A/A、A/B/B、B/B/B/A、B/B/A/B、A/A/B/B、A/B/A/B、A/B/B/A、B/B/A/A、B/A/B/A、B/A/A/B、B/B/B/A、A/A/A/B、B/A/A/A、A/B/A/A、A/A/B/A、A/B/B/B、B/A/B/B、B/B/A/B同样涵盖其它联合用药方式。
C.药理学治疗剂
药理学治疗剂及施用方法、剂量等是本领域技术人员众所周知的(参见例如“Physicians Desk Reference”、Klaassen的“The Pharmacological Basis ofTherapeutics”、“Remington′s Pharmaceutical Sciences”、和“The Merck Index,Eleventh Edition”,通过相关部分中的提及收入本文),而且可以根据本文的公开内容与本发明联合。根据所治疗受试者的状况,一些剂量变化会是必须的。无论如何,负责施用的人会为受试者个体确定适宜的剂量,而且此类个体确定在本领域普通技术人员的技术范围之内。
可用于本发明的药理学治疗剂的非限制性例子包括抗高脂蛋白药、抗动脉硬化药、抗血栓药/溶纤维蛋白药、凝血药、抗心率不齐药、抗高血压药、血管加压药(vesopresser)、充血性心力衰竭的治疗剂、抗心绞痛药、抗菌药或其组合。
另外,应当注意,任何下述各项可用于开发心脏疗法靶基因的新集合,而本发明实施例(见下文)中使用β-阻滞剂。虽然这些基因中许多可能交叠,但是可以开发新的基因靶。
i.抗高脂蛋白药
在某些实施方案中,可以将降低一种或多种血液脂质和/或脂蛋白浓度的药剂(在本文中称作“抗高脂蛋白药”)的施用与依照本发明的心血管疗法联合,特别是在动脉粥样硬化和血管组织增厚(thickening)或阻塞的治疗中。在某些方面,抗高脂蛋白药可以包括芳氧链烷酸/纤维酸(fibric acid)衍生物、树脂/胆汁酸螯合剂(sequesterant)、HMG CoA还原酶抑制剂、烟酸衍生物、甲状腺激素或甲状腺激素类似物、杂类药剂(miscellaneous agent)或其组合。
a.芳氧链烷酸/纤维酸衍生物
芳氧链烷酸/纤维酸衍生物的非限制性例子包括苄氯贝特(beclobrate)、enzafibrate、比尼贝特(binifibrate)、环丙贝特(ciprofibrate)、克利贝特(clinofibrate)、氯贝特或氯贝丁酯(clofibrate)(安脏美-S(atromide-S))、氯贝酸(clofibric acid)、依托贝特(etofibrate)、非诺贝特(fenofibrate)、吉非贝齐(gemfibrozil)(洛贝林(lobid))、尼可贝特(nicofibrate)、吡贝特(pirifibrate)、氯烟贝特(ronifibrate)、双贝特(simfibrate)和益多酯(theofibrate)。
b.树脂/胆汁酸螯合剂
树脂/胆汁酸螯合剂的非限制性例子包括考来烯胺(cholestyramine)(cholybar,questran)、考来替泊(colestipol)(colestid)和降胆葡胺(polidexide)。
c.HMG CoA还原酶抑制剂
HMG CoA还原酶抑制剂的非限制性例子包括洛伐他汀(lovastatin)(美降脂(mevacor))、普伐他汀(pravastatin)(pravochol)或辛伐他汀(simvastatin)(舒降之(zocor))。
d.烟酸衍生物
烟酸衍生物的非限制性例子包括烟酸盐(nicotinate)、阿西莫司(acepimox)、戊四烟酯(niceritrol)、尼可氯酯(nicoclonate)、尼可莫尔(nicomol)和氧烟酸(oxiniacic acid)。
e.甲状腺激素和类似物
甲状腺激素及其类似物的非限制性例子包括etoroxate、甲状丙酸(thyropropic acid)和甲状腺素(thyroxine)。
f.杂类抗高脂蛋白药
杂类抗高脂蛋白药的非限制性例子包括阿昔呋喃(acifran)、阿扎胆醇(azacosterol)、苯氟雷司(benfluorex)、β-亚苄基丁酰胺(benzalbutyramide)、肉碱(carnitine)、硫酸软骨素(chondroitin sulfate)、氯雌酮甲醚(clomestrone)、右旋糖酐(detaxtran)、硫酸右旋糖酐钠(dextran sulfate sodium)、5,8,11,14,17-二十碳五烯酸(eicosapentaenoic acid)、赤酮嘌呤(eritadenine)、夫拉扎勃(furazabol)、美格鲁托(meglutol)、甲亚油酰胺(melinamide)、双甲雌三醇(mytatrienediol)、鸟氨酸(ornithine)、γ-谷维素(oryzanol)、泛硫乙胺(pantethine)、季戊四醇四乙酸酯(pentaerythritol tetraacetate)、α-苯基丁酰胺(phenylbutyramide)、吡扎地尔(pirozadil)、普罗布考(probucol)(lorelco)、β-谷甾醇(sitosterol)、磺托酸-哌嗪盐(sultosilic acid-piperazine salt)、硫地醇(tiadenol)、曲帕拉醇(triparanol)和联苯丁酸(xenbucin)。
ii.抗动脉粥样硬化药
抗动脉粥样硬化药的非限制性例子包括吡啶醇氨基甲酸酯(pyridinolcarbamate)。
iii.抗血栓药/溶纤维蛋白药
在某些实施方案中,有助于清除或预防血块的药剂的施用可以与调控剂的施用联合,特别是在动脉粥样硬化和血管系统(例如动脉)阻塞的治疗中。抗血栓药和/或溶纤维蛋白药的非限制性例子包括抗凝剂、抗凝剂拮抗剂、抗血小板剂、血栓溶解剂、血栓溶解剂拮抗剂或其组合。
在某些方面,优选可以口服施用的抗血栓药,诸如例如阿司匹林(aspirin)和华法林(wafarin)(香豆定(Coumadin))。
a.抗凝剂
抗凝剂的非限制性例子包括醋硝香豆素(acenocoumarol)、安克洛酶(ancrod)、茴茚二酮(anisindione)、溴茚二酮(bromindione)、氯茚二酮(clorindione)、库美香豆素(coumetarol)、环香豆素(cyclocumarol)、硫酸右旋糖酐钠(dextran sulfate sodium)、双香豆素(dicumarol)、二苯茚酮(diphenadione)、双香豆素乙酯(ethyl biscoumacetate)、双香豆素亚乙酯(ethylidene dicoumarol)、氟茚二酮(fluindione)、肝素(heparin)、水蛭素(hirudin)、阿朴酸钠(lyapolate sodium)、奥沙二酮(oxazidione)、戊聚糖多硫酸酯(pentosanpolysulfate)、苯茚二酮(phenindione)、苯并香豆素(phenprocoumon)、卵黄高磷蛋白(phosvitin)、吡考他胺(picotamide)、噻氯香豆素(tioclomarol)和华法林warfarin)。
b.抗血小板剂
抗血小板剂的非限制性例子包括阿司匹林(aspirin)、右旋糖酐(dextran)、双嘧达莫(dipyridamole)(潘生丁(persantin))、肝素(heparin)、磺吡酮(sulfmpyranone)(安特灵(anturane))和噻氯匹定(ticlopidine)(力抗栓(ticlid))。
c.血栓溶解剂
血栓溶解剂的非限制性例子包括组织纤溶酶原激活物(Activase)、纤溶酶、尿激酶原、尿激酶(雅激酶(Abbokinase))、链激酶(Streptase)、阿尼普酶(anistreplase)/APSAC(依米那酶(eminase))。
iv.凝血药
在患者患有出血或出血可能性升高的某些实施方案中,可以使用可增强血液凝固的药剂。血液凝固促进剂的非限制性例子包括血栓溶解剂拮抗剂和抗凝剂拮抗剂。
a.抗凝剂拮抗剂
抗凝剂拮抗剂的非限制性例子包括鱼精蛋白(protamine)和维生素K1。
b.血栓溶解剂拮抗剂和抗血栓药
血栓溶解剂拮抗剂的非限制性例子包括氨基己酸(amicar)和氨甲环酸(amstat)。抗血栓药的非限制性例子包括阿那格雷(anagrelide)、阿加曲班(argatroban)、西鲁唑啉(cilstazol)、达曲班(daltroban)、去纤苷(defibrotide)、依诺肝素(enoxaparin)、速避凝(fraxiparine)、吲哚布吩(indobufen)、lamoparan、奥扎格雷(ozagrel)、吡考他胺(picotamide)、普拉贝脲(plafibride)、替地肝素(tedelparin)、噻氯匹定(ticlopidine)和三氟柳(triflusal)。
v.抗心率不齐药
抗心率不齐药的非限制性例子包括I类抗心率不齐药(钠通道阻滞剂)、II类抗心率不齐药(β-肾上腺素能阻滞剂)、III类抗心率不齐药(复极延长药)、IV类抗心率不齐药(钙通道阻滞剂)和杂类抗心率不齐药。
a.钠通道阻滞剂
钠通道阻滞剂的非限制性例子包括IA类、IB类和IC类抗心率不齐药。IA类抗心率不齐药的非限制性例子包括丙吡胺(disppyramide)(诺佩斯(norpace))、普鲁卡因胺(procainamide)(pronestyl)和奎尼丁(quinidine)(quinidex)。IB类抗心率不齐药的非限制性例子包括利多卡因(lidocaine)(赛洛卡因(xylocaine))、妥卡尼(tocainide)(妥卡胺(tonocard))和美西律(mexiletine(脉舒律(mexitil))。IC类抗心率不齐药的非限制性例子包括恩卡尼(encainide(恩犬(enkaid))和氟卡尼(flecainide)(tambocor)。
b.β阻滞剂
β阻滞剂(也称作β-肾上腺素能阻滞剂、β-肾上腺素能拮抗剂或II类抗心率不齐药)的非限制性例子包括醋丁洛尔(acebutolol)(sectral)、阿普洛尔(alprenolol)、氨磺洛尔(amosulalol)、阿罗洛尔(arotinolol)、阿替洛尔(atenolol)、苯呋洛尔(befunolol)、倍他洛尔(betaxolol)、贝凡洛尔(bevantolol)、比索洛尔(bisoprolol)、波吲洛尔(bopindolol)、布库洛尔(bucumolol)、布菲洛尔(bufetolol)、丁呋洛尔(bufuralol)、布尼洛尔(bunitrolol)、布拉洛尔(bupranolol)、盐酸布替君(butidrine hydrochloride)、丁非洛尔(butofilolol)、卡拉洛尔(carazolol)、卡替洛尔(carteolol)、卡维地洛(carvedilol)、塞利洛尔(celiprolol)、塞他洛尔(cetamolol)、氯拉洛尔(cloranolol)、地来洛尔(dilevalol)、依泮洛尔(epanolol)、艾司洛尔(esmolol)(brevibloc)、茚诺洛尔(indenolol)、拉贝洛尔(labetalol)、左布诺洛尔(levobunolol)、甲吲洛尔(mepindolol)、美替洛尔(metipranolol)、美托洛尔(metoprolol)、莫普洛尔(moprolol)、纳多洛尔(nadolol)、萘肟洛尔(nadoxolol)、硝苯洛尔(nifenalol)、尼普地洛(nipradilol)、氧烯洛尔(oxprenolol)、喷布洛尔(penbutolol)、吲哚洛尔(pindolol)、普拉洛尔(practolol)、丙萘洛尔(pronethalol)、萘心安(propanolol)(心得安(inderal))、索他洛尔(sotalol)(betapace)、硫氧洛尔(sulfinalol)、他林洛尔(talinolol)、特他洛尔(tertatolol)、噻吗洛尔(timolol)、托利洛尔(toliprolol)和希波酚(xibinolol)。在某些方面,β阻滞剂包括芳氧丙醇胺衍生物。芳氧丙醇胺衍生物的非限制性例子包括醋丁洛尔(acebutolol)、阿普洛尔(alprenolol)、阿罗洛尔(arotinolol)、阿替洛尔(atenolol)、倍他洛尔(betaxolol)、贝凡洛尔(bevantolol)、比索洛尔(bisoprolol)、波吲洛尔(bopindolol)、布尼洛尔(bunitrolol)、丁非洛尔(butofilolol)、卡拉洛尔(carazolol)、卡替洛尔(carteolol)、卡维地洛(carvedilol)、塞利洛尔(celiprolol)、塞他洛尔(cetamolol)、依泮洛尔(epanolol)、茚诺洛尔(indenolol)、甲吲洛尔(mepindolol)、美替洛尔(metipranolol)、美托洛尔(metoprolol)、莫普洛尔(moprolol)、纳多洛尔(nadolol)、尼普地洛(nipradilol)、氧烯洛尔(oxprenolol)、喷布洛尔(penbutolol)、吲哚洛尔(pindolol)、propanolol、他林洛尔(talinolol)、特他洛尔(tertatolol)、噻吗洛尔(timolol)和托利洛尔(toliprolol)。
c.复极延长剂
延长复极的药剂(也称作III类抗心率不齐药)的非限制性例子包括胺碘酮(amiodarone)(可达龙(cordarone))和索他洛尔(sotalol)(betapace)。
d.钙通道阻滞剂/拮抗剂
钙通道阻滞剂(也称作IV类抗心率不齐药)的非限制性例子包括芳烃胺(arylalkylamine)(例如bepridile、地尔硫卓(diltiazem)、芬地林(fendiline)、戈洛帕米(gallopamil)、普尼拉明(prenylamine)、特罗地林(terodiline)、维拉帕米(verapamil))、二氢吡啶衍生物(非洛地平(felodipine)、伊拉地平(isradipine)、尼卡地平(nicardipine)、硝苯地平(nifedipine)、尼莫地平(nimodipine)、尼索地平(nisoldipine)、尼群地平(nitrendipine))、哌嗪衍生物(例如桂利嗪(cinnarizine)、氟桂利嗪(flunarizine)、利多氟嗪(lidoflazine))或杂类钙通道阻滞剂诸如苄环烷(bencyclane)、依他苯酮(etafenone)、镁(magnesium)、米贝拉地尔(mibefradil)或哌克昔林(perhexiline)。在某些实施方案中,钙通道阻滞剂包括长效二氢吡啶(硝苯地平型)钙拮抗剂。
e.杂类抗心率不齐药
杂类抗心率不齐药的非限制性例子包括阿糖腺苷(adenosine)(腺苷(adenocard))、地高辛(digoxin)(拉诺辛(lanoxin))、乙酰卡尼(acecainide)、阿义马林(ajmaline)、克冠吗啉(amoproxan)、阿普林定(aprindine)、溴苄胺甲苯磺酸盐(bretylium tosylate)、丁萘夫汀(bunaftine)、布托苯定(butobendine)、卡泊酸(capobenic acid)、西苯唑啉(cifenline)、吡二丙胺(disopyranide)、二氢奎尼丁(hydroquinidine)、英地卡尼(indecainide)、异丙托溴铵(ipatropiumbromide)、利多卡因(lidocaine)、劳拉义明(lorajmine)、劳卡尼(lorcainide)、甲氧苯汀(meobentine)、莫雷西嗪(moricizine)、吡美诺(pirmenol)、丙缓脉灵(prajmaline)、普罗帕酮(propafenone)、吡诺林(pyrinoline)、奎尼丁聚半乳糖醛酸盐(quinidine polygalacturonate)、硫酸奎尼丁(quinidine sulfate)和维喹地尔(viquidil)。
vi.抗高血压药
抗高血压药的非限制性例子包括交感神经阻滞药、α/β阻滞剂、α阻滞剂、抗血管紧张素II药、β阻滞剂、钙通道阻滞剂、血管舒张剂和杂类抗高血压药。
a.α阻滞剂
α阻滞剂(也称作α-肾上腺素能阻滞剂或α-肾上腺素能拮抗剂)的非限制性例子包括氨磺洛尔(amosulalol)、阿罗洛尔(arotinolol)、达哌唑(dapiprazole)、多沙唑嗪(doxazosin)、甲磺酰二氢麦角毒(ergoloid mesylates)、芬司匹利(fenspiride)、吲哚拉明(indoramin)、拉贝洛尔(labetalol)、尼麦角林(nicergoline)、哌唑嗪(prazosin)、特拉唑嗪(terazosin)、妥拉唑林(tolazoline)、曲马唑嗪(trimazosin)和育亨宾(yohimbine)。在某些实施方案中,α阻滞剂可以包括喹唑啉衍生物。喹唑啉衍生物的非限制性例子包括阿夫唑嗪(alfuzosin)、布那唑嗪(bunazosin)、多沙唑嗪(doxazosin)、哌唑嗪(prazosin)、特拉唑嗪(terazosin)和曲马唑嗪(trimazosin)。
b.α/β阻滞剂
在某些实施方案中,抗高血压药既是α肾上腺素能拮抗剂又是β肾上腺素能拮抗剂。α/β阻滞剂的非限制性例子包括拉贝洛尔(labetalol)(normodyne、湍泰低(trandate))。
c.抗血管紧张素II类药
抗血管紧张素II类药的非限制性例子包括血管紧张素转化酶抑制剂和血管紧张素II受体拮抗剂。血管紧张素转化酶抑制剂(ACE抑制剂)的非限制性例子包括阿拉普利(alacepril)、依那普利(enalapril)(vasotec)、卡托普利(captopril)、西拉普利(cilazapril)、地拉普利(delapril)、依那普拉利(enalaprilat)、福辛普利(fosinopril)、赖诺普利(lisinopril)、莫维普利(moveltopril)、培哚普利(perindopril)、喹那普利(quinapril)和雷米普利(ramipril)。血管紧张素II受体阻滞剂(也称作血管紧张素II受体拮抗剂、ANG受体阻滞剂或ANG-H型-1受体阻滞剂(ARBS)的非限制性例子包括angiocandesartan、依普罗沙坦(eprosartan)、厄贝沙坦(irbesartan)、氯沙坦(losartan)和缬沙坦(valsartan)。
d.交感神经阻滞药
交感神经阻滞药的非限制性例子包括作用于中枢的交感神经阻滞药或作用于外周的交感神经阻滞药。作用于中枢的交感神经阻滞药(也称作中枢神经系统(CNS)交感神经阻滞药)的非限制性例子包括可乐定(clonidine)(catapres)、胍那苄(guanabenz)(wytensin)、胍法辛(guanfacine)(tenex)和甲基多巴(methyldopa)(爱道美(aldomet))。作用于外周的交感神经阻滞药的非限制性例子包括神经节阻滞剂、肾上腺素能神经元阻滞剂、β-肾上腺素能阻滞剂或α1-肾上腺素能阻滞剂。神经节阻滞剂的非限制性例子包括美卡拉明(mecamylamine)(inversine)和曲美芬(trimethaphan)(阿方那特(arfonad))。肾上腺素能神经元阻滞剂的非限制性例子包括胍乙啶(guanethidine)(依斯迈林(ismelin))和利舍平(reserpine)(serpasil)。β-肾上腺素能阻滞剂的非限制性例子包括醋丁洛尔(acenitolol)(sectral)、阿替洛尔(atenolol)(天诺敏(tenormin))、倍他洛尔(betaxolol)(卡尔仑(kerlone))、卡替洛尔(carteolol)(卡特洛尔(cartrol))、拉贝洛尔(labetalol)(normodyne、湍泰低(trandate))、美托洛尔(metoprolol)(lopressor)、纳多洛尔(nadanol)(康加尔多(corgard))、喷布洛尔(penbutolol)(levatol)、吲哚洛尔(pindolol)(visken)、普萘洛尔(propranolol)(心得安(inderal))和噻吗洛尔(timolol)(blocadren)。α1-肾上腺素能阻滞剂的非限制性例子包括哌唑嗪(prazosin)(脉宁平(minipress))、多沙唑嗪(doxazocin)(卡杜雷(cardura))和特拉唑嗪(terazosin)(高特灵(hytrin))。
e.血管舒张剂
在某些实施方案中,心血管扩张剂治疗剂可以包括血管舒张剂(例如脑血管舒张剂、冠状动脉血管舒张剂或周围血管舒张剂)。在某些优选的实施方案中,血管舒张剂包括冠状动脉血管舒张剂。冠状动脉血管舒张剂的非限制性例子包括胺氧三苯(amotriphene)、地巴唑(bendazol)、琥珀苯呋地尔(benfurodil hemisuccinate)、苯碘达龙(benziodarone)、氯酚嗪(chloracizine)、chromonar、氯苯呋醇(clobenfurol)、氯硝甘油(clonitrate)、地拉卓(dilazep)、双嘧达莫(dipyridamole)、氢普拉明(droprenilamine)、乙氧黄酮(efloxate)、赤藓醇四硝酸酯(erythrityl tetranitrane)、依他苯酮(etafenone)、芬地林(fendiline)、夫洛地尔(floredil)、更利芬(ganglefene)、乙烷雌酚双(β-二乙氨乙基醚)(herestrol bis(β-diethylaminoethyl ether)、海索苯定(hexobendine)、硝乙醇胺甲苯磺酸盐(itramin tosylate)、凯林(khellin)、利多氟嗪(lidoflanine)、甘露醇六硝酸酯(mannitol hexanitrane)、美地巴嗪(medibazine)、硝酸甘油(nicorglycerin)、戊四硝酯(pentaerythritol tetranitrate)、戊硝醇(pentrinitrol)、哌克昔林(perhexiline)、匹美茶碱(pimefylline)、曲匹地尔(trapidil)、tricromyl、曲美他嗪(trimetazidine)、磷酸三硝乙醇胺(trolnitrate phosphate)和维斯那定(visnadine)。
在某些方面,血管舒张剂可以包括长期疗法血管舒张剂或高血压紧急血管舒张剂。长期疗法血管舒张剂的非限制性例子包括肼屈嗪(hydralazine)(apresoline)和米诺地尔(minoxidil)(loniten)。高血压紧急血管舒张剂的非限制性例子包括硝普盐(nitroprusside)(nipride)、二氮嗪(diazoxide)(hyperstat IV)、肼屈嗪(hydralazine)(apresoline)、米诺地尔(minoxidil)(loniten)和维拉帕米(verapamil)。
f.杂类抗高血压药
杂类抗高血压药的非限制性例子包括阿义马林(ajmaline)、γ-氨基丁酸、丁苯碘胺(bufeniode)、西氯他宁(cicletainine)、环西多明(ciclosidomine)、鞣酸绿藜安(cryptenamine tannate)、非诺多泮(fenoldopam)、氟司喹南(flosequinan)、酮色林(ketanserin)、美布氨酯(mebutamate)、美卡拉明(mecamylamine)、甲基多巴(methyldopa)、甲基4-吡啶基酮硫代缩氨基脲(methyl 4-pyridyl ketonethiosemicarbazone)、莫唑胺(muzolimine)、帕吉林(pargyline)、潘必啶(pempidine)、吡那地尔(pinacidil)、哌罗克生(piperoxan)、普立哌隆(primaperone)、原藜芦碱(protoveratrine)、萝巴新(raubasine)、瑞西美托(rescimetol)、利美尼定(rilmenidene)、沙拉新(saralasin)、硝普钠(sodiumnitrorusside)、替尼酸(ticrynafen)、樟脑磺酸曲美芬(trimethaphan camsylate)、酪氨酸酶(tyrosinase)和乌拉地尔(urapidil)。
在某些方面,抗高血压药可以包括芳基乙醇胺衍生物、苯噻二嗪衍生物、N-羧烃基(肽/内酰胺)衍生物、二氢吡啶衍生物、胍衍生物、肼/酞嗪、咪唑衍生物、季铵化合物、利舍平衍生物或磺磷酰胺衍生物。
芳基乙醇胺衍生物.芳基乙醇胺衍生物的非限制性例子包括氨磺洛尔(amosulalol)、丁呋洛尔(bufuralol)、地来洛尔(dilevalol)、拉贝洛尔(labetalol)、丙萘洛尔(pronethalol)、索他洛尔(sotalol)和硫氧洛尔(sulfinalol)。
苯噻二嗪衍生物.苯噻二嗪衍生物的非限制性例子包括阿尔噻嗪(althizide)、苄氟噻嗪(bendroflumethiazide)、苄噻嗪(benzthiazide)、苄氢氯噻嗪(benzylhydrochlorothiazide)、布噻嗪(buthiazide)、氯噻嗪(chlorothiazide)、氯噻酮(chlorthalidone)、环戊噻嗪(cyclopenthiazide)、环噻嗪(cyclothiazide)、二氮嗪(diazoxide)、依匹噻嗪(epithiazide)、乙噻嗪(ethiazide)、芬喹唑(fenquizone)、氢氯噻嗪(hydrochlorothizide)、氢氟噻嗪(hydroflumethizide)、甲氯噻嗪(methyclothiazide)、美替克仑(meticrane)、美托拉宗(metolazone)、对氟噻嗪(paraflutizide)、泊利噻嗪(polythizide)、四氯噻嗪(tetrachlormethiazide)和三氯噻嗪(trichlormethiazide)。
N-羧烃基(肽/内酰胺)衍生物.N-羧烃基(肽/内酰胺)衍生物的非限制性例子包括阿拉普利(alacepril)、卡托普利(captopril)、西拉普利(cilazapril)、地拉普利(delapril)、依那普利(enalapril)、依那普拉利(enalaprilat)、福辛普利(fosinopril)、赖诺普利(lisinopril)、莫维普利(moveltipril)、培哚普利(perindopril)、喹那普利(quinapril)和雷米普利(ramipril)。
二氢吡啶衍生物.二氢吡啶衍生物的非限制性例子包括氨氯地平(amlodipine)、非洛地平(felodipine)、伊拉地平(isradipine)、尼卡地平(nicardipine)、硝苯地平(nifedipine)、尼伐地平(nilvadipine)、尼索地平(nisoldipine)和尼群地平(nitrendipine)。
胍衍生物.胍衍生物的非限制性例子包括倍他尼定(bethanidine)、异喹胍(debrisoquin)、胍那苄(guanabenz)、胍那克林(guanacline)、胍那决尔(guanadrel)、胍那佐定(guanazodine)、胍乙啶(guanethidine)、胍法辛(guanfacine)、胍氯酚(guanochlor)、胍诺沙苄(guanoxabenz)和胍生(guanoxan)。
肼/酞嗪.肼/酞嗪的非限制性例子包括布屈嗪(budralazine)、卡屈嗪(cadralazine)、双肼屈嗪(dihydralazine)、恩屈嗪(endralazine)、肼卡巴嗪(hydracarbazine)、肼屈嗪(hydralazine)、苯异丙肼(pheniprazine)、匹尔屈嗪(pildralazine)和托屈嗪(todralazine)。
咪唑衍生物.咪唑衍生物的非限制性例子包括可乐定(clonidine)、洛非西定(lofexidine)、酚妥拉明(phentolamine)、噻美尼定(tiamenidine)和托洛尼定(tolonidine)。
季铵化合物.季铵化合物的非限制性例子包括阿扎溴铵(azamethoniumbromide)、松达氯铵(chlorisondamine chloride)、六甲双铵(hexamethonium)、甲硫氰戊吗啉[pentacynium bis(methylsulfate)]、五甲溴铵(pentamethoniumbromide)、酒石酸戊双吡胺(pentolinium tartrate)、芬托氯铵(phenactropiniumchloride)和甲硫曲美替定(trimethidinium methosulfate)。
利舍平衍生物.利舍平衍生物的非限制性例子包括比他舍平(bietaserpine)、地舍平(deserpidine)、瑞西那明(rescinnamine)、利舍平(reserpine)和昔洛舍平(syrosingopine)。
磺磷酰胺衍生物.磺磷酰胺衍生物的非限制性例子包括安布赛特(ambuside)、氯帕胺(clopamide)、呋塞米(furosemide)、吲达帕胺(indapamide)、喹乙宗(quinethazone)、曲帕胺(tripamide)和希帕胺(xipamide)。
g.血管加压药(vesopressors)
血管加压药一般用于在外科程序中可能发生的休克过程中提高血压。血管加压药(也称作抗低血压药)的非限制性例子包括氨甲氧苯嗪甲基硫酸盐(amezinium methyl sulfate)、血管紧张素酰胺、二甲福林(dimetofrine)、多巴胺(dopamine)、依替非明(etifelmin)、依替福林(etilefrin)、吉培福林(gepefrine)、间羟胺(metaraminol)、米多君(midodrine)、去甲肾上腺素(norepinephrine)、福来君(pholedrine)和昔奈福林(synephrine)。
vii.用于充血性心力衰竭的治疗剂
用于充血性心力衰竭治疗的药剂的非限制性例子包括抗血管紧张素II药、后负荷-前负荷还原处理(reduction treatment)、利尿药和肌力药。
a.后负荷-前负荷减少
在某些实施方案中,可以用联合疗法来治疗不能耐受血管紧张素拮抗剂的动物患者。此类疗法可以联合肼屈嗪(hydralazine)(apresoline)和硝酸异山梨酯(isosorbide dinitrate)(isordil,sorbitrate)的施用。
b.利尿药
利尿剂的非限制性例子包括噻嗪(thiazide)或苯噻二嗪(benzothiadiazine)衍生物(例如阿尔噻嗪(althiazide)、苄氟噻嗪(bendroflumethazide)、苄噻嗪(benzthiazide)、苄氢氯噻嗪(benzylhydrochlorothiazide)、布噻嗪(buthiazide)、氯噻嗪(chlorothiazide)、氯噻嗪(chlorothiazide)、氯噻酮(chlorthalidone)、环戊噻嗪(cyclopenthiazide)、依匹噻嗪(epithiazide)、乙噻嗪(ethiazide)、乙噻嗪(ethiazide)、芬喹唑(fenquizone)、氢氯噻嗪(hydrochlorothiazide)、氢氟噻嗪(hydroflumethiazide)、甲氯噻嗪(methyclothiazide)、美替克仑(meticrane)、美托拉宗(metolazone)、对氟噻嗪(paraflutizide)、泊利噻嗪(polythizide)、四氯噻嗪(tetrachloromethiazide)、三氯噻嗪(trichlormethiazide))、有机汞(例如氯汞君(chlormerodrin)、美拉鲁利(meralluride)、汞罗茶碱(mercamphamide)、硫汞林钠(mercaptomerin sodium)、汞香豆酸(mercumallylic acid)、汞香豆林钠(mercumatilin dodium)、氯化亚汞(mercurous chloride)、汞撒利(mersalyl))、蝶啶(例如呋氨蝶啶(furterene)、氨苯蝶啶(triamterene))、嘌呤(例如茶碱乙酸哌嗪(acefylline)、7-吗啉甲茶碱(7-morpholinomethyltheophylline)、帕马溴帕马溴(pamobrom)、丙可可碱(protheobromine)、可可碱(theobromine))、类固醇(steroid)包括醛甾酮拮抗剂(例如坎利酮(canrenone)、夹竹桃苷(oleandrin)、螺内酯(spironolactone))、磺酰胺衍生物(例如乙酰唑胺(acetazolamide)、安布赛特(ambuside)、阿佐塞米(azosemide)、布美他尼(bumetanide)、布他唑胺(butazolamide)、氯米非那胺(chloraminophenamide)、氯非那胺(clofenamide)、氯帕胺(clopamide)、氯索隆(clorexolone)、二苯基甲烷-4,4′-二磺酰胺(diphenylmethane-4,4′-disulfonamide)、二磺法胺(disulfamide)、依索唑胺(ethoxzolamide)、呋塞米(furosemide)、吲达帕胺(indapamide)、美夫西特(mefruside)、醋甲唑胺(methazolamide)、吡咯他尼(piretanide)、喹乙宗(quinethazone)、托拉塞米(torasemide)、曲帕胺(tripamide)、希帕胺(xipamide))、尿嘧啶(例如氨美啶(aminometradine)、阿米美啶(amisometradine))、保钾拮抗剂(potassium sparing antagonist)(例如阿米洛利(amiloride)、氨苯蝶啶(triamterene))或杂类利尿剂诸如氯丙嗪(aminozine)、熊果苷(arbutin)、氯拉扎尼(chlorazanil)、依他尼酸(ethacrynic acid)、依托唑啉(etozolin)、肼卡巴嗪(hydracarbazine)、异山梨酯(isosorbide)、甘露醇(mannitol)、美托查酮(metochalcone)、莫唑胺(muzolimine)、哌克昔林(perhexiline)、替尼酸(ticrnafen)和脲(urea)。
c.肌力药
正性肌力药(也称作强心药)的非限制性例子包括茶碱乙酸(acefylline)、醋洋地黄毒苷(acetyldigitoxin)、2-氨基-4-皮考啉(2-amino-4-picoline)、氨力农(amrinone)、琥珀苯呋地尔(benfurodil hemisuccinate)、布拉地新(bucladesine)、黄夹次苷B(cerberosine)、樟吡他胺(camphotamide)、铃兰毒苷(convallatoxin)、磁麻苷(cymarin)、地诺帕明(denopamine)、去乙酰毛花苷(deslanoside)、毛地黄苷(digitalin)、毛地黄(digitalis)、洋地黄毒苷(digitoxin)、地高辛(digoxin)、多巴酚丁胺(dobutamine)、多巴胺(dopamine)、多培沙明(dopexamine)、依诺昔酮(enoximone)、红皮素(erythrophleine)、非那可明(fenalcomine)、吉他林(gitalin)、羟基洋地黄毒苷(gitoxin)、胍基乙酸(glycocyamine)、辛胺醇(heptaminol)、白毛莨分碱(hydrastinine)、异波帕胺(ibopamine)、毛花洋地黄苷(lanatoside)、甲氧酚酰胺(metamivam)、米力农(milrinone)、黄夹次苷B(nerifolin)、欧夹竹桃苷(oleandrin)、哇巴因(ouabain)、奥昔非君(oxyfedrine)、普瑞特罗(prenalterol)、海葱次苷(proscillaridine)、蟾力苏(resibufogenin)、海葱苷(scillaren)、海葱苷配基(scillarenin)、毒毛旋花素(strphanthin)、硫马唑(sulmazole)、可可碱(theobromine)和扎莫特罗(xamoterol)。
在具体的方面,正性肌力药是强心苷、β-肾上腺素能激动剂或磷酸二酯酶抑制剂。强心苷的非限制性例子包括地高辛(digoxin)(lanoxin)和洋地黄毒苷(digitoxin)(crystodigin)。β-肾上腺素能激动剂的非限制性例子包括沙丁胺醇(albuterol)、班布特罗(bambuterol)、比托特罗(bitolterol)、卡布特罗(carbuterol)、克仑特罗(clenbuterol)、氯丙那林(clorprenaline)、地诺帕明(denopamine)、双羟乙麻黄碱(dioxethedrine)、多巴酚丁胺(dobutamine)(独步催(dobutrex))、多巴胺(dopamine)(intropin)、多培沙明(dopexamine)、麻黄碱(ephedrine)、乙非君(etafedrine)、乙基去甲肾上腺素(ethylnorepinephrine)、非诺特罗(fenoterol)、福莫特罗(formoterol)、海索那林(hexoprenaline)、异波帕胺(ibopamine)、乙基异丙肾上腺素(isoetharine)、异丙肾上腺素(isoproterenol)、马布特罗(mabuterol)、奥西那林(metaproterenol)、甲氧那明(methoxyphenamine)、奥昔非君(oxyfedrine)、吡布特罗(pirbuterol)、丙卡特罗(procaterol)、普罗托醇(protokylol)、瑞普特罗(reproterol)、利米特罗(rimiterol)、利托君(ritodrine)、索特瑞醇(soterenol)、特布他林(terbutaline)、曲托喹酚(tretoquinol)、妥洛特罗(tulobuterol)和扎莫特罗(xamoterol)。磷酸二酯酶抑制剂的非限制性例子包括氨力农(amrinone)(inocor)。
d.抗心绞痛药
抗心绞痛药可以包括有机硝酸酯(organonitrate)、钙通道阻滞剂、β阻滞剂及其组合。
有机硝酸酯(也称作硝基血管舒张剂)的非限制性例子包括硝酸甘油(nitroglycerin)(nitro-bid,nitrostat)、二硝酸异山梨醇酯(isosorbide dinitrate)(isordil,sorbitrate)和硝酸戊酯(amyl nitrate)(aspirol,vaporole)。
viii.内皮缩血管肽受体拮抗剂
内皮缩血管肽(ET)是21个氨基酸的肽,其具有很强的生理学和病理生理学效应,这些效应似乎与心力衰竭的形成有关。ET的效应是经由与两类细胞表面受体的相互作用来介导的。A型受体(ET-A)与血管收缩和细胞生长有关,而B型受体(ET-B)与内皮细胞介导的血管舒张及与其它神经激素(诸如醛固酮)的释放有关。可抑制ET生成或抑制其刺激相关细胞的能力的药理学药剂是本领域已知的。对ET生成的抑制涉及使用能阻断一种酶的药剂,该酶称作内皮缩血管肽转化酶,涉及将该肽的前体加工成活性形式的作用。对ET刺激细胞的能力的抑制涉及使用能阻断ET与其受体相互作用的药剂。内皮缩血管肽受体拮抗剂(ERA)的非限制性例子包括波生坦(Bosentan)、恩拉生坦(Enrasentan)、安贝生坦(Ambrisentan)、达卢生坦(Darusentan)、替唑生坦(Tezosentan)、阿曲生坦(Atrasentan)、Avosentan、Clazosentan、Edonentan、司他生坦(sitaxsentan)、TBC 3711、BQ 123、和BQ 788。
D.外科治疗手段(surgical therapeutic agent)
在某些方面,次级(secondary)治疗手段可以包括一些类型的手术,包括例如预防性、诊断性或用于分期或分类的、治愈性和姑息性手术。手术,特别是治愈性手术,可以与其它疗法联合使用,诸如本发明和一种或多种其它药剂。
此类用于血管和心血管疾病和病症的外科治疗手段是本领域技术人员众所周知的,而且可以包括但不限于对生物体实施手术、提供心血管机械假体(cardiovascular mechanical prostheses)、血管成形术、冠状动脉再灌注、导管消融(catheter ablation)、给受试者提供可植入的心复律器除颤器(cardioverter defibrillator)、机械循环支持(mechanical circulatory support)或其组合。可用于本发明的机械循环支持的非限制性例子包括主动脉内球囊反搏(intra-aortic balloon counterpulsation)、左心室辅助装置(left ventricular assistdevice)或其组合。
E.药物配制剂和给患者施用的路径
在临床应用中,以适合于预定应用的形式制备药物组合物。通常,这需要制备基本上不含热原以及其它会对人类或动物有害的杂质的组合物。
通常会希望采用适宜的盐和缓冲剂来使得投递载体稳定和容许被靶细胞摄取。在将重组细胞导入患者中时,也会采用缓冲剂。本发明的水性组合物含有有效量的载体或细胞,它们溶解或分散在药学可接受的载体或水性介质中。短语“药学可接受的”或“药理学可接受的”指在施用给动物或人类时不产生不利的、过敏的、或其它不当的反应的分子实体和组合物。在用于本文时,“药学可接受的载体”包括溶剂、缓冲剂、溶液、分散介质、涂层、抗细菌和抗真菌药、等张剂和吸收延迟剂、等等在配制药品(诸如适合于给人类施用的药品)中可被接受使用的药剂。此类介质和药剂对药学活性物质的使用是本领域众所周知的。本发明涵盖任何常规介质或药剂在治疗性组合物中的使用,除非其与本发明的活性成分不相容。还可以将补充性的活性成分掺入组合物中,只要它们不使组合物的载体或细胞失活。
本发明的活性组合物可以包括药学制备物。这些依照本发明的组合物的施用可以经由任何普通路径,只要经该路径可达到靶组织。这包括口服(oral)、经鼻、或口含(buccal)。或者,施用可以是通过皮内、皮下、肌肉内、腹膜内或静脉内注射,或者通过直接注射入心脏组织。此类组合物通常会作为药学可接受的组合物来施用,如上文所述。
也可以胃肠外或腹膜内施用活性化合物。举例而言,可以在与表面活性剂诸如羟丙基纤维素适当混合的水中制备作为游离碱(free base)或药理学可接受盐的活性化合物溶液。也可以在甘油、液体聚乙二醇及其混合物中及在油中制备分散体。在贮存和使用的常规条件下,这些制备物一般含有防腐剂以预防微生物的生长。
适合于注射用途的药学形式包括例如无菌水溶液或分散体和无菌粉剂,无菌粉剂用于即时制备无菌可注射溶液或分散体。通常,这些制备物是无菌的且流动性达到易于注射的程度。制备物在生产和贮存的条件下应当是稳定的,而且应当具有针对微生物(诸如细菌和真菌)的污染作用的防护措施。适宜的溶剂或分散介质可以包括例如水、乙醇、多元醇(例如甘油、聚丙二醇、和液体聚乙二醇、等等)、它们的合适混合物、和植物油。例如,适当的流动性可以通过使用涂层(coating)(诸如卵磷脂)、通过维持所需粒度(在分散体的情况中)、和通过使用表面活性剂来维持。对微生物作用的预防可以通过多种抗细菌剂和抗真菌剂来得到,例如对羟基苯甲酸酯(parabens)、氯丁醇(chlorobutanol)、苯酚、山梨酸、硫柳汞(thimerosal)、等等。在许多情况中,优选包括等张剂,例如糖或氯化钠。可注射组合物的延长的吸收可以通过在组合物中使用延迟吸收的药剂(例如单硬脂酸铝和明胶)来得到。
无菌可注射溶液可以如下来制备,即,将活性化合物以适宜量掺入溶剂以及想要的任何其它成分(例如上文所列举的)中,继以过滤灭菌。通常,分散体如下来制备,即将各种已灭菌的活性成分掺入含有基础分散介质和想要的其它成分(例如上文所列举的)的无菌媒介中。对于用来制备无菌可注射溶液的无菌粉剂,优选的制备方法包括真空干燥和冷冻干燥技术,从事先经无菌过滤的溶液产生包含活性成分加上任何额外的期望成分的粉末。
对于口部施用(oral administration),一般将本发明的多肽与赋形剂掺合在一起,并以不可摄取(non-ingestible)的漱口剂和洁齿剂的形式使用。漱口剂可以如下来制备,即将活性成分以需要量掺入适宜溶剂(诸如硼酸钠溶液(Dobell氏液))中。或者,可以将活性成分掺入含有硼酸钠、甘油和碳酸氢钾的防腐洗液(antiseptic wash)中。也可以将活性成分分散在洁齿剂中,包括:凝胶剂、糊剂、粉剂和膏剂。可以将活性成分以治疗有效量添加至糊剂洁齿剂,其可以包括水、粘合剂、磨粉、芳香剂、起泡剂、和湿润剂。
本发明的组合物一般可以配制成中性的或盐的形式。药学可接受的盐包括例如酸加成盐(以蛋白质的游离氨基形成的),其衍生自无菌酸(例如盐酸或磷酸)或有机酸(例如醋酸、草酸、酒石酸、苦杏仁酸、等等)。以蛋白质的游离羧基形成的盐也可以衍生自无机碱(例如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙、或氢氧化铁)或有机碱(例如异丙胺、三甲胺、组氨酸、普鲁卡因等等)。
一旦配制好后,优选以与剂型(dosage formulation)相容的方式和以治疗上有效的量来施用溶液。可以以多种剂型(dosage form)来容易地施用配制剂,诸如可注射溶液、药物释放胶囊、等等。例如,对于水溶液的胃肠外施用,一般将溶液适当缓冲,并首先使得液体稀释剂等张(例如用充足的盐水或葡萄糖)。此类水溶液可以用于例如静脉内、肌肉内、皮下和腹膜内施用。优选地,采用无菌水性介质,正如本领域技术人员已知的,特别是根据本发明的公开内容。举例而言,可以将单个剂量溶解于1ml等张NaCl溶液,并且将其或是添加至1000ml皮下输液液体中,或是注射于建议的输注部位(参见“Remington′s Pharmaceutical Sciences”第15版,pp 1035-1038和1570-1580)。取决于所治疗的受试者的状况,剂量必然会有一些变化。无论如何,负责施用的人会为受试者个体确定适宜的剂量。此外,对于人类施用,制备物应当达到FDA生物制品标准办公室(Office of Biologies standards)所要求的无菌性、热原性、整体安全性和纯度标准。
IV.治疗肌肉骨骼疾病和纤维变性疾病的方法
在miR-208突变型小鼠的心脏中观察到了数种快速骨骼肌收缩蛋白质基因的上调。miR-208突变型小鼠的心脏中快速骨骼肌收缩蛋白质基因的这种上调指示了miR-208遏制快速骨骼肌基因程序(program)。在骨骼肌中,对慢速纤维基因的遏制和对快速纤维基因的激活与众多肌肉骨骼病症有关,包括失用性萎缩、应答无重力的肌肉消耗、和失神经支配。如此,骨骼肌细胞中miR-208的表达在遏制快速纤维基因,及由此激活慢速纤维基因的交互性表达中可能是有用的。因而,在某些实施方案中,本发明提供了用于通过给患有或有风险发生肌肉骨骼病症的受试者的骨骼肌施用miR-208来治疗肌肉骨骼病症的方法。
根据特化的收缩和代谢特性,成年骨骼肌纤维可以分成快速颤搐(fasttwitch)和慢速颤搐(slow twitch)亚型。这些特性反映了肌球蛋白重链和轻链、原肌球蛋白、和肌钙蛋白以及肌红蛋白的快速和慢速收缩蛋白同等型的特定集合的表达(Naya等,2000)。慢速颤搐肌肉主要在慢性活动,诸如姿势维持和持久的运动活动中被使用。快速颤搐纤维主要用于大力爆发性活动。成年骨骼肌表型不是静态的,而是保持适应载荷承担和收缩使用样式的变化的调整的能力,导致形态、表型、和收缩特性的适应。例如,对于啮齿类和人类,太空飞行的微重力环境中身体负荷的消除导致程度显著的肌肉萎缩及与收缩和代谢特性从慢到快变化有关的蛋白质表型改变(Tsika等,2002;Baldwin和Haddad,2001;Edgerton和Roy,2000;Fitts等,2000)。如此,在某些实施方案中,本发明提供了通过给骨骼肌施用miR-208来治疗或预防应答重力环境降低的肌肉消耗的方法。
失用性萎缩是因肌肉缺乏使用所致的肌肉萎缩。失用性萎缩通常见于卧床不起者、四肢上石膏者、或出于其它原因不活动者。另外,对肌纤维电活性的破坏,包括失神经支配,可导致肌肉萎缩。在短期失用后,肌肉萎缩是可逆的。然而,极端的肌肉失用可导致骨骼肌纤维的永久丧失,并且被结缔组织所取代。发明人设想,通过遏制骨骼肌中的快速纤维基因,从而激活慢速纤维基因的交互性表达,可以减轻或预防肌肉萎缩的症状。如此,在某些实施方案中,本发明提供了通过给骨骼肌施用miR-208来治疗或预防肌肉萎缩的方法。
在控制心脏中的纤维化中发挥重要作用之外,miR-29分子家族的遍在表达意味着它还可在其它纤维变性症候中发挥作用,诸如那些累及肾、肝和肺的纤维变性症候。还观察到糖尿病继发的纤维化。1型和2型糖尿病患者的心肌病风险升高。糖尿病中的心肌病伴随着一群特征,包括降低的舒张期顺应性、间质纤维化和肌细胞肥大。由于miR-208抑制miR-29,因此对miR-208的抑制可用于阻断心脏纤维化以及非心脏纤维化二者。
先天性肝纤维化(CHF)是一种罕见的侵袭肝和肾二者的疾病。患者遗传得到常染色体隐性性状。肝异常是肝大、将血液从不同器官运送至肝的静脉系统的压力升高(门静脉高压)、和蔓延整个肝脏的纤维样结缔组织(肝纤维化),常常称作肝损害。患病个体肾功能也受损,这通常是由常染色体隐性多囊性肾疾病(ARPKD)引起的。成人中与CHF相关的肾功能受损是由常染色体显性多囊性肾疾病(ADPKD)引起的。
肾功能的渐进性损失不仅伴随着肾小球硬化的发展,而且伴随着间质纤维化。间质纤维化的特征在于对肾小管和间质毛细管的破坏以及细胞外基质蛋白质的积累。小管间质性纤维化的严重性早已被认为是人类和实验性肾小球肾炎二者中渐进性肾损伤的决定性因素。
肺纤维化,或称肺的瘢痕形成,是纤维变性组织逐渐取代正常肺气囊的结果。在瘢痕形成时,组织变厚,引起组织将氧传递入血流的能力不可逆丧失。症状包括气短(特别是伴有费力)、慢性频繁干咳、疲劳和虚弱、胸部不适、食欲丧失和体重快速减轻。
有人假设肺纤维化可能是自身免疫病症,或者是病毒感染的后效应。然而,越来越多的人相信遗传素因是关键因素。已经发现具有肺纤维化病史的家族中存在SP-C蛋白中的突变。最近的看法是,纤维变性过程是一种针对肺微观损伤的(遗传上偏向的)反应。虽然仍然不知道确切的原因,但是已经与吸入的环境和职业污染物、吸烟、疾病(诸如硬皮病、类风湿性关节炎、狼疮和结节病)、某些医药和治疗性辐射联系起来。
患者中的糖尿病心肌病的特征在于心肌肥大、间质纤维化、毛细管内皮变化、和毛细管基片增厚,其继发于胶原结构的改变。胶原积累增加主要见于心外膜和血管周区域,在那里它诱导LV舒张功能受损,常常导致心力衰竭。
V.试剂盒
本文所述的任何组合物可包括在试剂盒中。在一个非限制性例子中,miRNA个体包括在试剂盒中。试剂盒可以进一步包括水和杂交缓冲液以便于miRNA两条链的杂交。试剂盒还可以包括一种或多种转染试剂以便于将miRNA投递至细胞。
试剂盒的成分可以在水性介质中或以冻干形式包装。试剂盒的容纳手段一般会包括至少一个管形瓶、试管、烧瓶、瓶、注射器或其它容纳手段,其中可以装盛成分,优选经过合适等分的成分。若试剂盒中有超过一种成分(标记试剂和标记物可以包装在一起),则试剂盒一般还会包括第二、第三或其它额外容器,将所述额外成分分开装盛。然而,管形瓶中可以装有各种成分组合。本发明的试剂盒通常还会包括装盛核酸的手段,和任何其它试剂容器,其为了商业销售是封闭固定的。此类容器可以包括注射或吹塑模制的塑料容器,其中放置想要的管形瓶。
若在一种和/或多种液体溶液中提供试剂盒的各成分,则所述液体溶液是水溶液,特别优选无菌水溶液。
然而,试剂盒的各成分可以作为干燥粉剂来提供。若以干粉来提供各试剂和/或各成分,则所述粉剂可以通过添加合适的溶剂来重建。还可以在另一容纳手段中提供所述溶剂。
容纳手段一般会包括至少一个管形瓶、试管、烧瓶、瓶、注射器或其它容器手段,其中装有核酸配制剂,优选合适分配的。试剂盒还可以包括第二容器手段,用于装盛无菌的、药学可接受的缓冲剂和/或其它稀释剂。
本发明的试剂盒通常还会包括用于装盛管形瓶的手段,其为了商业销售是封闭固定的,诸如例如注射/或吹塑模制的塑料容器,其中放置需要的管形瓶。
此类试剂盒还可以包括保持或维持miRNA或保护其免于降解的成分。此类成分可以是不含RNA酶的,或提供针对RNA酶的保护。此类试剂盒一般会为每种试剂或溶液提供合适的单独容器。
试剂盒还会包括采用试剂盒成分以及使用未包括在试剂盒中的任何其它试剂的说明(书)。说明(书)可以包括可以实施的变化形式。
此类试剂是本发明试剂盒的实施方案。然而,此类试剂盒不限于上文所列举的具体项目,而可以包括任何用于操作或表征miRNA的试剂。
VI.筛选方法
本发明进一步包括用于鉴定在预防或治疗或逆转心脏肥大或心力衰竭中有用的miR-208抑制剂的方法。这些测定法可以包括对候选物质大型文库的随机筛选;或者,所述测定法可以用于针对已经过选择的化合物的集中筛选,所述选择是针对使得化合物更有可能抑制miR-208的表达和/或功能的结构属性而进行的。
为了鉴定miR-208的调控剂,一般会在存在和不存在候选物质时测定miR-208功能。例如,所述方法一般包括:
(a)提供候选调控剂;
(b)将候选调控剂与miR-208混合;
(c)测量miR-208活性;并
(d)比较步骤(c)中的活性与不存在候选调控剂时的活性,
其中测量得到的活性之间有差异指示候选调控剂确实是miR-208的调控剂。
所述测定法也可以在分离的细胞、器官、或活的生物体中实施。
当然,应当理解,本发明的所有筛选方法本身是有用的,即使有可能无法找到有效的候选物。本发明提供了用于筛选此类候选物的方法,而不仅仅是找到它们的方法。
A.调控剂
在用于本文时,术语“候选物质”指任何可能调控miR-208的诱导β-MHC的功能的分子。通常会从各种商业来源获得认为达到有用药物的基本标准的分子文库,以“强力”推动有用化合物的鉴定。对此类文库(包括组合产生的文库,例如antagomir文库)的筛选是对大量相关的(和无关的)化合物进行活性筛选的快速且高效的方式。组合法也可用来在具有活性的但在其它方面并不理想的化合物的基础上创建第二代、第三代、和第四代化合物,从而有助于潜在药物的快速进化。
B.体外测定法
体外测定法是一种运行快速、廉价且容易的测定法。此类测定法一般使用分离的分子,可以快速地、大量地运行,由此提高在短时间内可获得的信息量。可以使用多个器皿来运行测定,包括试管、板、盘和其它表面,诸如测验片(dipstick)或珠子。
WO 84/03564中记载了一种高通量化合物筛选技术。可以在固体基质(诸如塑料针或一些其它表面)上合成大量的antogomir小化合物。可以对此类分子快速筛选它们与miR-208杂交的能力。
C.细胞内(In cyto)测定法
本发明还涵盖在细胞中筛选化合物调控miR-208表达和功能的能力。可以利用多种细胞系,包括衍生自骨骼肌细胞的细胞系,来实施此类筛选测定法,包括为此目的进行了专门工程改造的细胞。也可以使用原代心脏细胞,正如可以使用H9C2细胞系。
D.体内测定法
体内测定法涉及使用心脏疾病或肌肉骨骼疾病的各种动物模型,包括转基因动物,它们经过工程改造而具有特定的缺陷,或者携带可用于测量候选物质达到和影响生物体内不同细胞的能力的标志物。由于它们的大小、易操作性、和关于它们的生理学和遗传组成的信息,小鼠是一种优选的实施方案,尤其是对于转基因而言。然而,其它动物也是合适的,包括大鼠、家兔、仓鼠、豚鼠、沙鼠、旱獭、猫、犬、绵羊、山羊、猪、牛、马和猴(包括黑猩猩、长臂猿和狒狒)。针对抑制剂的测定法可以使用衍生自上述任一物种的动物模型来实施。
用测试化合物处理动物可涉及以适宜形式给动物施用化合物。施用可以通过任何可用于临床目的的路径。测定化合物在体内的效力可涉及多种不同标准,包括但不限于肥大性信号传导途径和肥大体征的改变。测量毒性和剂量响应也可以以比体外测定法和细胞内测定法更有意义的方式在动物中实施。
VII.用于克隆、基因转移和表达的载体
在某些实施方案中,采用表达载体来表达miR-208或其抑制剂。表达要求在载体中提供适宜的信号,包含多种调节元件,诸如来自病毒和哺乳动物二者来源的、驱动感兴趣基因在宿主细胞中表达的增强子/启动子。还定义了设计成优化信使RNA在宿主细胞中的稳定性和可翻译性的元件。还提供了为了建立表达产物的永久的、稳定的细胞克隆而使用多种显性药物选择标记的条件,以及将药物选择标记的表达与多肽的表达联系起来的元件。
A.调节元件
在本申请全文中,术语“表达构建体”意图包括任何类型的遗传构建体,其包含编码基因产物的核酸,该部分或整个核酸编码序列能够被转录。转录物可以被翻译成蛋白质,但它不需要被翻译成蛋白质。在某些实施方案中,“表达”既包括基因的转录,又包括mRNA翻译成基因产物。在其它实施方案中,“表达”只包括编码感兴趣基因的核酸的转录。
在某些实施方案中,编码基因产物的核酸在启动子的转录控制之下。“启动子”指被细胞的合成机构或导入的合成机构所识别,并且为启动基因的特异性转录所需的DNA序列。短语“在转录控制之下”意味着启动子相对于核酸处于正确位置和取向以控制RNA聚合酶启动和基因表达。
术语“启动子”在本文中会用于指一组在RNA聚合酶II的起始位点周围簇集的转录控制模块。关于启动子如何组织的看法大多来源于对数种病毒启动子的分析,包括HSV胸苷激酶(tk)和SV40早期转录单元的启动子。这些研究(它们得到了后来工作的支持)显示了启动子由离散的功能性模块构成,每个模块由大约7-20bp DNA组成,且包含一个或多个转录激活物识别位点或阻遏蛋白识别位点。
每种启动子中的至少一个模块起着确定RNA合成起始位点的位置的功能。对此了解最多的例子是TATA盒,但是在一些缺乏TATA盒的启动子中,诸如哺乳动物末端脱氧核苷酸转移酶基因的启动子和SV40晚期基因的启动子,由一个与起始位点自身有交叠的离散元件来帮助确定起始位置。
别的启动子元件调节转录起始的频率。通常,这些元件位于起始位点上游30-110bp的区域内,尽管最近证明许多启动子在起始位点的下游也有功能性元件。启动子各元件之间的间距通常是灵活的,使得在某元件相对于另一元件颠倒或移动时启动子功能得到保持。在tk启动子中,启动子各元件之间的间距可以提高至相距50bp,之后活性开始降低。取决于启动子,似乎元件个体可协作地或独立地发挥激活转录的功能。
在其它实施方案中,可以使用人巨细胞病毒(CMV)立即早期基因启动子、SV40早期启动子、Rous氏肉瘤病毒长末端重复、大鼠胰岛素启动子和甘油醛-3-磷酸脱氢酶来高水平表达感兴趣编码序列。还涵盖使用本领域众所周知的其它病毒或哺乳动物细胞或细菌噬菌体启动子来实现感兴趣编码序列的表达,只要表达水平对于给定目的是足够的。
通过采用具有公知特性的启动子,转染或转化后感兴趣蛋白质的表达水平和表达样式可以得到优化。另外,通过选择应答于特定生理信号而受到调节的启动子,可为基因产物的诱导型表达提供条件。表1和表2列举了数种在本发明的内容中可用于调节感兴趣基因表达的调节元件。该表并非意图穷举所有可能涉及启动基因表达的元件,仅仅是例示性的。
增强子是提高位于同一DNA分子上远端位置的启动子所致转录的遗传元件。增强子的组织与启动子很像。也就是说,它们由许多个体元件构成,每个元件结合一种或多种转录蛋白。
增强子与启动子之间的基本区别是运作上的(operational)。增强子区作为整体必须能够远距离刺激转录,而启动子区或其组成元件则不需要如此。另一方面,启动子必须具有一种或多种指导RNA合成在特定位点和以特定取向起始的元件,而增强子缺乏这些特性。启动子和增强子常常是交叠的和毗邻的,似乎常常具有非常相似的模块组织。
下文是可以在表达构建体中与编码感兴趣基因的核酸联合使用的病毒启动子、细胞启动子/增强子和诱导型启动子/增强子的列表(表1和表2)。另外,也可以使用任何启动子/增强子组合(根据真核启动子数据库EPDB)来驱动基因的表达。如果提供了适宜的细菌聚合酶的话(作为投递复合体的一部分,或作为另一遗传表达构建体来提供),真核细胞可支持某些细菌启动子的细胞质转录。
特别感兴趣的是肌肉特异性启动子,尤其是心脏特异性启动子。这些包括肌球蛋白轻链-2启动子(Franz等,1994;Kelly等,1995)、α肌动蛋白启动子(Moss等,1996)、肌钙蛋白1启动子(Bhavsar等,1996);Na4VCa2+交换器启动子(Barnes等,1997)、抗肌萎缩蛋白启动子(Kimura等,1997)、α7整联蛋白启动子(Ziober和Kramer,1996)、脑钠尿肽启动子(LaPointe等,1996)和αB-晶体蛋白/小热休克蛋白启动子(Gopal-Srivastava,1995)、α肌球蛋白重链启动子(Yamauchi-Takihara等,1989)和ANF启动子(LaPointe等,1988)。
若采用cDNA插入序列,则通常会希望包括多腺苷酸化信号以实现基因转录物的正确多腺苷酸化。认为多腺苷酸化信号的性质对于本发明的成功实施不是至关重要的,而且可以采用任何此类序列,诸如人生长激素和SV40多腺苷酸化信号。表达盒的元件还涵盖终止子。这些元件可用于增强信息水平,并最大程度地减少从所述盒到其它序列的通读。
B.选择标记
在本发明的某些实施方案中,细胞包含本发明的核酸构建体,可以通过在表达构建体中引入标记来在体外或在体内识别细胞。此类标记会赋予细胞以可识别的变化,从而有可能容易地识别包含表达构建体的细胞。通常,药物选择标记的引入有助于克隆和转化体的选择,例如赋予针对新霉素、嘌呤霉素、潮霉素、DHFR、GPT、zeocin和组氨醇的抗性的基因是有用的选择标记。或者,可以采用酶,诸如单纯疱疹胸苷激酶(tk)或链霉素乙酰转移酶(CAT)。也可以采用免疫学标记。认为所采用的选择标记不是重要的,只要它能够与编码基因产物的核酸同时表达。选择标志的其它例子是本领域技术人员众所周知的。
C.多基因构建体和IRES
在本发明的某些实施方案中,使用内部核糖体结合位点(IRES)元件来创建多基因或多顺反子信息。IRES元件能够绕开5′甲基化帽依赖性翻译的核糖体扫描模型并在内部位点处开始翻译(Pelletier和Sonenberg,1988)。已经记载了来自小核糖核酸病毒(picanovirus)家族两个成员(脊髓灰质炎和脑心肌炎)的IRES元件(Pelletier和Sonenberg,1988),以及来自哺乳动物信息的IRES(Macejak和Sarnow,1991)。可以将IRES元件与异源可读框连接。可以一起转录多个可读框,每个可读框以IRES分开,创建多顺反子信息。依靠IRES元件,核糖体可阅读每个可读框,从而实现高效翻译。可以通过用单个启动子/增强子转录出单条信息来高效表达多个基因。
可以将任何异源可读框与IRES元件连接。这包括分泌型蛋白质、由独立基因编码的多亚基蛋白质、细胞内或膜结合蛋白质和选择标记的基因。这样,可以利用单一构建体和单一选择标记改造细胞使其同时具有数种蛋白质的表达。
D.表达载体的投递
有许多方式可以将表达载体导入细胞中。在本发明的某些实施方案中,表达构建体包括病毒或衍生自病毒基因组的工程改造构建体。某些病毒经受体介导的胞吞进入细胞、整合入宿主细胞基因组中、及稳定且高效地表达病毒基因的能力使得它们成为将外来基因转移入哺乳动物细胞中的有吸引力的候选物(Ridgeway,1988;Nicolas和Rubenstein,1988;Baichwal和Sugden,1986;Temin,1986)。最早用作基因载体的病毒是DNA病毒,包括乳多空病毒(猿病毒40、牛乳头状瘤病毒、和多瘤病毒)(Ridgeway,1988;Baichwal和Sugden,1986)和腺病毒(Ridgeway,1988;Baichwal和Sugden,1986)。它们对外来DNA序列的容量相对较低,而且宿主谱有限。此外,它们在允许细胞中的致瘤潜力和细胞病变效应引起了人们对于安全性的担忧。它们只能容纳多至8kB的外来遗传材料,但是能容易地导入多种细胞系和实验室动物中(Nicolas和Rubenstein,1988;Temin,1986)。
用于体内投递的优选方法之一涉及使用腺病毒表达载体。“腺病毒表达载体”意图包括那些包含足以(a)支持构建体的包装和(b)表达已经克隆其中的反义多核苷酸的腺病毒序列的构建体。在此语境中,表达不要求基因产物被合成。
表达载体包括遗传工程形式的腺病毒。关于腺病毒——一种36kB的线性的双链DNA病毒——的遗传组织的知识,容许人们用多至7kB的外来序列替代大段腺病毒DNA(Grunhaus和Horwitz,1992)。与逆转录病毒相反,腺病毒对宿主细胞的感染不导致染色体整合,因为腺病毒DNA能以附加体方式复制,没有潜在的基因毒性。还有,腺病毒在结构上是稳定的,而且在广泛扩增后没有检测到基因组重排。腺病毒能感染几乎所有上皮细胞,不管它们的细胞周期阶段如何。迄今为止,腺病毒感染似乎只与轻微的疾病有关,诸如人类中的急性呼吸道疾病。
由于其中等大小的基因组、易于操作、滴度高、靶细胞范围宽和感染性高,腺病毒特别适合于用作基因转移载体。该病毒基因组的两个末端都包含100-200bp的反向重复(ITR),它们是病毒DNA复制和包装所必需的顺式元件。基因组的早期(E)和晚期(L)区域包含不同转录单元,由病毒DNA复制的发作分开。E1区(E1A和E1B)编码负责调节病毒基因组转录的蛋白质和一些细胞基因。E2区(E2A和E2B)的表达导致用于病毒DNA复制的蛋白质的合成。这些蛋白质涉及DNA复制、晚期基因表达和宿主细胞关闭(shut-off)(Renan,1990)。晚期基因的产物,包括大多数病毒壳体蛋白质,只在由主要晚期启动子(MLP)产生的单一处理转录物受到显著加工后方才表达。MLP(位于16.8m.u.)在感染晚期效率特别高,而且由此启动子产生的所有mRNA都具有5′-三元前导(TPL)序列,使得它们成为翻译所优选的mRNA。
在一种现有的系统中,自穿梭载体与前病毒载体之间的同源重组产生重组腺病毒。由于两个前病毒载体之间可能的重组,可能自此过程产生野生型腺病毒。因此,自单个噬斑分离病毒的单克隆并检验其基因组结构是至关重要的。
现有的复制缺陷型腺病毒载体的生成和繁殖依赖于一种独特的辅助细胞系,称作293,它是通过用Ad5DNA片段转化人胚胎肾细胞得到的,且组成性表达E1蛋白(Graham等,1977)。由于E3区不是腺病毒基因组所必需的(Jones和Shenk,1978),现有的腺病毒载体借助293细胞在E1、D3之任一或两个区域中携带外来DNA(Graham和Prevec,1991)。在自然界中,腺病毒能包装野生型基因组的大约105%(Ghosh-Choudhury等,1987),从而提供了额外的大约2kb DNA的容量。结合E1和E3区域中可替换的大约5.5kb DNA,现有的腺病毒载体的最大容量在7.5kb以下,或者说载体总长度的大约15%。超过80%的腺病毒基因组保留在载体主链中,而且是载体传播的细胞毒性的来源。还有,E1删除病毒的复制缺陷是不完全的。
辅助细胞系可以衍生自人细胞,诸如人胚胎肾细胞、肌肉细胞、造血细胞或其它人胚胎间充质或上皮细胞。或者,辅助细胞可以衍生自对人腺病毒允许的其它哺乳动物物种的细胞。此类细胞包括例如Vero细胞或其它猴胚胎间充质或上皮细胞。如上所述,优选的辅助细胞系是293。
Racher等(1995)披露了用于培养293细胞和繁殖腺病毒的改良方法。在一种模式下,将细胞个体接种入装有100-200ml培养基的1升渗硅旋转烧瓶(Techne,Cambridge,UK),来培养天然细胞聚集体。以40rpm搅动后,用锥虫蓝估计细胞存活力。在另一种模式下,如下采用Fibra-Cel微载体(Bibby Sterlin,Stone,UK)(5g/l)。将重悬在5ml培养基中的细胞接种体添加至250ml锥形瓶中的载体(50ml)并静置1-4小时,偶尔搅动。然后用50ml新鲜培养基更换培养基并开始摇动。为了病毒生成,让细胞生长至大约80%汇合,之后更换培养基(至25%总体积)并以0.05的MOI添加腺病毒。将培养物静置过夜,之后将体积增加至100%并再摇动72小时。
除了腺病毒载体是复制缺陷的或者至少是条件性缺陷的这一要求之外,认为腺病毒载体的性质对于本发明的成功实施不是至关重要的。腺病毒可以是42种不同的已知血清型或亚群A-F之任一。为了获得用于本发明的条件性缺陷的腺病毒载体,亚群C的5型腺病毒是优选的起始材料。这是因为5型腺病毒是人腺病毒,已经知道了关于它的许多生化和遗传信息,而且在传统上采用腺病毒作为载体的构建方法大多使用它。
如上所述,依照本发明的典型载体是复制缺陷的,而且不会有腺病毒E1区。如此,在已经去除了E1编码序列的位置导入编码感兴趣基因的多核苷酸会是最方便的。然而,在腺病毒序列内构建体插入的位置对于本发明不是至关重要的。也可以将编码感兴趣基因的多核苷酸插入E3置换型载体中来取代已被删除的E3区的位置,如Karlsson等(1986)所记载的,或者插入E4区,此时由辅助细胞系或辅助病毒来补足E4缺陷。
腺病毒易于培养和操作,而且在体外和在体内展现出宽宿主范围。可以以高滴度获得这组病毒,例如109-1012个噬斑形成单位每ml,而且它们是高度感染性的。腺病毒的生命周期不要求整合入宿主细胞基因组中。通过腺病毒载体投递的外来基因是附加体型的,因此对于宿主细胞具有较低的基因毒性。在用野生型腺病毒进行的疫苗接种的研究中没有副作用的报告(Couch等,1963;Top等,1971),证明了它们作为体内基因转移载体的安全性和治疗潜力。
腺病毒载体已经用于真核基因表达(Levrero等,1991;Gomez-Foix等,1992)和疫苗开发(Grunhaus和Horwitz,1992;Graham和Prevec,1991)。最近,动物研究提示重组腺病毒可用于基因疗法(Stratford-Perricaudet和Perricaudet,1991;Stratford-Perricaudet等,1990;Rich等,1993)。给不同组织使用重组腺病毒的研究包括气管滴注(Rosenfeld等,1991;Rosenfeld等,1992)、肌肉注射(Ragot等,1993)、周围静脉内注射(Herz和Gerard,1993)、和立体定向(stereotactic)脑中接种(Le GaI La Salle等,1993)。
逆转录病毒是一组单链RNA病毒,其特征在于在受感染细胞中通过逆转录将它们的RNA转变成双链DNA的能力(Coffin,1990)。然后,所得DNA稳定地整合入细胞染色体中成为原病毒并指导病毒蛋白质的合成。整合导致病毒基因序列在受体细胞及其后代中的保持。逆转录病毒基因组包含三种基因,即gag、pol、和env,它们分别编码壳体蛋白、聚合酶、和被膜成分。在gap基因上游存在的一种序列包含将基因组包装入病毒体中的信号。病毒基因组的5′和3′末端存在两个长末端重复(LTR)序列。它们包含强启动子和增强子序列,而且也是整合到宿主细胞基因组中所要求的(Coffin,1990)。
为了构建逆转录病毒载体,在将编码感兴趣基因的核酸插入病毒基因组中来取代(in the place of)某些病毒序列,以生成复制缺陷的病毒。为了生成病毒体,构建包含gag、pol、和env基因但不含LTR和包装成分的包装细胞系(Mann等,1983)。若将包含cDNA以及逆转录病毒LTR和包装序列的重组质粒导入此细胞系中(例如通过磷酸钙沉淀),包装序列容许重组质粒的RNA转录物包装入病毒颗粒中,然后这些病毒颗粒被分泌入培养液中(Nicolas和Rubenstein,1988;Temin,1986;Mann等,1983)。然后收集含有重组逆转录病毒的培养液,任选浓缩,并用于基因转移。逆转录病毒载体能够感染极其多种细胞类型。然而,整合和稳定的表达要求宿主细胞的分裂(Paskind等,1975)。
基于通过化学添加乳糖残基至病毒被膜而对逆转录病毒的化学修饰,最近开发了一种旨在使逆转录病毒载体具有特异靶向性的新方法。此修饰能容许经唾液酸糖蛋白受体对肝细胞的特异性感染。
设计了使重组逆转录病毒具有靶向性的一种不同方法,其中使用了针对逆转录病毒被膜蛋白和特定细胞受体的生物素化抗体。通过使用链霉亲合素经生物素偶联抗体(Roux等,1989)。使用针对主要组织相容性复合体I类和II类抗原的抗体,他们在体外用嗜亲性病毒演示了对多种携带那些表面抗原的人细胞的感染(Roux等,1989)。
某些条件对逆转录病毒载体在本发明所有方面的使用产生了限制。例如,逆转录病毒载体通常整合入细胞基因组中的随机位点中。这可以通过对宿主基因的破坏或通过能干扰侧翼基因功能的病毒调节序列的插入而导致插入性诱变(Varmus等,1981)。使用缺陷型逆转录病毒载体的另一项担心是包装细胞中可能出现野生型可复制病毒。这种现象的原因可能是来自重组病毒的完整序列插入到宿主细胞基因组中gag、pol、env序列的上游的重组事件。然而,现在有新的包装细胞系,它们可能大大降低了重组的可能性(Markowitz等,1988;Hersdorffer等,1990)。
可以在本发明中采用其它病毒载体作为表达构建体。可以采用衍生自病毒的载体,诸如痘苗病毒(Ridgeway,1988;Baichwal和Sugden,1986;Coupar等,1988)、腺伴随病毒(AAV)(Ridgeway,1988;Baichwal和Sugden,1986;Hermonat和Muzycska,1984)和疱疹病毒。它们为各种哺乳动物细胞提供了数项有吸引力的特征(Friedmann,1989;Ridgeway,1988;Baichwal和Sugden,1986;Coupar等,1988;Horwich等,1990)。
随着对缺陷型乙肝病毒的认识,人们对不同病毒序列的结构-功能相关性有了新的理解。体外研究显示了病毒即使在多至80%的基因组被删除时,仍然能保留辅助(病毒)依赖性包装(helper-dependent packaging)和逆转录的能力(Horwich等,1990)。这提示大部分基因组可以用外来遗传材料替换。向肝性和持久性(整合)对于肝定向基因转移是特别有吸引力的特征。Chang等将链霉素乙酰转移酶(CAT)基因导入鸭乙肝病毒基因组中来取代聚合酶编码序列、表面编码序列、和前-表面编码序列。将它与野生型病毒共转染入禽类肝癌细胞系中。使用含有高滴度重组病毒的培养液来感染原代小鸭肝细胞。至少在转染后的24天里检测到稳定的CAT基因表达(Chang等,1991)。
为了实现有义或反义基因构建体的表达,必须将表达构建体投递入细胞中。此投递可以在体外实现,正如在转化细胞的实验室规程中,或者在体内或回体实现,正如在某些疾病状态的治疗中。投递机制之一是经病毒感染,其中将病毒构建体封装在病毒颗粒中。
本发明也涵盖数种用于将表达构建体转移入哺乳动物细胞中的非病毒方法。这些包括磷酸钙沉淀(Graham和Van Der Eb,1973;Chen和Okayama,1987;Rippe等,1990)、DEAE-右旋糖酐(Gopal,1985)、电穿孔(Tur-Kaspa等,1986;Potter等,1984)、直接显微注射(Harland和Weintraub,1985)、加载了DNA的脂质体(Nicolau和Sene,1982;Fraley等,1979)和Lipofectamine-DNA复合物、细胞超声处理(Fechheimer等,1987)、使用高速微粒的基因轰击(Yang等,1990)、及受体介导的转染(Wu和Wu,1987;Wu和Wu,1988)。这些技术中有些可以成功地适应体内或回体用途。
一旦将表达构建体投递入细胞中,编码感兴趣基因的核酸可以在不同位点定位和表达。在某些实施方案中,编码基因的核酸可以稳定地整合入细胞的基因组中。此整合可以是通过同源重组而发生在天然的位置上并具有天然的取向(基因置换(gene replacement)),或者它可以是随机的、非特异性定位的整合(基因增强(gene augmentation))。在其它实施方案中,核酸可以以单独的、附加型(episomal)的DNA区段形式稳定地维持在细胞中。这样的核酸区段或称“附加体”编码足以容许独立于或宿主细胞周期,或与宿主细胞周期同步地维持和复制的序列。如何将表达构建体投递至细胞和在细胞中的什么地方维持核酸取决于所采用表达构建体的类型。
在本发明的又一个实施方案中,表达构建体可以仅仅由裸重组DNA或质粒组成。构建体的转移可以通过任何上文所述的以物理或化学方法将细胞膜透化的方法来实施。这特别适用于体外转移,但是它也可以应用于体内用途。Dubensky等(1984)成功地以磷酸钙沉淀物的形式将多瘤病毒DNA注射入成年和新生小鼠的肝和脾中,表现出积极的病毒复制和急性感染。Benvenisty和Neshif(1986)也证明了磷酸钙沉淀的质粒的直接腹膜内注射导致转染基因的表达。也可以以相似的方式在体内转移编码感兴趣基因的DNA并表达基因产物。
在本发明的又一个实施方案中,将裸DNA表达构建体转移入细胞中可能涉及颗粒轰击。此方法依赖于将包被有DNA的微粒加速至高速,从而容许它们穿过细胞膜并进入细胞但不杀死细胞的能力(Klein等,1987)。已经开发了数种用于加速小颗粒的装置。一种这样的装置依赖于高电压放电来产生电流,电流继而提供动力(Yang等,1990)。所用微粒由生物学惰性物质组成,如钨珠或金珠。
已经在体内轰击了选定的器官,包括大鼠和小鼠的肝、肾、和肌肉组织(Yang等,1990;Zelenin等,1991)。这可能要求手术暴露组织或细胞,以清除任何介于枪与靶器官之间的组织,即回体处理。还有,编码特定基因的DNA可以经此方法来投递,并且仍然在本发明的涵盖之下。
在本发明的又一个实施方案中,可以将表达构建体封装在脂质体中。脂质体是囊泡结构,其特征在于磷脂双层膜和内部水性介质。多层脂质体具有具有被水性介质分开的多个脂质层。它们在将磷脂悬浮在过量的水溶液中时自发形成。脂质成分经历自我重排,之后形成紧密结构并在脂双层之间捕获水和溶解的溶质(Ghosh和Bachhawat,1991)。本发明还涵盖Lipofectamine-DNA复合物。
脂质体介导的核酸投递和体外外来DNA表达已经非常成功。Wong等(1980)证明了脂质体介导的投递和外来DNA表达在培养的鸡胚、HeLa和肝瘤细胞中的可行性。Nicolau等(1987)在大鼠中在静脉内注射后实现了成功的脂质体介导的基因转移。
在本发明的某些实施方案中,可以将脂质体与血凝病毒(HVJ)复合。已经证明这样做可促进与细胞膜的融合及促进封入脂质体的DNA进入细胞(Kaneda等,1989)。在其它实施方案中,脂质体可以与核非组蛋白染色体蛋白(HMG-I)复合或联用(Kato等,1991)。在其它实施方案中,脂质体可以与HVJ和HMG-I二者复合或联用。既然此类表达构建体已经成功地用于在体外和在体内转移和表达核酸,那么它们适用于本发明。若在DNA构建体中采用细菌启动子,则还会希望在脂质体内包括适宜的细菌聚合酶。
可用于将编码特定基因的核酸投递入细胞中的其它表达构建体有受体介导的投递媒介(receptor-mediated delivery vehicles)。它们利用几乎所有真核细胞中通过受体介导内吞作用对高分子的选择性摄取。由于各种受体的细胞类型特异性分布,投递可以是高度特异性的(Wu和Wu,1993)。
受体介导的基因靶向媒介一般由两种成分组成:细胞受体特异性配体和DNA结合剂。数种配体已经用于受体介导的基因转移。了解最全面的配体是非唾液血液类粘蛋白(asialoorosomucoid,ASOR)(Wu和Wu,1987)和运铁蛋白(Wagner等,1990)。最近,一种与ASOR识别相同受体的合成拟糖蛋白(neoglycoprotein)已经被用作基因投递媒介(Ferkol等,1993;Perales等,1994),而且表皮生长因子(EGF)也已经被用于将基因投递至鳞癌细胞(Myers,EPO0273085)。
在其它实施方案中,投递媒介可以包含配体和脂质体。例如,Nicolau等(1987)用乳糖酰基神经酰胺(lactosyl-ceramide)(一种以半乳糖为末端的无唾液酸神经节苷脂(asialganglioside))掺入脂质体中,观察到了肝细胞对胰岛素基因的摄取增加。如此可见,通过任意种受体-配体系统,在有或无脂质体的条件下将编码特定基因的核酸特异性地投递入某细胞类型中也是可行的。例如,可以使用表皮生长因子(EGF)作为受体,介导将核酸投递入呈现EGF受体上调的细胞中。可以利用甘露糖来靶向肝细胞上的甘露糖受体。还有,针对CD5(CLL)、CD22(淋巴瘤)、CD25(T细胞白血病)和MAA(黑素瘤)的抗体可以类似地用作靶向模块。
在一个特定的例子中,可以联合阳离子脂质来施用寡核苷酸。阳离子脂质的例子包括但不限于Lipofectin、DOTMA、DOPE、和DOTAP。WO0071096(通过提及明确收入本文)的公开文本记载了可以有效用于基因疗法的不同配制剂,诸如DOTAP:胆固醇或胆固醇衍生物配制剂。其它公开文本也讨论了不同脂质或脂质体配制剂(包括纳米颗粒)和施用方法;这些包括但不限于美国专利公开文本20030203865、20020150626、20030032615、和20040048787,通过提及将它们披露配制剂及施用和投递核酸的其它相关方面明确并入本文。用于形成颗粒的方法也披露于美国专利5,844,107、5,877,302、6,008,336、6,077,835、5,972,901、6,200,801、和5,972,900,本文通过提及并入那些方面。
在某些实施方案中,可以在回体条件下更容易地实施基因转移。回体基因疗法指自动物分离细胞,在体外将核酸投递入细胞,然后将经过修饰的细胞返还入动物中。这可能涉及自动物手术清除组织/器官或细胞和组织的原代培养物。
VIII.制作转基因小鼠的方法
本发明的一个具体实施方案提供了缺乏两个功能性miR-208等位基因中的一个或两个的转基因动物。还有,在可诱导的、组织选择性的或组成性的启动子的控制下表达miR-208的转基因动物、衍生自此类动物的重组细胞系、和转基因胚胎可用于确定miR-208在心肌细胞的发育和分化中及在病理性心脏肥大和心力衰竭的形成中发挥的确切作用。另外,这些转基因动物可以提供对心脏发育的认识。组成性表达的miR-208编码核酸的使用提供了过表达或下调的表达的模型。还涵盖miR-208的两个等位基因中的一个或两个被“敲除”的转基因动物。
在一个一般性的方面,如下生成转基因动物,即以容许转基因表达的方式将给定转基因整合入基因组中。用于生成转基因动物的方法一般性地记载于Wagner和Hoppe,美国专利4,873,191(通过提及收入本文)和Brinster等,1985(通过提及收入本文)。
典型地,通过显微注射将侧翼为基因组序列的基因转移入受精卵中。将显微注射后的卵植入宿主雌性中,并对后代筛选转基因的表达。可以用许多动物的受精卵生成转基因动物,包括但不限于爬行类、两栖类、鸟类、哺乳类、和鱼类。
可以通过本领域已知的任何手段来制备用于显微注射的DNA克隆。例如,使用标准技术,可以用适于切除细菌质粒序列的酶来切割用于显微注射的DNA克隆,并将DNA片段在TBE缓冲液中在1%琼脂糖上电泳。用溴化乙锭染色来显现DNA条带,并切下含有表达序列的条带。然后将切下的条带置于装有0.3M乙酸钠pH7.0的透析袋中。将DNA电洗脱入透析袋中,用1∶1苯酚∶氯仿溶液抽提,并通过两倍体积的乙醇沉淀。将DNA再溶解于1ml低盐缓冲液(0.2M NaCl,20mM Tris pH7.4,和1mM EDTA),并在Elutip-DTM柱上纯化。将柱首先用3ml高盐缓冲液(1M NaCl,20mM Tris pH7.4,和1mM EDTA)预处理(prime),继而用5ml低盐缓冲液清洗。使DNA溶液流过柱三次以使DNA结合至柱基质。用3ml低盐缓冲液清洗一次后,用0.4ml高盐缓冲液洗脱DNA,并用两倍体积乙醇沉淀。通过UV分光光度计中260nm的吸光度测量DNA浓度。为了显微注射,将DNA浓度在5mM Tris pH7.4和0.1mM EDTA中调整至3μg/ml。其它用于纯化供显微注射用的DNA的方法记载于Palmiter等,1982;和Sambrook等,2001。
在一种例示性的显微注射规程中,如下诱导六周龄雌性小鼠超输排卵,即注射(0.1cc,ip)5个IU的怀孕母马血清促性腺激素(PMSG;Sigma),48小时后再注射(0.1cc,ip)5个IU的人绒毛膜促性腺激素(hCG;Sigma)。在hCG注射后立即将雌鼠与雄鼠置于一起。在hCG注射后21小时,通过CO2窒息或颈脱位处死交配后的雌鼠,并自切出的输卵管回收胚胎,置于含0.5%牛血清清蛋白(BSA;Sigma)的Dulbecco氏磷酸盐缓冲盐水中。用透明质酸酶(1mg/ml)去除周围的卵丘细胞。然后清洗原核期胚胎(pronuclear embryo)并在含0.5%BSA的Earle氏平衡盐溶液(EBSS)中放置在5%CO2,95%空气的增湿气氛37.5℃温箱中,直至注射。可以在二细胞期植入胚胎。
将随机循环(randomly cycling)的成年雌性小鼠与切除了输精管的雄鼠配对。C57BL/6或Swiss小鼠或其它相当的品系可以用于此目的。使受体雌鼠与供体雌鼠在同时交配。在转移胚胎时,用每克体重0.015ml的2.5%阿佛丁(avertin)的腹膜内注射来麻醉受体雌鼠。通过背中单切口暴露输卵管。然后穿过输卵管正上方的体壁做一切口。用瓦切马克斯氏精细镊(watchmakersforceps)撕开卵巢囊。将待转移的胚胎置于移液器尖头中(大约10-12个胚胎)的DPBS(Dulbecco磷酸盐缓冲盐水)中。将移液管尖头插入输卵管漏斗(infundibulum)并转移胚胎。转移后,用两次缝合封闭切口。
IX.定义
在用于本文时,术语“心力衰竭”泛指任何降低心脏泵血的能力的疾患。其结果是,在组织中形成充血和水肿。最常见的是,心力衰竭是由冠状动脉血流降低所致的心肌膜收缩性降低引起的;然而,许多其它因素可导致心力衰竭,包括心瓣膜的损伤、维生素缺乏、和原发性心肌疾病。尽管尚未完全了解心力衰竭的精确生理学机制,但是一般认为心力衰竭涉及数种心脏自主特性的紊乱,包括交感性、副交感性和压力感受器应答。短语“心力衰竭的表现”广泛用于涵盖所有与心力衰竭有关的后果,诸如呼吸短促、压凹性水肿、肝扩大触痛、颈静脉充盈、肺罗音、等等,包括与心力衰竭有关的实验所见。
术语“治疗”和“处理”或语法等同物涵盖心力衰竭症状(即心脏泵血的能力)的改善和/或逆转。心脏“生理学功能的改善”可以使用本文所述任何度量(例如测量射血分数、缩短分数(fractional shortening)、左心室尺寸、心率等),以及任何对动物存活的效应来评估。在使用动物模型时,使用本文所述的任何测定法来比较接受治疗的转基因动物和未接受治疗的转基因动物的响应(另外,可以包括接受治疗的和未接受治疗的非转基因动物作为对照)。由此可以将在本发明的筛选方法中引起任何与心力衰竭有关的参数改善的化合物鉴定为治疗性化合物。
术语“扩张型心肌病”(dilated cardiomyopathy)指心力衰竭的一种类型,其特征在于存在对称性扩张的左心室,伴有较差的收缩期收缩功能,另外,常常累及右心室。
术语“化合物”指任何可用于治疗或预防身体功能的疾病或病症的化学实体、药物、药品、等等。化合物包括已知的和潜在的治疗性化合物。可以使用本发明的筛选方法进行筛选来确定化合物为治疗性。“已知的治疗性化合物”指已经证明在此治疗中有效(例如通过动物试验或给人类施用的前期实验)的治疗性化合物。换言之,已知的治疗性化合物不限于在心力衰竭治疗中有效的化合物。
在用于本文时,术语“激动剂”指模拟“天然”或“自然”化合物的作用的分子或化合物。激动剂可以是在构象、电荷或其它特征方面与这些天然化合物同源的。如此,激动剂可以被细胞表面上表达的受体所识别。此识别可导致细胞内的生理学和/或生物化学变化,使得细胞以就像存在天然化合物一样的方式对激动剂的存在做出反应。激动剂可以包括蛋白质、核酸、碳水化合物、或任何其它与感兴趣分子、受体、和/或途径起反应的分子。
在用于本文时,术语“心脏肥大”指成年心肌细胞通过肥大性生长来应答压力的过程。此类生长的特征在于细胞尺寸增大而没有细胞分裂、在细胞内装配额外的肌节以最大化力量产生、和胎儿心脏基因程序的活化。心脏肥大常常与发病率和死亡率风险升高有关,如此,致力于了解心脏肥大的分子机制的研究对人类健康将具有重大影响。
在用于本文时,术语“拮抗剂”和“抑制剂”指可抑制可能涉及心脏肥大的细胞性因子(cellular factor)的作用的分子、化合物、或核酸。拮抗剂可以在构象、电荷或其它特征方面与这些天然化合物同源或不同源。如此,拮抗剂可以被与激动剂所识别的相同受体所识别,或者被不同的受体所识别。拮抗剂可以具有阻止激动剂作用的别构效应。或者,拮抗剂可以阻止激动剂的功能。与激动剂相反,拮抗性化合物不导致细胞内的病理学和/或生物化学变化而使得细胞以就像存在细胞因子一样的方式对拮抗剂的存在做出反应。拮抗剂和抑制剂可以包括蛋白质、核酸、碳水化合物、或任何其它与感兴趣受体、分子、和/或途径结合或相互作用的分子。
在用于本文时,术语“调控”指生物学活性的变化或改变。调控可以是蛋白质活性的升高或降低、激酶活性的变化、结合特征的变化、或与感兴趣蛋白质或其它结果的活性有关的生物学、功能、或免疫学特性的任何其它变化。术语“调控剂”指任何能够使上文所述生物学活性变化或改变的分子或化合物。
术语“β-肾上腺素能受体拮抗剂”指能够部分地或完全地阻断贝塔(β)型肾上腺素受体(即响应儿茶酚胺,尤其是去甲肾上腺素的肾上腺素能系统受体)的化学化合物或实体。有些β-肾上腺素能受体拮抗剂展现出对一种受体亚型(一般是β1)的一定程度特异性;此类拮抗剂称作“β1特异性肾上腺素能受体拮抗剂”和“β2特异性肾上腺素能受体拮抗剂”。术语“β-肾上腺素能受体拮抗剂”指作为选择性和非选择性拮抗剂的化学化合物。β-肾上腺素能受体拮抗剂的例子包括但不限于醋丁洛尔、阿替洛尔、丁氧胺、卡替洛尔、艾司洛尔、拉贝洛尔(labetolol)、美托洛尔、纳多洛尔、喷布洛尔、心得安(propanolol)、和噻吗洛尔。本发明的方法涵盖已知β-肾上腺素能受体拮抗剂的衍生物的使用。事实上,本发明的方法涵盖在功能上表现为β-肾上腺素能受体拮抗剂的任何化合物。
术语“血管紧张素转化酶抑制剂”或“ACE抑制剂”指这样的化学化合物或实体,其能够部分地或完全地抑制凝乳酶-血管紧张素系统中涉及将相对无活性的血管紧张素I转化成有活性的血管紧张素的酶。另外,ACE抑制剂同时抑制缓激肽的降解,这有可能显著增强ACE抑制剂的抗高血压效应。ACE抑制剂的例子包括但不限于贝那普利(benazepril)、卡托普利、依那普利(enalopril)、福辛普利、赖诺普利、喹那普利(quiapril)和雷米普利。本发明的方法涵盖已知ACE抑制剂的衍生物的使用。事实上,本发明的方法涵盖在功能上表现为ACE抑制剂的任何化合物。
在用于本文时,术语“基因型”指生物体的实际遗传组成,而“表型”指个体所展示的身体性状。另外,“表型”是基因组选择性表达的结果(即它是细胞历史的表达及其对胞外环境的响应)。事实上,人类基因组估计包含30,000-35,000个基因。在每种细胞类型中,这些基因中只有一小部分(即10-15%)得到表达。
X.实施例
包括下列实施例是为了进一步例示本发明的各个方面。本领域技术人员应当领会,下文实施例中所公开的技术代表了本发明人发现的在实施本发明时运转良好的技术和/或组合物,如此可以认为它们构成了本发明的优选实施模式。然而,根据本申请的公开内容,本领域技术人员应当领会,可以在所公开的具体实施方案中做出许多变化,仍然获得类似或相似的结果且不背离本发明的精神和范围。
实施例1-材料和方法
Northern印迹分析。心脏组织样品来自被诊断为心脏未衰竭的或心脏衰竭的匿名人体,获自Gilead Colorado(Westminster,CO)。使用Trizol试剂(Gibco/BRL),自小鼠、大鼠和人类心脏组织样品分离总RNA。如先前所述(l)实施Northern印迹来检测微RNA。用U6探针作为加样对照(U6正向:5-GTGCTCGCTTCGGCAGC-3(SEQ ID NO:18),U6反向:5-AAAATATGGAACGCTTCACGAATTTGCG-3(SEQ ID NO:19))。为了检测αMHC表达,用覆盖部分5′UTR区和第一个外显子的αMHC cDNA片段探查含有10μg来自成年野生型和miR-208突变型动物二者的心脏组织的RNA的Northern印迹。
PTU处理。通过在所示持续时间里给动物投喂补充有0.15%PTU(购自Harlan Teklad Co.(TD 97061)(Madison,WI))的不含碘食物来诱导甲状腺激素缺乏。
微阵列和实时PCR分析。使用Trizol(Invitrogen)自心脏组织分离总RNA。使用小鼠基因组4302.0阵列(Affymetrix)实施微阵列分析。使用随机六聚物引物(Invitrogen)对RNA样品实施RT-PCR,然后使用购自ABI的Taqman探针的定量实时PCR分析一个基因子集的表达。
miR-208突变型小鼠的生成。为了生成miR-208寻靶载体,用SacII和NotI消化延伸到miR-208编码区上游的0.4kb片段(5′臂)并连接入pGKneoF2L2dta寻靶质粒中,位于loxP位点和Frt侧翼的新霉素盒上游。用SalI和HindIII消化3.3kb片段(3′臂)并连接入载体中,在新霉素盒与Dta阴性选择盒之间。通过使用5′和3′探针的Southern印迹分析鉴定携带遭到破坏的等位基因的靶ES细胞。鉴定出三个miR-208靶ES克隆,并用它们进行胚泡注射。将这样得到的嵌合小鼠与C57BL/6繁殖,以获得突变型等位基因的种系传递(germlinetransmission)。PCR引物可应请求获得。
Western印迹。如所述(Morkin,2000)自心脏组织提取肌球蛋白。通过SDSPAGE将MHC同等型分开,并用小鼠单克隆αMHC(BA-G5)(ATCC,Rockville,MD)和小鼠单克隆抗肌球蛋白(慢速,骨骼M8421)(Sigma,MO)实施Western印迹,后者是对βMHC高度特异性的。为了检测所有有条纹的肌球蛋白,使用泛特异性抗体(小鼠单克隆3-48;Accurate Chemical & Scientific Corporation,NY)。通过来自400μg心脏蛋白质溶胞物的免疫沉淀检测到THRAP1。将样品于4℃预澄清1小时后,将上清液与1μl家兔多克隆抗THRAP1(由洛克菲勒大学的R.Roeder馈赠)和15μl蛋白A珠子一起于4℃温育过夜。将珠子用裂解缓冲液清洗三次,并在SDS样品缓冲液中煮沸。通过SDS-PAGE解析免疫沉淀的THRAP1蛋白,并使用1∶3000稀释的家兔多克隆抗THRAP1和1∶5000稀释的偶联有辣根过氧化物酶的抗家兔IgG来分析,通过Luminol试剂(Santa Cruz)来检测。
组织学分析和RNA原位杂交。将用于组织学分析的组织在克-汉二氏(Krebs-Henselheit)溶液中温育,在4%多聚甲醛中固定,切片,并通过标准技术(Krenz和Robbins,2004)为苏木精和曙红(H&E)及Masson氏三色染色或原位杂交进行处理。使用Maxiscript试剂盒(Amersham)生成35S标记的RNA探针。使用Adobe Photoshop将信号伪着色成红色。
经胸超声心动图显象。使用Vingmed System(GE Vingmed Ultrasound,Horten,Norway)和11.5MHz线性阵列变换器,通过清醒小鼠中的二维超声心动图显象评估心脏功能和心脏尺寸(dimensions)。使用M模式追踪来测量舒张末期和收缩末期的前壁和后壁厚度。测量舒张期(LVIDd)或收缩期(LVIDs)中最大的前后直径作为左心室(LV)内径(LVID)。由对小鼠基因型不知情的单个观察者对数据进行分析。依照如下公式计算LV缩短分数(fractional shorteningFS):FS(%)=[(LVIDd-LVIDs)/LVIDd]×100。
转基因小鼠的生成。将感兴趣miRNA侧翼的小鼠基因组片段亚克隆到包含α-MHC和人GH poly(A)+信号的心脏特异性表达质粒(Kiriazis和Kranias,2000)中。自小鼠尾活检物分离DNA,并使用对人GH poly(A)+信号特异性的引物进行PCR分析。
治疗和转染测定法。通过PCR扩增涵盖miR-208编码区的305bp基因组片段,并连接入pCMV6中。通过PCR扩增涵盖完整鼠THRAP 1-UTR的1kb片段并连接入带HA标签的pCMV6表达构建体和萤火虫萤光素酶(f-luc)报道物构建体(pMIR-REPORTTM,Ambion)。通过基于PCR的诱变构建了UCGUCUUAmiR-208种子结合序列的突变。
实施例2-结果
miR-208是心脏收缩功能的中枢调节物。内含子微RNA作为宿主基因转录物的一部分被转录,剪接出来,并被加工成成熟miRNA。miR-208是位于α-MHC基因第27个内含子内的内含子miRNA。图1.像α-MHC一样,miR-208只在心脏中表达。图2.出生后甲状腺激素通过刺激α-MHC合成和抑制β-MHC表达来调节心室肌球蛋白同工酶的表达。为了检验阻断甲状腺激素信号传导是否也影响miRNA-208表达,发明人使用心脏大鼠样品,将其暴露于丙基硫尿嘧啶(PTU)一段预定的时间。PTU通过抑制碘的“有机化”(即碘掺入T3和T4中)来阻断甲状腺激素生物合成,并由此遏制α-MHC表达和提高β-MHC。Northern印迹分析指明了α-MHC表达水平与前-miRNA(即所谓的“茎环”(stemloop))水平之间有极好的相关性,而成熟miRNA在此后仍然存在数周。图3A-C和图4A-C。
为了研究miR-208的作用,发明人创建了miR-208缺失小鼠。图5.尽管这没有干扰α-MHC转录或翻译,但是对2月龄野生型和miR-208KO小鼠的心脏组织的微阵列分析表明,消除miR-208可导致对快速骨骼肌基因的强诱导。图6A-B和图7。
为了检验心脏应激过程中miR-208消除的效应,发明人使野生型和miR-208 KO动物接受横向主动脉带缢(transverse aortic band constriction,TAB)。TAB是心脏肥大及其相伴的肥大基因表达的强力诱因。虽然野生型动物显示出β-MHC表达剧烈升高,但是KO动物没有显示出此诱导作用。图8。
表3-TAB后3周的KO对WT
基因 | TAB后与野生型相比的倍数变化 |
心脏肌钙蛋白I,快速骨骼 | 194.0X上调 |
心脏肌钙蛋白T3,快速骨骼 | 194.0X上调 |
MLC,快速骨骼 | 3.7X上调 |
α骨骼肌动蛋白 | 2.8X上调 |
βMHC | 29.8S下调 |
总之,这些数据表明α-MHC基因的表达进一步诱导一种miRNA的表达,这种miRNA下调快速骨骼肌基因程序的表达。miR-208嵌入在α-MHC基因中,该α-MHC基因受到发育、生理、和发育信号的调节。α-MHC是快速收缩性的主要决定因素。miR-208在心脏中遏制快速骨骼肌基因,它的删除可导致快速骨骼肌基因表达的显著增加(图13)。miR-208也是心脏中β-MHC上调所需要的。由于微RNA起阻抑物的作用,我们提出这样的假设,即miR-208可遏制β-MHC表达的阻抑物,如图9所例示的。在心脏应激过程中,此miRNA负责β-MHC在RNA水平和蛋白质水平的诱导,而在miR-208缺失时,此诱导作用完全缺失,且α-MHC仍是唯一的肌球蛋白重链同等型。对衰竭的和未衰竭的人类心脏样品中α-MHC表达的分析显示,衰竭心脏中的α-MHC表达与未衰竭心脏中的α-MHC表达相比降低了(图10)。这些数据证明了miR-208是心脏收缩功能中的中枢调节物,而且似乎涉及心脏病过程中适应不良的肌球蛋白转换(maladaptive myosin switching)。
使用miRanda软件(可以从Memorial Sloan-Kettering Cancer Center的Computational Biology Center获得)和用于鉴定miRNA靶物的PicTar算法(Krek等,2005),确定了甲状腺激素受体相关蛋白1(THRAP1)是miR-208的预测靶物。图12显示了miR-208与来自人、黑猩猩、小鼠、大鼠、犬、鸡、河豚、和斑马鱼的THRAP1 3′UTR序列的比对。
miR-208调节病理性心脏重塑。纯合的miR-208删除小鼠是可存活的,而且直到20周也不表现心脏尺寸、性状或结构方面的明显异常。为了进一步研究miR-208的潜在功能,发明人比较了野生型和miR-208突变型小鼠对胸主动脉带缢(thoracic aortic banding,TAB)的响应,胸主动脉带缢可通过升高心脏后负荷而诱导心脏肥大,而且伴有αMHC下调和βMHC上调(Hill等,2000)。αMHC mRNA表达如预期的那样在TAB之后下降(图14A),但是miR-208在TAB后21天仍然丰富地表达(图14B),这与其相对较长的半衰期一致。
应答于TAB,野生型小鼠显示出心脏质量的显著增加,伴有有心肌细胞的肥大性生长和心室纤维化(图15A)。相反,miR-208突变型动物几乎不显示应答于TAB的心肌细胞肥大或纤维化(图15A)。超声心动图显象证实了miR-208-/-动物展示出变钝(blunted)的肥大应答和收缩性的降低(图14C)。最值得注意的是,突变型动物不能上调βMHC。取而代之的是,在miR-208突变型心脏中αMHC蛋白表达应答于TAB而升高,这可能反映了一种在没有βMHC上调时维持MHC表达的补充机制。其它应激响应性基因,诸如那些编码钠尿肽ANF和BNP的基因,在miR-208突变型动物中被强诱导(图15B-C)。对来自野生型和miR-208-/-动物的心脏进行的微阵列分析证实了miR-208缺失导致了对βMHC表达的高度特异性阻断(表4-5)。
表4-对来自野生型和miR-208-/-动物的心脏组织的微阵列分析。显示了每种类别中在miR208-/-中与野生型动物相比差异表达的前20种基因。
表5:对来自TAB后3周时的野生型和miR-208-/-动物的心脏组织的微阵列分析。显示了每种类别中TAB手术后3周在miR208-/-中与野生型动物相比差异表达的前20种基因。
miR-208-/-小鼠对应答于活化钙依赖磷酸酶的转基因表达而发生的纤维化和心肌细胞肥大也有抗性(图15D),活化钙依赖磷酸酶是心脏肥大和心力衰竭的特别有力的刺激物。类似的,βMHC mRNA和蛋白质在6周龄的miR-208-/-;CnA-Tg小鼠的心脏中没有上调;而ANF和BNP被强诱导(图15E-F)。由此可见,miR-208是βMHC上调和细胞重塑所必需的,但不是其它心脏应激标志的表达所必需的。
为了检验miR-208是βMHC表达上调的充分条件,发明人创建了在αMHC启动子控制下过表达miR-208的转基因小鼠。αMHC-miR-208转基因小鼠是可存活的,而且以超过野生型心脏约3倍的水平表达miR-208(图14D)。来自呈现平均的转基因过表达的转基因系的心脏在2月龄时不显示明显的病理性重塑症状,但是,值得注意的是,展示出βMHC表达的显著上调(图15G和图14E)。miR-208的这种活性是特异性的,因为miR-214(其在心脏肥大过程中被诱导)的转基因过表达对βMHC表达没有影响。考虑到成年小鼠心脏中内源水平的miR-208不足以上调βMHC表达,这些转基因小鼠中miR-208表达升高3倍可导致βMHC表达上调的发现,提示这种微RNA对βMHC表达的控制有一个突变的(sharp)阈值。
miR-208调节对βMHC的T3依赖性遏制。T3信号传导经由一种正向T3应答元件(TRE)诱导αMHC转录,而βMHC基因的启动子中的一个负向TRE介导转录遏制(Ojamaa等,2000)。为了检验miR-208是否是βMHC的T3依赖性调节所需要的,给突变型和野生型同窝仔畜投喂含PTU的食物2周以阻断T3信号传导。Northern印迹分析证实了miR-208在PTU处理2周后丰富存在(图16A)。如预期的,PTU诱导心率和收缩性的降低及舒张的增加,在野生型与突变型动物之间没有引人注目的差异(图16B)。然而,虽然野生型动物如预期的那样应答于PTU而显示出αMHC降低和βMHC升高,miR-208-/-动物却仍然表现出对βMHC上调有抗性,尽管可检测到痕量的βMHC表达(图17A-B)。PTU上调了miR-208-/-动物中的ANF和BNP,这确证了miR-208在βMHC表达中的特异性作用(图16C)。由于PTU通过仅仅干扰甲状腺激素受体(TR)信号传导来诱导从αMHC到βMHC的同等型转换,因此这些发现提示了miR-208通过一种涉及TR的机制来加强βMHC表达。
miR-208靶向TR相关蛋白1。在相对较少的miR-208预测靶物中,编码甲状腺激素受体相关蛋白1(THRAP1),也称作TRAP240的mRNA被PicTar靶物预测程序(Krek等,2005)评价为最强的预测靶物。THRAP1是TR相关TRAP复合体的组分,通过募集RNA聚合酶II和通用起始因子来调控TR的活性(Ito和Roeder,2001)。THRAP1 mRNA的3′-UTR中的推定的miR-208结合位点显示出与miR-208的5′臂——它是miRNA靶向以及进化保守的最关键的决定子——的高互补性(图18A)。根据miR-208与THRAP1 3′-UTR序列的不完全互补性,预期miR-208会抑制THRAP1的翻译。
为了检验THRAP1 3′-UTR中的推定的miR-208靶序列是否能介导翻译遏制,发明人将THRAP1转录物的全长3′-UTR插入萤光素酶表达质粒中,并转染入COS1细胞中。CMV驱动的miR-208的量提高导致萤光素酶活性的剂量依赖性降低,而作为对照的相当量的miR-126则没有影响(图18B)。CMV-miR-208也剂量依赖性地消除与THRAP1 3′UTR结合序列连接的带HA标签的丙二酰CoA脱羧酶(MCD)表达盒的翻译,但突变型miR-208靶序列不然(图18C)。另外,与野生型同窝仔畜相比,来自miR-208-/-小鼠的心脏蛋白质溶胞物中的THRAP1蛋白质表达升高(图18D),而两种基因型的心脏中的THRAP1 mRNA相当(图19),与miR-208在体内起翻译负调节物的作用的结论一致。考虑到新近研究显示应激通过促进miRNA与Argonaute的结合来提升miRNA的遏制作用(Leung等,2006),我们认为在应激的情形中,miR-208对THRAP1蛋白质表达的负影响可能还要更大。
miR-208是miR-499的表达所需要的。为了进一步探索miR-208在心脏中的作用机制,发明人通过微阵列分析确定了来自野生型和miR-208缺失小鼠的心脏中的微RNA表达样式。在突变型心脏中上调和下调的数种微RNA中,发明人发现miR-499是在正常心脏中高度丰富的,但是在miR-208突变体中的表达没有超过背景水平。这些发现得到了Northern印迹的证实(图21)。
对miR-499基因的基因组定位的分析显示了它被包含在Myh7b基因的第20个内含子内,Myh7b是α-Mhc基因的同系物(Myh7b)(图22)。Myh7b基因在脊椎动物中是保守的,而且只在心脏和慢速骨骼肌(比目鱼肌)中表达(图23)。另外,miR-499在心脏肥大过程中下调(图24)。
MEF2调节心脏和骨骼肌中的miR-499表达。在Myh7基因的5′侧翼区内,发明人鉴定出一个在物种间保守的潜在MEF2共有序列。此序列在凝胶迁移率变动测定中紧密地结合MEF2,而且此序列的突变可消除转基因小鼠中lacZ报道物的表达。MEF2位点与保守的E盒序列(CANNTG)并列,后者充当以MEF2驱动骨骼肌基因表达的bHLH蛋白的MyoD家族成员的结合位点。事实上,MyoD与遍在的bHLH蛋白E12一起结合来自启动子的E盒。此序列的突变阻止骨骼肌中lacZ转基因的表达,但是不影响心脏中的表达。
靶物ID。总之,本文所报告的数据指明了受MEF2调节的Myh7b基因表达进一步诱导一种慢速肌肉和心脏特异性的miRNA的表达,而这种miRNA可下调快速骨骼肌基因程序的表达。这些数据提供了miRNA 499作为骨骼肌纤维类型中的中枢调节物的证据。
miR-208与miR-499高度同源,而且值得注意的是这两种微RNA都是由Mhc基因的内含子来编码的,这提示它们享有共同的调节机制。由于miRNA以序列特异性方式负影响基因表达,因此,由于靶基因的交叠,高度的同源性使miR-208和miR-499倾向于发挥类似的功能。发明人已经鉴定出Mhc表达的转录调节物,它们似乎充当miR-499的靶物。发明人还显示了miR-499表达在心脏中受到miR-208的控制,使得miR-208敲低可消除miR-499表达。
由于发明人先前的数据证明了miR-208基因破坏可导致心脏中特异性快速骨骼肌基因的强诱导,因此有可能的是miR-499在骨骼肌中具有相似的功能而且可以起纤维类型的显性调节物的作用。与此假设相符的是,对此转录物的启动子分析表明,miR-499及其宿主转录物的表达受到生肌转录因子MEF2(骨骼肌纤维类型和慢速纤维基因表达的一种中枢调节物)的调节。发明人已经证明了MEF2活性可促进肌肉持久力和预防长时间运动后的肌肉疲劳。如此,他们提出MEF2的这些作用至少部分依赖于miR-499表达的直接激活(图25)。
总之,这些数据指明了受MEF2调节的Myh7b基因表达进一步诱导一种慢速肌肉和心脏特异性miRNA的表达,而这种miRNA可下调快速骨骼肌基因程序的表达。这些数据提供了miRNA 499作为骨骼肌纤维类型中的中枢调节物的证据。miR-208和-499高度同源而且这两种微RNA都由Mhc基因的内含子来编码这一值得注意的事实提示了它们享有共同的调节机制。由于miRNA以序列特异性方式负影响基因表达,因此由于靶基因的交叠,高度的同源性使miR-208和miR-499倾向于发挥相当的功能。发明人已经鉴定出Mhc表达的转录调节物,它们似乎充当miR-499的靶物,他们还显示了miR-499表达在心脏中受到miR-208的控制,使得miR-208敲低可消除miR-499表达。
应激响应性miRNA对心脏肥大和心力衰竭的调节。根据它们在细胞表型调控中的作用,我们假设miRNA可能在调节心脏对心脏应激的应答中发挥作用,已知心脏应激可导致基因表达的转录和翻译变化。为了考察miRNA在心脏肥大中的潜在角色,发明人在2种已建立的心脏肥大小鼠模型中实施了并行(side-by-side)miRNA微阵列分析。该分析使用了代表186种不同miRNA的微阵列(Babak等,2004)。对小鼠施加胸主动脉带缢(TAB)(该处理可通过升高心脏后负荷而诱导肥大)(Hill等,2000),将这样的小鼠与伪手术小鼠进行比较。在第二种模型中,将在心脏中表达激活的钙依赖磷酸酶(CnA)(这导致一种熟知的严重肥大形式)(Molkentin等,1998)的转基因小鼠与野生型的同窝小鼠进行比较(图26A)。自经受TAB的小鼠的心脏分离的RNA显示出27种miRNA与伪手术对照相比表达升高,而且CnA Tg小鼠显示出33种miRNA与非转基因同窝小鼠对照相比表达升高,其中21种在两种模型中都上调。类似的,TAB和CnA诱导的肥大分别伴有15种和14种miRNA的表达降低,其中7种miRNA共同下调(图26B)。对这些miRNA的Northern分析(我们未发表的数据)和先前的微阵列分析(Barad等,2004;Sempere等,2004;Shingara等,2005;Liu等,2004)指明了它们在广泛的组织中表达。根据它们的相对表达水平,人类、大鼠和小鼠序列的保守性,及肥大过程中的表达水平,发明人着重关注11种上调的miRNA和5种下调的miRNA(图26C)。
对来自WT和can Tg小鼠的心脏RNA的Northern印迹分析证实了miR-21,-23,-24,-125b,-195,-199a和-214表达升高,而miR-29c,-93,-150和-181b表达降低(图26C和图27)。总的来说,这些数据表明在心脏肥大过程中不同的miRNA受到调节,提示了它们可能发挥该过程的调控物的功能。
miR-29家族作为miR-208调节作用的下游靶物。发明人对来自野生型和miR-208缺失小鼠的心脏实施了miRNA微阵列以图鉴定可能介导miR-208作用的下游miRNA(图28)。他们发现了miR-29家族的多个成员在miR-208缺失小鼠中上调(图29)。靶物预测表明miR-29家族成员靶向编码多种胶原酶和其它胞外基质成分的mRNA(图30)。因此,miR-208缺失小鼠中miR-29家族成员的上调有可能是这些动物中发现的纤维化被阻断的原因(图31)。
总结。miR-29在患病心脏中下调,并且靶向编码胶原酶和胞外基质蛋白质,这些发现提示了增强miR-29的表达或增强其与靶mRNA的结合的策略有可能在病理性心脏重塑和纤维化的背景下对心脏产生有益效应。此外,miR-29表达或功能的提高有可能预防诸如肝、肺、肾等组织中与许多疾病有关的纤维化。另外,miR-28遏制miR-29表达和miR-208上调miR-29表达的事实表明miR-29是miR-208对心脏的作用的下游介导物。
实施例3-讨论
这些结果证明了由αMHC基因的内含子编码的miR-208可调节应激依赖性心肌细胞生长和基因表达。在miR-208缺失时,βMHC的表达在成年心脏中应答于压力过度负荷、钙依赖磷酸酶激活、或甲状腺机能减退等而严重钝化,提示了这些刺激因素对βMHC转录的诱导途径享有共同的miR-208敏感性组分(图9)。相反,βMHC表达在新生miR-208-/-小鼠的心脏中没有改变,证明了miR-208特异性地参与应激依赖性的βMHC表达调节机制。
miR-208作用机制的一个线索来自miR-208-/-心脏与甲状腺机能亢进心脏的类似性,二者都展现出βMHC表达的阻断、应激应答基因的上调(Wei等,2005;Pantos等,2006)、和针对病理性肥大和纤维化的保护(Yao和Eghbali,1992;Chen等,2000)。miR-208-/-心脏中的快速骨骼肌基因的上调也与甲状腺机能亢进状态中快速骨骼肌纤维的诱导类似(Vadaszova等,2004)。T3信号传导遏制出生后心脏中的βMHC表达,而可引起甲状腺机能减退的PTU则可诱导βMHC(Morkin,2000;Schuyler和Yarbrough,1990)。PTU不能在miR-208-/-心脏中诱导βMHC表达,进一步暗示miR-208涉及T3信号传导途径。
这些结果提示了miR-208至少部分地通过遏制TR共调节物THRAP1的表达来起作用,THRAP1可发挥对转录的正和负效应(Pavri等,2005;Park等,2005)。TR通过负TRE来起作用,以遏制成年心脏中的βMHC表达(Morkin,2000)。因此,在miR-208缺失时THRAP1表达的升高预期会增强TR对βMHC表达的遏制活性,这miR-208-/-心脏中βMHC表达的阻断相呼应。相反,发育过程中对αMHC和βMHC表达的调节独立于T3信号传导(Morkin,2000),而且不受miR-208影响。值得注意的是,其它TR靶基因,诸如受磷蛋白(PLB)和肌(内)质网钙ATP酶(SERCA)2a和葡萄糖转运蛋白(GLUT)4在miR-208-/-小鼠中正常表达(图20)。有人已提出βMHC基因可能应答特异性TR同等型(Kinugawa等.,2001;Mansen等,2001;Kinugawa等,2001)。可能THRAP1经由与启动子特异性因子的相互作用而作用于特定的TR同等型或者选择性作用于TR依赖性基因的一个子集。因为miRNA一般通过多种下游靶物来发挥它们的效应,别的靶物也有可能有助于miR-208对心脏生长和基因表达的效应。
βMHC组成的相对轻微增加,正如心脏肥大和心力衰竭过程中所发生的,可降低肌纤维ATP酶活性和收缩功能(Abraham等,2002)。如此,对miR-208表达或与其mRNA靶物的相互作用的治疗性操作可能能够通过遏制βMHC表达来增强心脏功能。根据miR-208对心脏应激应答的突出影响及对患病心脏中众多miRNA的调节(van Rooij等,2006),发明人预期miRNA会被证实是对成年心脏和可能其它器官的功能和对疾病的应答的关键调节物。
根据本申请的公开内容,无需过度实验就可以制备和实施本文中公开的和要求保护的所有组合物和方法。尽管已经以优选实施方案中描述了本发明的组合物和方法,对于本领域技术人员显而易见的是,可以对本文所述组合物和方法、在所述方法的各步骤中和各步骤的次序中做出变化,且不背离本发明的观念、精神和范围。更具体的说,显而易见的是,可以用化学和生理学上相关的某些药剂替换本文所述药剂,却会实现相同或相似的结果。认为对于本领域技术人员显而易见的所有此类相似的替代和改良在本发明的精神、范围和概念的范围内,其由所附权利要求来限定。
XI.参考文献
将下列参考文献明确通过提及收入本文,但限于为本文给出的方法等细节提供进一步补充。
美国专利4,873,191
美国专利5,604,251
美国专利5,844,107
美国专利5,877,302
美国专利5,972,900
美国专利5,972,901
美国专利6,008,336
美国专利6,077,835
美国专利6,200,801
美国公开文本20020150626
美国公开文本20030032615
美国公开文本20030203865
美国公开文本20040048787
Abraham等,MoI Med.,8:750-760,2002.
Ambros,Cell,113(6):673-676,2003.
Angel等,Cell,49:729,1987b.
Angel等,Mol Cell.Biol,7:2256,1987a.
Atchison和Perry,Cell,46:253,1986.
Atchison和Perry,Cell,48:121,1987.
Babak等,RNA 10:1813-1819,2004.
Baichwal和Sugden,《Gene Transfer》,Kucherlapati编,Plenum Press,NY,117-148,1986.
Baldwin和Haddad,J.Appl Physiol.,90:345-357,2001.
Banerji等,Cell,27(2Pt l):299-308,1981.
Banerji等,Cell,33(3):729-740,1983.
B&r&等.,Genome Res.14:2486-2494,1997.
Barnes等,J.Biol.Chem.,272(17):11510-11517,1997.
Benvenisty和Neshif,Proc.Natl.Acad.Sd.USA,83(24):9551-9555,1986.
Berkhout等,Cell,59:273-282,1989.
Bhavsar等,Genomics,35(1):11-23,1996.
BUnar等,EMBO J.,8:1139,1989.
Bodine和Ley,EMBO J.,6:2997,1987.
Boshart等,Cell,41:521,1985.
Bosze等,EMBO J.,5(7)1616-1623,1986.
Braddock等,Cell,58:269,1989.
Brennecke等.,Cell,113:25-36,2003.
Brinster等.,Proc.Natl.Acad.Sci USA,82(13):4438-4442,1985.
Bristow,Cardiology,92:3-6,1999.
Bulla和Siddiqui,J.Virol,62:1437,1986.
Calin等,Proc.Natl.Acd.Sci USA,99:15524-15529,2002.
Campbell和Villarreal,Mol.Cell.Biol,8:1993,1988.
Campere和Tilghman,Genes and Dev.,3:537,1989.
Campo等,Nature,303:77,1983.
Carrington等Science,301(5631):336-338,2003.
Celander和Haseltine,J.Virology,61:269,1987.
Celander等,J.Virology,62:1314,1988.
Chandler等,Cell,33:489,1983.
Chang和Karin,Nature,410(6824):37-40,2001.
Chang等,Biochim.Biophys.Acta,1092(2):153-160,1991.
Chang等,Mol.Cell Biol,9:2153,1989.
Chang等,Nature,430(7001):785-789,2004.
Chatterjee等,Proc.Natl.Acad.Sci USA,86:9114,1989.
Chen和Okayama,Mo/.Cell Biol,7(8):2745-2752,1987.
Chen等,Mol Cell Endocrinol,162:45-55,2000.
Chen等,Science,303(5654):83-86,2004.
Choi等,Cell,53:519,1988.
Coffin,In:Virology,Fields等编,Raven Press,NY,1437-1500,1990.
Cohen等,J.Cell Physiol,5:75,1987.
Costa等,Mol Cell.Biol,8:81,1988.
Couch等,Am.Rev.Resp.Dis.,88:394-403,1963.
Coupar等,Gene,68:1-10,1988.
Cripe等,EMBO J.,6:3745,1987.
Culotta和Hamer,Mol Cell.Biol,9:1376,1989.
Dandolo等.,J.Virology,47:55-64,1983.
Oe ViUiers等.,Nature,312(5991):242-246,1984.
Deschamps等,Science,230:1174-1177,1985.
Dubensky等,JProc.Natl.Acad.Sci USA,81:7529-7533,1984.
Durand等,Ann.Med.,27:311-317,1995.
Edbrooke等,Mol.Cell.Biol,9:1908,1989.
Edgerton和Roy,J.Appl Physiol,89:1224-1231,2000.
Edlund等,Science,230:912-916,1985.
Eichhorn和Bristow,Circulation,94:2285-2296,1996.
EPO 0273085
Fechheimer,等,Proc Natl Acad.Sci.USA,84:8463-8467,1987.
Feng和Holland,Nature,334:6178,1988.
Ferkol等,FASEB J.,7:1081-1091,1993.
Firak和Subramanian,Mol Cell.Biol,6:3667,1986.
Fitts等,J.Appl Physiol,89:823-839,2000.
Foecking和Hofstetter,Gene,45(1):101-105,1986.
Fraley等,Proc.Natl.Acad.Sci.USA,76:3348-3352,1979.
Franz等,Cardioscience,5(4):235-43,1994.
Friedman等,Genes Devel,3:1314,1989.
Fujita等,Cell,49:357,1987.
Ghosh和Bachhawat,《Liver Diseases,Targeted Diagnosis and Therapy UsingSpecific Receptors and Ligands》,Wu等编,Marcel Dekker,NY,87-104,1991.
Ghosh-Choudhury等,EMBO J.,6:1733-1739,1987.
Gilles等,Cell,33:717,1983.
Gloss等,EMBO J,6:3735,1987.
Godbout等,Mol Cell.Biol,8:1169,1988.
Gomez-Foix等,J.Biol.Chem.,267:25129-25134,1992.
Goodbourn和Maniatis,Proc.Natl.Acad.Sci.USA,85:1447,1988.
Goodbourn等,Cell,45:601,1986.
Gopal,Mol.Cell Biol,5:1188-1190,1985.
Gopal-Srivastava等,J.Mol.Cell Biol 15(12):7081-7090,1995.
Graham和Prevec,《Methods in Molecular Biology:Gene Transfer andExpression Protocol》,Murray编,Humana Press,Clifton,NJ,7:109-128,1991.
Graham和Van Der Eb,Virology,52:456-467,1973.
Graham等,J.Gen.Virl,36(1):59-74,1977.
Greene等,Immunology Today,10:272,1989
Grishok等,Cell,106:23-34,2001.
Grosschedl和Baltimore,Cell,41:885,1985.
Grunhaus和Horwitz,Seminarin Virology,3:237-252,1992.
Harland和Weintraub,J.Cell Biol,101(3):1094-1099,1985.
Haslinger和Karin,Proc.Natl.Acad.Sci.USA,82:8572,1985.
Hauber和Cullen,J.Virology,62:673,1988.
Hen等,Nature,321:249,1986.
Hensel等,Lymphokine Res.,8:347,1989.
Hermonat和Muzycska,Proc.Natl.Acad.Sci.USA,81:6466-6470,1984.
Herr和Clarke,Cell,45:461,1986.
Hersdorffer等,DNA Cell Biol,9:713-723,1990.
Herz和Gerard,Proc.Natl Acad.Sci.USA,90:2812-2816,1993.
Hill等,Circulation,101:2863-2869,2000.
Hirochika等,J.Virol,61:2599,1987.
Hirsch等,Mol Cell Biol,10:1959,1990.
Holbrook等,Virology,157:211,1987.
Horlick和Benfield,Mol Cell.Biol,9:2396,1989.
Horwich等.J.Virol,64:642-650,1990.
Huang等,Cell,27:245,1981.
Hug等,Mol Cell.Biol,8:3065,1988.
Hutvagner等,PLoS Biol,2(4):E98,2004.
Hwang等,Mol Cell.Biol,10:585,1990.
Imagawa等,Cell,51:251,1987.
Imbra和Karin,Nature,323:555,1986.
lrnler等,Mol.Cell Biol,7:2558,1987.
Imperiale和Nevins,Mol Cell.Biol,4:875,1984.
Ito和Roeder,Trends Endocrinol.Metab.,12:127-134,2001.
Jakobovits等,Mol Cell.Biol,8:2555,1988.
Jameel和Siddiqui,Mol Cell.Biol,6:710,1986.
Jaynes等,Mol Cell.Biol,8:62,1988.
Johnson等,Mol Cell Biol,9:3393,1989.
Jones和Shenk,Cell,13:181-188,1978.
Kadesch和Berg,Mol Cell.Biol,6:2593,1986.
Kaneda等,Science,243:375-378,1989.
Karin等,Mol.Cell.Biol,7:606,1987.
Karin等,Mol.Cell.Biol,7:606,1987.
Karlsson等,EMBO J.,5:2377-2385,1986.
Katinka等,Cell,20:393,1980.
Katinka等,Nature,290:720,1981.
Kato等,J.Biol Chem.,266:3361-3364,1991.
Kawamoto等,Mol.Cell Biol,8:267,1988.
Kelly等,J.Cell Biol,129(2):383-396,1995.
Kiledjian等,Mol.Cell Biol,8:145,1988.
Kimura等,Dev.Growth Differ.39(3):257-265,1997.
Kinugawa等,Circ.Res.,89:591-598,2001.
Kinugawa等,J.Clin.Endocrinol Metab.,86:5089-5090,2001.
Kiriazis和Kranias,Annu.Rev.Physiol,62:321-351,2000.
Klamut等,Mol Cell Biol,10:193,1990.
Klein等,Nature,327:70-73,1987.
Koch等,Mol Cell Biol,9:303,1989.
Krek等,Nat.Genet.,37:495-500,2005.
Krek等,Nature Genetics,37:495-500,2005.
Krenz和Robbins,J.Am.Coll Cardiol,44:2390-2397,2004.
Kriegler和Botchan,《Eukaryotic Viral Vectors》,Gluzman编,Cold SpringHarbor:Cold Spring Harbor Laboratory,NY,1982.
Kriegler和Botchan,Mol Cell.Biol,3:325,1983a.
Kriegler等,Cell,38:483,1984.
Kriegler等,Cell,53:45,1988.
Kriegler等,《Gene Expression》,Alan Liss编,Hamer和Rosenberg,New York,1983b.
Krutzfeldt等,Nature,438:685-689,2005.
Kuhl等,Cell,50:1057,1987.
Kunz等,Nucl Acids Res.,17:1121,1989.
Lagos-Quintana等,Science,294(5543):853-858,2001.
LaPointe等,Hypertension 27(3Pt 2):715-22,1996.
LaPointe等,J.Biol.Chem.,263(19):9075-8,1988.
Lavsen等,Proc Natl.Acαd.Sci USA.,83:8283,1986.
Laspia等,Cell,59:283,1989.
等,Mol.Cell.Biol.,10:760,1990.
Lau等,Science,294(5543):858-862,2001.
Le Gal La Salle等,Science,259:988-990,1993.
Lee和Ambros,Science,294(5543):862-864,2001.
Lee等,Nature,294:228,1981.
Lee等,Nucleic Acids Res.,12:4191-206,1984.
Leung等,Proc.Natl.Acad.Sci USA,48:18125-18130,2006.
Levinson等,Nature,295:79,1982.
Levrero等,Gene,101:195-202,1991.
Lin等,Mol.Cell.Biol.,10:850,1990.
Liu等,Proc Natl Acad Sci USA 101:9740-9744,2004.
Luria等,EMBO J.,6:3307,1987.
Lusky和Botchan,Proc.Natl.Acad.Sci USA,83:3609,1986.
Lusky等,Mol Cell.Biol,3:1108,1983.
Macejak和Sarnow,Nature,353:90-94,1991.
Majors和Varmus,Proc.Natl Acad.Sci USA,80:5866,1983.
Mann等,Cell,33:153-159,1983.
Mansen等,Mol Endocrinol,15:2106-2114,2001.
Markowitz等,J.Virol,62:1120-1124,1988.
McNeall等,Gene,76:81,1989.
Meister和Tuschl,Nature,431:343-9,2004.
Miksicek等,Cell,46:203,1986.
Molkentin等,Cell 93:215-228,1998.
Mordacq和Linzer,Genes and Dev.,3:760,1989.
Moreau等,Nucl Acids Res.,9:6047,1981.
Morkin,Microsc.Res.Tech.,50:522-531,2000.
Moss等,Biol.Che m.,271(49):31688-31694,1996.
Muesing等,Cell,48:691,1987.
Naya等,J Biol Chem,275(7):4545-4548,2000.
Ng等,Nuc.Acids Res.,17:601,1989.
Nicolas和Rubinstein,《Vectors:A survey of molecular cloning vectors and theiruses》,Rodriguez和Denhardt(编),Stoneham:Butterworth,494-513,1988.
Nicolau和Sene,Biochim.Biophys.Acta,721:185-190,1982.
Nicolau等.,Methods Enzymol.,149:157-176,1987.
Ojamaa等.,Endocrinology,141:2139-2144,2000.
Ondek等,EMBO J,6:1017,1987.
Ornitz等,Mol.Cell.Biol,7:3466,1987.
Palmiter等,Nature,300:611,1982.
Pantos等,Horm.Metab.Res.,38:308-313,2006.
Park等,Mol Cell.,19:643-653,2005.
Paskind等,Virology,67:242-248,1975.
Pasquinelli和Ruvkun,Ann.Rev.Cell Dev.Biol.,18:495-513,2002.
Pavri等,Mol.Cell.,18:83-96,2005.
PCT公开文本WO 0071096
PCT公开文本WO 84/03564
PCT公开文本WO 98/33791
Pech等.,Mol.Cell.Biol,9:396,1989.
Pelletier和Sonenberg,Nature,334(6180):320-325,1988.
Perales等,Proc.Natl.Acad.Sci USA,91:4086-4090,1994.
Perez-Stable和Constantini,Mol Cell.Biol,10:1116,1990.
Physicians Desk Reference
Picard和Schaffner,Nature,307:83,1984.
Pinkert等,Genes and Dev.,1:268,1987.
Ponta等.,Proc.Natl.Acad.Sci USA,82:1020,1985.
Porton等,Mol.Cell.Biol,10:1076,1990.
Potter等,Proc.Natl.Acad.Sci USA,81:7161-7165,1984.
Queen和Baltimore,Cell,35:741,1983.
Quinn等.,Mol.Cell.Biol,9′AlU,1989.
Racher等,Biotechnology Techniques,9:169-174,1995.
Ragot等,Nature,361:647-650,1993.
Redondo等,Science,247:1225,1990.
Reisman和Rotter,Mol.Cell.Biol,9:3571,1989.
《Remington′s Pharmaceutical Sciences》,第15版,第1035-1038和1570-1580页,Mack Publishing Company,Easton,PA,1980.
Renan,Radiother.Oncol,19:197-218,1990.
Resendez Jr.等,Mol Cell.Biol,8:4579,1988.
Rich等,Hum.Gene Ther.,4:461-476,1993.
Ridgeway,《Vectors:A Survey of Molecular Cloning Vectors and Their Uses》,Rodriguez等编,Stoneham:Butterworth,467-492,1988.
Ripe等,Mol.Cell.Biol,9:2224,1989.
Rippe,等,Mol.Cell Biol,10:689-695,1990.
Rittling等,Nuc.Acids Res.,17:1619,1989.
Rosen等,Cell,41:813,1988.
Rosenfeld等,Science,252:431-434,1991.
Rosenfeld,等,Cell,68:143-155,1992.
Roux等.,Proc.Natl Acad.Sci USA,86:9079-9083,1989.
Sakai等,Genes and Dev.,2:1144,1988.
Sambrook和Russell,《Molecular Cloning:A Laboratory Manual》第3版,ColdSpring Harbor Laboratory Press,2001.
Satake等,J.Virology,62:970,1988.
Schaffner等,J.Mol Biol,201:81,1988.
Schuyler和Yarbrough,Basic Res.Cardiol,85:481-494,1990.
Searle等,Mol Cell.Biol,5:1480,1985.
Sempere等,Genome Biol 5:R13,2004.
Sharp和Marciniak,Cell,59:229,1989.
Shaul和Ben-Levy,EMBO J.,6:1913,1987.
Sherman等,Mol Cell.Biol,9:50,1989.
Shingara等.,RNA 11:1461-1470,2005.
Sleigh和Lockett,J EMBO,4:3831,1985.
Spalholz等,Cell,42:183,1985.
Spandau和Lee,J.Virology,62:427,1988.
Spandidos和Wilkie,EMBOJ.,2:1193,1983.
Stephens和Hentschel,Biochem.J,248:1,1987.
Stratford-Perricaudet和Perricaudet,《Human Gene Transfer》,Cohen-Haguenauer和Boiron编,John Libbey Eurotext,France,51-61,1991.
Stratford-Perricaudet等,Hum.Gene.Ther.,1:241-256,1990.
Stuart等,Nature,317:828,1985.
Sullivan和Peterlin,Mol Cell.Biol,7:3315,1987.
Swartzendruber和Lehman,J.Cell.Physiology,85:179,1975.
Takebe等,Mol Cell.Biol,8:466,1988.
Tavernier等,Nature,301:634,1983.
Taylor和Kingston,Mol Cell.Biol,10:165,1990a.
Taylor和Kingston,Mol.Cell.Biol,10:176,1990b.
Taylor等,J.Biol.Chem.,264:15160,1989.
Temin,《Gene Transfer》,Kucherlapati编,NY,Plenum Press,149-188,1986.
The Merck Index,第8版
Thiesen等,J.Virology,62:614,1988.
Top等,J.Infect.Dis.,124:155-160,1971.
Treisman,Cell,46(4):567-174,1986
Tranche等.,Mol Biol.Med.,7:173,1990.
Tranche等,Mol.Cell Biol,9(11):4759-4766,1989.
Trudel和Constantini,Genes and Dev.,6:954,1987.
Tsika等,Am.J.Physiol Cell Physiol,283:C1761-C1775,2002.
Tur-Kaspa等,Mol Cell Biol,6:716-718,1986.
Tyndell等,Nuc.Acids.Res.,9:6231,1981.
Vadaszova等,Physiol.Res.53(1):S57-61,2004.
van Rooij等,Proc.Natl Acad.Sci USA,103(48):18255-18260,2006.
Vannice和Levinson,J.Virology,62:1305,1988.
Varmus等,Cell,25:23-36,1981.
Vasseur等,Proc Natl.Acad.Sci USA,77:1068,1980.
Wagner等,Proc.Natl Acad.Sci USA 87(9):3410-3414,1990.
Wang和Calame,Cell,47:241,1986.
Weber等,Cell,36:983,1984.
Wei等,J.Endocrinol Invest.,28:8-11,2005.
Weinberger等Mol Cell.Biol,8:988,1984.
Winoto和Baltimore,Cell,59:649,1989.
Wong等,Gene,10:87-94,1980.
Wu和Wu,Adv.Drug Delivery Rev.,12:159-167,1993.
Wu和Wu,Biochemistry,27:887-892,1988.
Wu和Wu,J.Biol Chem.,262:4429-4432,1987.
Xu等,Curr.Biol,13:790-795,2003.
Yamauchi-Takihara等,Proc.Natl.Acad.Sci USA,86(10):3504-3508,1989.
Yang和Russell,Proc.Natl Acad.Sci USA,87:4144-4148,1990.
Yao和Eghbali,Circ.Res.71:831-839,1992.
Young等,《Handbook of Applied Therapeutics》,7.1-7.12和9.1-9.10,1989.
Yutzey等Mol.Cell.Biol,9:1397,1989.
Zelenin等,FEBS Lett.,287(1-2):118-120,1991.
Zeng等,Cancer Res.,62(13):3630-3635,2002.
Ziober和Kramer,J.Bio.Chem.,271(37):22915-22,1996.
Claims (9)
1.miR-208的表达或活性的抑制剂用于制备治疗或预防有需要的受试者中的病理性心脏肥大、心肌梗死、或心力衰竭的药物的用途,其中所述miR-208的表达或活性的抑制剂是由与SEQ ID NO:5的序列互补的序列组成的单链寡核苷酸。
2.权利要求1的用途,其中所述miR-208的表达或活性的抑制剂是antagomir或2’-O-甲基反义寡核苷酸。
3.权利要求1的用途,其中所述药物被配制为供静脉内施用或直接注射入心脏组织。
4.权利要求1的用途,其中所述药物被配制为供口服、经皮、持续释放、受控释放、延迟释放、栓剂、或舌下施用。
5.权利要求1的用途,其中所述药物还包含第二心脏肥大药物。
6.权利要求5的用途,其中所述第二心脏肥大药物是β阻滞剂、肌力药、利尿药、ACE-I、AII拮抗剂、BNP、Ca++-阻滞剂、内皮缩血管肽受体拮抗剂、或HDAC抑制剂。
7.权利要求1的用途,其中所述药物改善病理性心脏肥大或心力衰竭的一种或多种症状。
8.权利要求1的用途,其中所述药物延迟从心脏肥大到心力衰竭的转化。
9.权利要求1的用途,其中所述受试者具有选自下组的一种或多种风险因子:长期不受控制的高血压、未矫正的瓣膜病、慢性心绞痛、新近的心肌梗死、心脏病的先天素因或心脏病理性肥大。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US83466706P | 2006-08-01 | 2006-08-01 | |
US60/834,667 | 2006-08-01 | ||
US95291107P | 2007-07-31 | 2007-07-31 | |
US95291707P | 2007-07-31 | 2007-07-31 | |
PCT/US2007/074866 WO2008016924A2 (en) | 2006-08-01 | 2007-07-31 | Identification of a micro-rna that activates expression of beta-myosin heavy chain |
US60/952,911 | 2007-07-31 | ||
US60/952,917 | 2007-07-31 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101522222A CN101522222A (zh) | 2009-09-02 |
CN101522222B true CN101522222B (zh) | 2012-04-18 |
Family
ID=38896739
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2007800367837A Expired - Fee Related CN101522222B (zh) | 2006-08-01 | 2007-07-31 | 激活β-肌球蛋白重链表达的微RNA的鉴定 |
Country Status (17)
Country | Link |
---|---|
US (1) | US8304397B2 (zh) |
EP (2) | EP2434017A3 (zh) |
JP (2) | JP5718570B2 (zh) |
KR (1) | KR101485495B1 (zh) |
CN (1) | CN101522222B (zh) |
AU (1) | AU2007281261B2 (zh) |
BR (1) | BRPI0714794A2 (zh) |
CA (1) | CA2659364C (zh) |
CY (1) | CY1113539T1 (zh) |
DK (1) | DK2056882T3 (zh) |
ES (1) | ES2397439T3 (zh) |
HK (1) | HK1134042A1 (zh) |
MX (1) | MX2009001281A (zh) |
NZ (1) | NZ574563A (zh) |
PL (1) | PL2056882T3 (zh) |
PT (1) | PT2056882E (zh) |
WO (1) | WO2008016924A2 (zh) |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL2056882T3 (pl) | 2006-08-01 | 2013-03-29 | Univ Texas | Identyfikacja mikro-RNA, który aktywuje ekspresję łańcucha ciężkiego beta-miozyny |
US20090306181A1 (en) * | 2006-09-29 | 2009-12-10 | Children's Medical Center Corporation | Compositions and methods for evaluating and treating heart failure |
US20100305195A1 (en) * | 2006-11-10 | 2010-12-02 | The Uab Research Foundation | microrna mediator of cardiomyopathy and heart failure |
WO2008076324A2 (en) * | 2006-12-14 | 2008-06-26 | Novartis Ag | Compositions and methods to treat muscular & cardiovascular disorders |
US8440636B2 (en) * | 2007-07-31 | 2013-05-14 | The Board Of Regents, The University Of Texas System | Micro-RNA family that modulates fibrosis and uses thereof |
CN105030808B (zh) * | 2007-07-31 | 2018-12-14 | 得克萨斯系统大学董事会 | 调控纤维化的微小rna家族及其用途 |
AU2008283794B2 (en) | 2007-07-31 | 2014-03-20 | Board Of Regents, The University Of Texas System | Micro-RNAs that control myosin expression and myofiber identity |
EP2331143B1 (en) * | 2008-09-04 | 2016-08-17 | Universität Zürich Prorektorat Mnw | Treatment of scleroderma |
AU2010210605B2 (en) | 2009-02-04 | 2015-08-13 | Board Of Regents, The University Of Texas System | Dual targeting of miR-208 and miR-499 in the treatment of cardiac disorders |
EP2427472B1 (en) | 2009-05-05 | 2016-06-22 | Miragen Therapeutics | Lipophilic polynucleotide conjugates |
WO2011154553A2 (en) * | 2010-06-11 | 2011-12-15 | Cellartis Ab | Novel micrornas for the detection and isolaton of human embryonic stem cell-derived cardiac cell types |
CN103492569B (zh) | 2010-11-05 | 2020-04-07 | 米拉根医疗公司 | 碱基经修饰的寡核苷酸 |
EP2652151A2 (en) | 2010-12-15 | 2013-10-23 | Miragen Therapeutics | Microrna inhibitors comprising locked nucleotides |
CN104011208B (zh) * | 2011-09-06 | 2020-04-10 | 马普科技促进协会 | 作为治疗靶的miRNA-212/132家族 |
AU2013201303C1 (en) * | 2011-10-06 | 2016-06-23 | MiRagen Therapeutics, Inc. | Control of whole body energy homeostasis by microRNA regulation |
US9388408B2 (en) | 2012-06-21 | 2016-07-12 | MiRagen Therapeutics, Inc. | Oligonucleotide-based inhibitors comprising locked nucleic acid motif |
CN102719436A (zh) * | 2012-06-27 | 2012-10-10 | 南开大学 | 一种寡核苷酸及其制备在防治心肌肥大与心力衰竭药物中的用途 |
US10076384B2 (en) | 2013-03-08 | 2018-09-18 | Symple Surgical, Inc. | Balloon catheter apparatus with microwave emitter |
EP2968396B1 (en) | 2013-03-15 | 2018-12-19 | Miragen Therapeutics, Inc. | Locked nucleic acid inhibitor of mir-145 and uses thereof |
GB201400598D0 (en) | 2014-01-14 | 2014-03-05 | Univ Glasgow | Materials and methods for modulation of tendon healing |
JP2018503646A (ja) | 2015-01-20 | 2018-02-08 | ミラゲン セラピューティクス, インコーポレイテッド | miR−92阻害剤およびその使用 |
CN105695606B (zh) * | 2016-04-07 | 2020-08-28 | 昆明理工大学 | 用于非治疗目的的肥厚型心肌病相关致病基因突变的筛查方法 |
US10150115B2 (en) * | 2016-07-21 | 2018-12-11 | Spacepharma SA | System and method for rehydrating powder and delivering the rehydrated powder to a reactor |
WO2018047148A1 (en) | 2016-09-12 | 2018-03-15 | Novartis Ag | Compounds for the inhibition of mirna |
CN109097461B (zh) * | 2018-09-06 | 2021-07-30 | 北京中关村生命科学园生物医药科技孵化有限公司 | 一种心肌病相关基因检测试剂及其应用 |
Family Cites Families (48)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4873191A (en) | 1981-06-12 | 1989-10-10 | Ohio University | Genetic transformation of zygotes |
NZ207394A (en) | 1983-03-08 | 1987-03-06 | Commw Serum Lab Commission | Detecting or determining sequence of amino acids |
EP0273085A1 (en) | 1986-12-29 | 1988-07-06 | IntraCel Corporation | A method for internalizing nucleic acids into eukaryotic cells |
US6867195B1 (en) | 1989-03-21 | 2005-03-15 | Vical Incorporated | Lipid-mediated polynucleotide administration to reduce likelihood of subject's becoming infected |
TW215434B (zh) | 1992-03-07 | 1993-11-01 | Hoechst Ag | |
US5972901A (en) | 1994-03-23 | 1999-10-26 | Case Western Reserve University | Serpin enzyme complex receptor--mediated gene transfer |
WO1995025809A1 (en) | 1994-03-23 | 1995-09-28 | Ohio University | Compacted nucleic acids and their delivery to cells |
US6077835A (en) | 1994-03-23 | 2000-06-20 | Case Western Reserve University | Delivery of compacted nucleic acid to cells |
US5844107A (en) | 1994-03-23 | 1998-12-01 | Case Western Reserve University | Compacted nucleic acids and their delivery to cells |
CA2277965A1 (en) | 1997-02-04 | 1998-08-06 | Marc A. Bruce | Dihydropyrimidone derivatives as npy antagonists |
EP1180016B1 (en) | 1999-05-24 | 2006-09-27 | Introgen Therapeutics, Inc. | Methods and compositions for non-viral gene therapy for treatment of hyperproliferative diseases |
WO2001014581A2 (en) * | 1999-08-20 | 2001-03-01 | Board Of Regents, The University Of Texas System | Hdac4 and hdac5 in the regulation of cardiac gene expression |
DE10004858A1 (de) * | 2000-02-03 | 2001-08-16 | Schering Ag | Verwendung von Proteinkinase-Inhibitor-alpha |
US20020042388A1 (en) | 2001-05-01 | 2002-04-11 | Cooper Mark J. | Lyophilizable and enhanced compacted nucleic acids |
US20020150626A1 (en) | 2000-10-16 | 2002-10-17 | Kohane Daniel S. | Lipid-protein-sugar particles for delivery of nucleic acids |
CA2445947A1 (en) | 2001-04-30 | 2002-11-07 | Targeted Genetics Corporation | Lipid-comprising drug delivery complexes and methods for their production |
US20050124568A1 (en) | 2001-05-18 | 2005-06-09 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of acetyl-CoA-carboxylase gene expression using short interfering nucleic acid (siNA) |
EP2385122B1 (en) | 2001-09-28 | 2018-04-25 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | MicroRNA molecules |
US20080214437A1 (en) | 2002-09-06 | 2008-09-04 | Mohapatra Shyam S | Methods and compositions for reducing activity of the atrial natriuretic peptide receptor and for treatment of diseases |
US7781415B2 (en) | 2003-02-07 | 2010-08-24 | Roche Madison Inc. | Process for delivering sirna to cardiac muscle tissue |
EP2530157B1 (en) * | 2003-07-31 | 2016-09-28 | Regulus Therapeutics Inc. | Oligomeric compounds and compositions for use in modulation of miRNAs |
WO2005047505A2 (en) * | 2003-08-07 | 2005-05-26 | Whitehead Institute For Biomedical Research | Methods and products for expression of micro rnas |
WO2005017145A1 (ja) | 2003-08-13 | 2005-02-24 | Japan Biological Informatics Consortium | 機能性rnaが制御する被制御遺伝子の同定・予測方法及びその利用方法 |
WO2005018673A1 (en) * | 2003-08-21 | 2005-03-03 | Osaka University | Pharmaceutical composition for preventing or remedying cardiac hypertrophy and cardiocascular disease caused thereby |
WO2005078096A2 (en) | 2004-02-09 | 2005-08-25 | University Of Massachusetts | Dual functional oligonucleotides for use in repressing mutant gene expression |
EP2295604B1 (en) | 2004-02-09 | 2015-04-08 | Thomas Jefferson University | Diagnosis and treatment of cancers with microRNA located in or near cancer-associated chromosomal features |
CA2556435C (en) | 2004-02-13 | 2014-08-12 | The Rockefeller University | Anti-microrna oligonucleotide molecules |
EP2471924A1 (en) | 2004-05-28 | 2012-07-04 | Asuragen, INC. | Methods and compositions involving microRNA |
US7635563B2 (en) * | 2004-06-30 | 2009-12-22 | Massachusetts Institute Of Technology | High throughput methods relating to microRNA expression analysis |
PL2302055T3 (pl) | 2004-11-12 | 2015-02-27 | Asuragen Inc | Sposoby i kompozycje z wykorzystaniem miRNA oraz cząsteczek inhibitorowych miRNA |
WO2006063356A1 (en) | 2004-12-10 | 2006-06-15 | Isis Phamaceuticals, Inc. | Regulation of epigenetic control of gene expression |
US20060185027A1 (en) | 2004-12-23 | 2006-08-17 | David Bartel | Systems and methods for identifying miRNA targets and for altering miRNA and target expression |
EP1838870A2 (en) | 2004-12-29 | 2007-10-03 | Exiqon A/S | NOVEL OLIGONUCLEOTIDE COMPOSITIONS AND PROBE SEQUENCES USEFUL FOR DETECTION AND ANALYSIS OF MICRORNAS AND THEIR TARGET MRNAs |
US8071306B2 (en) | 2005-01-25 | 2011-12-06 | Merck Sharp & Dohme Corp. | Methods for quantitating small RNA molecules |
BRPI0608829A2 (pt) | 2005-04-19 | 2011-03-15 | Basf Plant Science Gmbh | método para a expressão transgênica com especificidade intensificada em uma planta, uso de um construto de ácido nucleico quimérico, seqüência de ribonucleotìdeo quimérica, construto de expressão, vetor de expressão, organismo não-humano ou célula transformada, semente transformada, e, preparação farmacêutica |
CA2609142C (en) | 2005-05-27 | 2016-02-09 | Fondazione Centro San Raffaele Del Monte Tabor | Therapeutic gene vectors comprising mirna target sequences |
US20070087179A1 (en) * | 2005-10-17 | 2007-04-19 | Horn Donald R | Solid surface composite |
NZ569738A (en) | 2005-12-12 | 2012-03-30 | Univ North Carolina | MicroRNAs (miRNA) that regulate muscle cell proliferation and differentiation |
EP2388328A1 (en) | 2006-01-27 | 2011-11-23 | Isis Pharmaceuticals, Inc. | Oligomeric compounds and compositions for the use in modulation of micrornas |
CA2649045C (en) | 2006-04-03 | 2019-06-11 | Santaris Pharma A/S | Pharmaceutical composition comprising anti-mirna antisense oligonucleotides |
PL2056882T3 (pl) | 2006-08-01 | 2013-03-29 | Univ Texas | Identyfikacja mikro-RNA, który aktywuje ekspresję łańcucha ciężkiego beta-miozyny |
US20090306181A1 (en) | 2006-09-29 | 2009-12-10 | Children's Medical Center Corporation | Compositions and methods for evaluating and treating heart failure |
EP2476762B1 (de) | 2006-10-09 | 2014-01-08 | Julius-Maximilians-Universität Würzburg | MicroRNA (miRNA) zur Diagnose und Therapie von Herzerkrankungen |
JP2010509923A (ja) | 2006-11-23 | 2010-04-02 | ミルクス セラピューティクス アンパーツゼルスカブ | 標的rnaの活性を変化させるためのオリゴヌクレオチド |
WO2008076324A2 (en) | 2006-12-14 | 2008-06-26 | Novartis Ag | Compositions and methods to treat muscular & cardiovascular disorders |
US20090137504A1 (en) | 2006-12-21 | 2009-05-28 | Soren Morgenthaler Echwald | Microrna target site blocking oligos and uses thereof |
CA2687336C (en) | 2007-05-23 | 2014-12-23 | Dharmacon, Inc. | Micro-rna scaffolds and non-naturally occurring micro-rnas |
EP2192925A4 (en) | 2007-08-23 | 2013-04-03 | Keren Pharmaceuticals | TARGETING RNA WITH EXTERNAL GUIDE SEQUENCES |
-
2007
- 2007-07-31 PL PL07813595T patent/PL2056882T3/pl unknown
- 2007-07-31 CN CN2007800367837A patent/CN101522222B/zh not_active Expired - Fee Related
- 2007-07-31 NZ NZ574563A patent/NZ574563A/en not_active IP Right Cessation
- 2007-07-31 MX MX2009001281A patent/MX2009001281A/es active IP Right Grant
- 2007-07-31 EP EP11190352A patent/EP2434017A3/en not_active Withdrawn
- 2007-07-31 CA CA2659364A patent/CA2659364C/en not_active Expired - Fee Related
- 2007-07-31 PT PT07813595T patent/PT2056882E/pt unknown
- 2007-07-31 JP JP2009523016A patent/JP5718570B2/ja not_active Expired - Fee Related
- 2007-07-31 BR BRPI0714794-5A patent/BRPI0714794A2/pt not_active Application Discontinuation
- 2007-07-31 WO PCT/US2007/074866 patent/WO2008016924A2/en active Application Filing
- 2007-07-31 KR KR1020097004411A patent/KR101485495B1/ko not_active IP Right Cessation
- 2007-07-31 ES ES07813595T patent/ES2397439T3/es active Active
- 2007-07-31 US US11/831,427 patent/US8304397B2/en not_active Expired - Fee Related
- 2007-07-31 DK DK07813595.1T patent/DK2056882T3/da active
- 2007-07-31 AU AU2007281261A patent/AU2007281261B2/en not_active Ceased
- 2007-07-31 EP EP07813595A patent/EP2056882B1/en not_active Not-in-force
-
2010
- 2010-03-01 HK HK10102134.1A patent/HK1134042A1/xx not_active IP Right Cessation
-
2013
- 2013-01-11 CY CY20131100028T patent/CY1113539T1/el unknown
- 2013-09-30 JP JP2013203794A patent/JP5798165B2/ja not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
US20090180957A1 (en) | 2009-07-16 |
EP2434017A2 (en) | 2012-03-28 |
EP2434017A3 (en) | 2012-09-05 |
JP5798165B2 (ja) | 2015-10-21 |
CN101522222A (zh) | 2009-09-02 |
NZ574563A (en) | 2012-02-24 |
MX2009001281A (es) | 2009-04-16 |
KR101485495B1 (ko) | 2015-01-22 |
KR20090037968A (ko) | 2009-04-16 |
BRPI0714794A2 (pt) | 2013-05-21 |
EP2056882A2 (en) | 2009-05-13 |
CA2659364A1 (en) | 2008-02-07 |
CA2659364C (en) | 2017-08-22 |
ES2397439T3 (es) | 2013-03-07 |
WO2008016924A2 (en) | 2008-02-07 |
EP2056882B1 (en) | 2012-10-24 |
PL2056882T3 (pl) | 2013-03-29 |
WO2008016924A3 (en) | 2008-08-07 |
AU2007281261B2 (en) | 2013-03-21 |
PT2056882E (pt) | 2012-11-19 |
JP5718570B2 (ja) | 2015-05-13 |
HK1134042A1 (en) | 2010-04-16 |
US8304397B2 (en) | 2012-11-06 |
JP2014001243A (ja) | 2014-01-09 |
AU2007281261A1 (en) | 2008-02-07 |
CY1113539T1 (el) | 2016-06-22 |
JP2009545615A (ja) | 2009-12-24 |
DK2056882T3 (da) | 2012-11-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101522222B (zh) | 激活β-肌球蛋白重链表达的微RNA的鉴定 | |
US9078919B2 (en) | Micro-RNAs of the miR-15 family modulate cardiomyocyte survival and cardiac repair | |
CN101883576B (zh) | 调控纤维化的微小rna家族及其用途 | |
CN101808649B (zh) | 控制肌球蛋白表达和肌纤维身份的微小rna | |
WO2009058818A2 (en) | Compositions comprising a micro-rna and methods of their use in regulating cardiac remodeling | |
CN105030808B (zh) | 调控纤维化的微小rna家族及其用途 | |
AU2014200897A1 (en) | A micro-rna family that modulates fibrosis and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1134042 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1134042 Country of ref document: HK |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120418 Termination date: 20180731 |
|
CF01 | Termination of patent right due to non-payment of annual fee |