JP6859369B2 - Ｖｅｇｆ−ａポリペプチドをコードする改変ｒｎａ、製剤、およびそれに関連する使用 - Google Patents
Ｖｅｇｆ−ａポリペプチドをコードする改変ｒｎａ、製剤、およびそれに関連する使用 Download PDFInfo
- Publication number
- JP6859369B2 JP6859369B2 JP2018564389A JP2018564389A JP6859369B2 JP 6859369 B2 JP6859369 B2 JP 6859369B2 JP 2018564389 A JP2018564389 A JP 2018564389A JP 2018564389 A JP2018564389 A JP 2018564389A JP 6859369 B2 JP6859369 B2 JP 6859369B2
- Authority
- JP
- Japan
- Prior art keywords
- vegf
- modified rna
- formulation
- composition
- citrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000000203 mixture Substances 0.000 title claims description 392
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 title claims description 367
- 102000009524 Vascular Endothelial Growth Factor A Human genes 0.000 title claims description 366
- 238000009472 formulation Methods 0.000 title claims description 217
- 108091032973 (ribonucleotides)n+m Proteins 0.000 title description 17
- 102000040650 (ribonucleotides)n+m Human genes 0.000 title description 17
- 239000000872 buffer Substances 0.000 claims description 233
- 238000000034 method Methods 0.000 claims description 203
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 201
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 184
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 100
- 201000010099 disease Diseases 0.000 claims description 88
- 239000011575 calcium Substances 0.000 claims description 72
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 71
- 229910052791 calcium Inorganic materials 0.000 claims description 71
- 239000011777 magnesium Substances 0.000 claims description 67
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 66
- 229910052749 magnesium Inorganic materials 0.000 claims description 66
- 108090000623 proteins and genes Proteins 0.000 claims description 53
- 208000010125 myocardial infarction Diseases 0.000 claims description 51
- 150000002632 lipids Chemical class 0.000 claims description 46
- 239000002105 nanoparticle Substances 0.000 claims description 46
- 102000004169 proteins and genes Human genes 0.000 claims description 45
- 238000011282 treatment Methods 0.000 claims description 42
- 150000001768 cations Chemical class 0.000 claims description 39
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 32
- -1 isotonics Substances 0.000 claims description 31
- 230000000747 cardiac effect Effects 0.000 claims description 30
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 30
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 29
- 238000002360 preparation method Methods 0.000 claims description 27
- 238000002560 therapeutic procedure Methods 0.000 claims description 25
- 230000002829 reductive effect Effects 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 21
- 229920000642 polymer Polymers 0.000 claims description 20
- 239000002502 liposome Substances 0.000 claims description 18
- 239000003085 diluting agent Substances 0.000 claims description 17
- 230000004064 dysfunction Effects 0.000 claims description 17
- 206010019280 Heart failures Diseases 0.000 claims description 16
- 239000006185 dispersion Substances 0.000 claims description 15
- 206010040943 Skin Ulcer Diseases 0.000 claims description 14
- 239000003995 emulsifying agent Substances 0.000 claims description 14
- 230000000302 ischemic effect Effects 0.000 claims description 14
- 208000031225 myocardial ischemia Diseases 0.000 claims description 14
- 231100000019 skin ulcer Toxicity 0.000 claims description 14
- 208000005764 Peripheral Arterial Disease Diseases 0.000 claims description 13
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 13
- 208000024248 Vascular System injury Diseases 0.000 claims description 13
- 208000012339 Vascular injury Diseases 0.000 claims description 13
- 108020004999 messenger RNA Proteins 0.000 claims description 13
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 13
- 102000001974 Hyaluronidases Human genes 0.000 claims description 12
- 108050009363 Hyaluronidases Proteins 0.000 claims description 12
- 239000007853 buffer solution Substances 0.000 claims description 12
- 210000003748 coronary sinus Anatomy 0.000 claims description 12
- 239000003755 preservative agent Substances 0.000 claims description 12
- 239000004094 surface-active agent Substances 0.000 claims description 12
- 239000000725 suspension Substances 0.000 claims description 12
- 239000002562 thickening agent Substances 0.000 claims description 12
- 206010056340 Diabetic ulcer Diseases 0.000 claims description 11
- 208000017169 kidney disease Diseases 0.000 claims description 10
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 9
- 239000002612 dispersion medium Substances 0.000 claims description 9
- 238000007918 intramuscular administration Methods 0.000 claims description 8
- 210000004165 myocardium Anatomy 0.000 claims description 8
- 238000007920 subcutaneous administration Methods 0.000 claims description 8
- 230000000472 traumatic effect Effects 0.000 claims description 8
- 239000011258 core-shell material Substances 0.000 claims description 7
- 238000002054 transplantation Methods 0.000 claims description 4
- 230000020411 cell activation Effects 0.000 claims 1
- 229920002477 rna polymer Polymers 0.000 description 549
- 239000007924 injection Substances 0.000 description 197
- 238000002347 injection Methods 0.000 description 197
- 210000001519 tissue Anatomy 0.000 description 154
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 95
- 206010052428 Wound Diseases 0.000 description 89
- 239000003981 vehicle Substances 0.000 description 89
- 101000808011 Homo sapiens Vascular endothelial growth factor A Proteins 0.000 description 86
- 102000058223 human VEGFA Human genes 0.000 description 85
- 239000011780 sodium chloride Substances 0.000 description 85
- 208000027418 Wounds and injury Diseases 0.000 description 79
- 241000699670 Mus sp. Species 0.000 description 61
- 210000004962 mammalian cell Anatomy 0.000 description 58
- 210000002216 heart Anatomy 0.000 description 57
- 238000012360 testing method Methods 0.000 description 54
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 53
- 230000001965 increasing effect Effects 0.000 description 50
- 230000000694 effects Effects 0.000 description 49
- 229960000281 trometamol Drugs 0.000 description 49
- 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 48
- 239000002953 phosphate buffered saline Substances 0.000 description 48
- 230000002861 ventricular Effects 0.000 description 45
- 206010061216 Infarction Diseases 0.000 description 44
- 241000699666 Mus <mouse, genus> Species 0.000 description 39
- 230000017531 blood circulation Effects 0.000 description 39
- 210000004027 cell Anatomy 0.000 description 39
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 38
- 210000004369 blood Anatomy 0.000 description 35
- 239000008280 blood Substances 0.000 description 35
- 229910052760 oxygen Inorganic materials 0.000 description 35
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 34
- 239000001301 oxygen Substances 0.000 description 34
- 239000000523 sample Substances 0.000 description 33
- 230000007574 infarction Effects 0.000 description 31
- 230000002107 myocardial effect Effects 0.000 description 29
- 241000700159 Rattus Species 0.000 description 27
- 238000004458 analytical method Methods 0.000 description 27
- 230000014616 translation Effects 0.000 description 27
- 230000029663 wound healing Effects 0.000 description 27
- 230000033115 angiogenesis Effects 0.000 description 26
- 239000008194 pharmaceutical composition Substances 0.000 description 25
- 239000003814 drug Substances 0.000 description 24
- 210000005069 ears Anatomy 0.000 description 24
- 238000005259 measurement Methods 0.000 description 24
- 150000007523 nucleic acids Chemical class 0.000 description 24
- 238000001890 transfection Methods 0.000 description 24
- 241000282887 Suidae Species 0.000 description 23
- 238000003384 imaging method Methods 0.000 description 23
- 230000004048 modification Effects 0.000 description 23
- 238000012986 modification Methods 0.000 description 23
- 210000003491 skin Anatomy 0.000 description 23
- 241001465754 Metazoa Species 0.000 description 22
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 22
- 239000002609 medium Substances 0.000 description 22
- 238000010186 staining Methods 0.000 description 22
- 210000001367 artery Anatomy 0.000 description 20
- 239000007925 intracardiac injection Substances 0.000 description 20
- 238000004519 manufacturing process Methods 0.000 description 20
- 244000309715 mini pig Species 0.000 description 20
- 101800000407 Brain natriuretic peptide 32 Proteins 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 18
- 229940079593 drug Drugs 0.000 description 18
- 230000006870 function Effects 0.000 description 18
- 238000002474 experimental method Methods 0.000 description 17
- 238000001727 in vivo Methods 0.000 description 17
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 16
- 210000002889 endothelial cell Anatomy 0.000 description 16
- 238000011156 evaluation Methods 0.000 description 16
- 229920001184 polypeptide Polymers 0.000 description 16
- 230000004865 vascular response Effects 0.000 description 16
- 238000001690 micro-dialysis Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 206010016654 Fibrosis Diseases 0.000 description 14
- 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 14
- 108060001084 Luciferase Proteins 0.000 description 14
- 241000283973 Oryctolagus cuniculus Species 0.000 description 14
- 230000033228 biological regulation Effects 0.000 description 14
- 210000001736 capillary Anatomy 0.000 description 14
- 230000004761 fibrosis Effects 0.000 description 14
- 239000008103 glucose Substances 0.000 description 14
- 230000001939 inductive effect Effects 0.000 description 14
- 210000005240 left ventricle Anatomy 0.000 description 14
- 102000039446 nucleic acids Human genes 0.000 description 14
- 108020004707 nucleic acids Proteins 0.000 description 14
- 230000003827 upregulation Effects 0.000 description 14
- 210000004204 blood vessel Anatomy 0.000 description 13
- 210000000038 chest Anatomy 0.000 description 13
- 210000003414 extremity Anatomy 0.000 description 13
- 210000005003 heart tissue Anatomy 0.000 description 13
- 231100000419 toxicity Toxicity 0.000 description 13
- 230000001988 toxicity Effects 0.000 description 13
- 230000002792 vascular Effects 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 241000282898 Sus scrofa Species 0.000 description 12
- 108010005774 beta-Galactosidase Proteins 0.000 description 12
- 230000037396 body weight Effects 0.000 description 12
- 208000035475 disorder Diseases 0.000 description 12
- 125000003729 nucleotide group Chemical group 0.000 description 12
- 238000011002 quantification Methods 0.000 description 12
- 210000000115 thoracic cavity Anatomy 0.000 description 12
- 238000013519 translation Methods 0.000 description 12
- DJJCXFVJDGTHFX-XVFCMESISA-N uridine 5'-monophosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 DJJCXFVJDGTHFX-XVFCMESISA-N 0.000 description 12
- OPIFSICVWOWJMJ-AEOCFKNESA-N 5-bromo-4-chloro-3-indolyl beta-D-galactoside Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OC1=CNC2=CC=C(Br)C(Cl)=C12 OPIFSICVWOWJMJ-AEOCFKNESA-N 0.000 description 11
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 11
- 231100000673 dose–response relationship Toxicity 0.000 description 11
- RQFCJASXJCIDSX-UUOKFMHZSA-N guanosine 5'-monophosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O RQFCJASXJCIDSX-UUOKFMHZSA-N 0.000 description 11
- 229960002725 isoflurane Drugs 0.000 description 11
- 238000002595 magnetic resonance imaging Methods 0.000 description 11
- 239000002121 nanofiber Substances 0.000 description 11
- 102000040430 polynucleotide Human genes 0.000 description 11
- 108091033319 polynucleotide Proteins 0.000 description 11
- 239000002157 polynucleotide Substances 0.000 description 11
- 238000001356 surgical procedure Methods 0.000 description 11
- 238000012384 transportation and delivery Methods 0.000 description 11
- 238000002399 angioplasty Methods 0.000 description 10
- 235000013928 guanylic acid Nutrition 0.000 description 10
- 230000004217 heart function Effects 0.000 description 10
- 208000014674 injury Diseases 0.000 description 10
- 231100001231 less toxic Toxicity 0.000 description 10
- 239000012528 membrane Substances 0.000 description 10
- 238000006213 oxygenation reaction Methods 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- 102100026189 Beta-galactosidase Human genes 0.000 description 9
- 108091028043 Nucleic acid sequence Proteins 0.000 description 9
- DJJCXFVJDGTHFX-UHFFFAOYSA-N Uridinemonophosphate Natural products OC1C(O)C(COP(O)(O)=O)OC1N1C(=O)NC(=O)C=C1 DJJCXFVJDGTHFX-UHFFFAOYSA-N 0.000 description 9
- 239000003125 aqueous solvent Substances 0.000 description 9
- 210000002565 arteriole Anatomy 0.000 description 9
- 239000011324 bead Substances 0.000 description 9
- IERHLVCPSMICTF-XVFCMESISA-N cytidine 5'-monophosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(O)=O)O1 IERHLVCPSMICTF-XVFCMESISA-N 0.000 description 9
- 230000006378 damage Effects 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- 210000004379 membrane Anatomy 0.000 description 9
- 210000000130 stem cell Anatomy 0.000 description 9
- 108010065729 Troponin I Proteins 0.000 description 8
- 239000007979 citrate buffer Substances 0.000 description 8
- 239000003636 conditioned culture medium Substances 0.000 description 8
- 239000013317 conjugated microporous polymer Substances 0.000 description 8
- 238000002592 echocardiography Methods 0.000 description 8
- 230000006698 induction Effects 0.000 description 8
- 238000007431 microscopic evaluation Methods 0.000 description 8
- 239000002773 nucleotide Substances 0.000 description 8
- 239000002504 physiological saline solution Substances 0.000 description 8
- 230000035755 proliferation Effects 0.000 description 8
- 230000029058 respiratory gaseous exchange Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 230000001360 synchronised effect Effects 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 206010002091 Anaesthesia Diseases 0.000 description 7
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 7
- 206010063560 Excessive granulation tissue Diseases 0.000 description 7
- 239000005089 Luciferase Substances 0.000 description 7
- 206010072170 Skin wound Diseases 0.000 description 7
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 7
- LNQVTSROQXJCDD-UHFFFAOYSA-N adenosine monophosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(CO)C(OP(O)(O)=O)C1O LNQVTSROQXJCDD-UHFFFAOYSA-N 0.000 description 7
- 230000037005 anaesthesia Effects 0.000 description 7
- 230000036772 blood pressure Effects 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- IERHLVCPSMICTF-UHFFFAOYSA-N cytidine monophosphate Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(COP(O)(O)=O)O1 IERHLVCPSMICTF-UHFFFAOYSA-N 0.000 description 7
- 206010012601 diabetes mellitus Diseases 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 210000001126 granulation tissue Anatomy 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000002777 nucleoside Substances 0.000 description 7
- 150000003833 nucleoside derivatives Chemical class 0.000 description 7
- 230000035790 physiological processes and functions Effects 0.000 description 7
- 230000000291 postprandial effect Effects 0.000 description 7
- 238000011084 recovery Methods 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 230000011664 signaling Effects 0.000 description 7
- 230000004218 vascular function Effects 0.000 description 7
- SXUXMRMBWZCMEN-UHFFFAOYSA-N 2'-O-methyl uridine Natural products COC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 SXUXMRMBWZCMEN-UHFFFAOYSA-N 0.000 description 6
- GJTBSTBJLVYKAU-XVFCMESISA-N 2-thiouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=S)NC(=O)C=C1 GJTBSTBJLVYKAU-XVFCMESISA-N 0.000 description 6
- AOKQNZVJJXPUQA-KQYNXXCUSA-M 7-methylguanosine 5'-phosphate(1-) Chemical compound C1=2N=C(N)NC(=O)C=2[N+](C)=CN1[C@@H]1O[C@H](COP([O-])([O-])=O)[C@@H](O)[C@H]1O AOKQNZVJJXPUQA-KQYNXXCUSA-M 0.000 description 6
- 208000001778 Coronary Occlusion Diseases 0.000 description 6
- 206010011086 Coronary artery occlusion Diseases 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 239000000090 biomarker Substances 0.000 description 6
- 230000004663 cell proliferation Effects 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 238000007906 compression Methods 0.000 description 6
- 230000006835 compression Effects 0.000 description 6
- 238000002565 electrocardiography Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 208000038002 heart failure with reduced ejection fraction Diseases 0.000 description 6
- 230000000004 hemodynamic effect Effects 0.000 description 6
- 230000006872 improvement Effects 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 230000010412 perfusion Effects 0.000 description 6
- 210000003240 portal vein Anatomy 0.000 description 6
- 230000036316 preload Effects 0.000 description 6
- 230000008929 regeneration Effects 0.000 description 6
- 238000011069 regeneration method Methods 0.000 description 6
- 230000000250 revascularization Effects 0.000 description 6
- 231100000241 scar Toxicity 0.000 description 6
- 241000894007 species Species 0.000 description 6
- 230000002459 sustained effect Effects 0.000 description 6
- 238000013518 transcription Methods 0.000 description 6
- 230000035897 transcription Effects 0.000 description 6
- 210000005167 vascular cell Anatomy 0.000 description 6
- 208000019553 vascular disease Diseases 0.000 description 6
- SXUXMRMBWZCMEN-ZOQUXTDFSA-N 2'-O-methyluridine Chemical compound CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 SXUXMRMBWZCMEN-ZOQUXTDFSA-N 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 206010029113 Neovascularisation Diseases 0.000 description 5
- 102000013394 Troponin I Human genes 0.000 description 5
- 238000002583 angiography Methods 0.000 description 5
- 230000034303 cell budding Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000002591 computed tomography Methods 0.000 description 5
- 239000011162 core material Substances 0.000 description 5
- 238000002586 coronary angiography Methods 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000007943 implant Substances 0.000 description 5
- 238000007901 in situ hybridization Methods 0.000 description 5
- 230000028709 inflammatory response Effects 0.000 description 5
- 239000007927 intramuscular injection Substances 0.000 description 5
- 238000010255 intramuscular injection Methods 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 230000011218 segmentation Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000009885 systemic effect Effects 0.000 description 5
- 238000002627 tracheal intubation Methods 0.000 description 5
- 230000008733 trauma Effects 0.000 description 5
- 210000005166 vasculature Anatomy 0.000 description 5
- 210000003462 vein Anatomy 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- 108020005345 3' Untranslated Regions Proteins 0.000 description 4
- 108020003589 5' Untranslated Regions Proteins 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 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 4
- 241000282412 Homo Species 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 239000000853 adhesive Substances 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 238000000540 analysis of variance Methods 0.000 description 4
- 230000036760 body temperature Effects 0.000 description 4
- 210000001054 cardiac fibroblast Anatomy 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- FPUGCISOLXNPPC-IOSLPCCCSA-N cordysinin B Chemical compound CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(N)=C2N=C1 FPUGCISOLXNPPC-IOSLPCCCSA-N 0.000 description 4
- 230000003111 delayed effect Effects 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 238000005538 encapsulation Methods 0.000 description 4
- 230000003511 endothelial effect Effects 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 238000003364 immunohistochemistry Methods 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 229960003299 ketamine Drugs 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 230000036387 respiratory rate Effects 0.000 description 4
- 239000002047 solid lipid nanoparticle Substances 0.000 description 4
- 230000004936 stimulating effect Effects 0.000 description 4
- 230000002123 temporal effect Effects 0.000 description 4
- 230000024883 vasodilation Effects 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- GRYSXUXXBDSYRT-WOUKDFQISA-N (2r,3r,4r,5r)-2-(hydroxymethyl)-4-methoxy-5-[6-(methylamino)purin-9-yl]oxolan-3-ol Chemical compound C1=NC=2C(NC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1OC GRYSXUXXBDSYRT-WOUKDFQISA-N 0.000 description 3
- OTFGHFBGGZEXEU-PEBGCTIMSA-N 1-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-methoxyoxolan-2-yl]-3-methylpyrimidine-2,4-dione Chemical compound CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N(C)C(=O)C=C1 OTFGHFBGGZEXEU-PEBGCTIMSA-N 0.000 description 3
- QPHRQMAYYMYWFW-FJGDRVTGSA-N 1-[(2r,3s,4r,5r)-3-fluoro-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@]1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 QPHRQMAYYMYWFW-FJGDRVTGSA-N 0.000 description 3
- OVYNGSFVYRPRCG-UHFFFAOYSA-N 2'-O-Methylguanosine Natural products COC1C(O)C(CO)OC1N1C(NC(N)=NC2=O)=C2N=C1 OVYNGSFVYRPRCG-UHFFFAOYSA-N 0.000 description 3
- OVYNGSFVYRPRCG-KQYNXXCUSA-N 2'-O-methylguanosine Chemical compound CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=C(N)NC2=O)=C2N=C1 OVYNGSFVYRPRCG-KQYNXXCUSA-N 0.000 description 3
- MXHRCPNRJAMMIM-SHYZEUOFSA-N 2'-deoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-SHYZEUOFSA-N 0.000 description 3
- ZLOIGESWDJYCTF-UHFFFAOYSA-N 4-Thiouridine Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=S)C=C1 ZLOIGESWDJYCTF-UHFFFAOYSA-N 0.000 description 3
- ZLOIGESWDJYCTF-XVFCMESISA-N 4-thiouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=S)C=C1 ZLOIGESWDJYCTF-XVFCMESISA-N 0.000 description 3
- IPRQAJTUSRLECG-UHFFFAOYSA-N 5-[6-(dimethylamino)purin-9-yl]-2-(hydroxymethyl)-4-methoxyoxolan-3-ol Chemical compound COC1C(O)C(CO)OC1N1C2=NC=NC(N(C)C)=C2N=C1 IPRQAJTUSRLECG-UHFFFAOYSA-N 0.000 description 3
- OGHAROSJZRTIOK-KQYNXXCUSA-O 7-methylguanosine Chemical compound C1=2N=C(N)NC(=O)C=2[N+](C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OGHAROSJZRTIOK-KQYNXXCUSA-O 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 3
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 208000000059 Dyspnea Diseases 0.000 description 3
- 206010013975 Dyspnoeas Diseases 0.000 description 3
- 102000001554 Hemoglobins Human genes 0.000 description 3
- 108010054147 Hemoglobins Proteins 0.000 description 3
- 208000001953 Hypotension Diseases 0.000 description 3
- 239000012097 Lipofectamine 2000 Substances 0.000 description 3
- IYYIBFCJILKPCO-WOUKDFQISA-O N(2),N(2),N(7)-trimethylguanosine Chemical compound C1=2NC(N(C)C)=NC(=O)C=2N(C)C=[N+]1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O IYYIBFCJILKPCO-WOUKDFQISA-O 0.000 description 3
- ZBYRSRLCXTUFLJ-IOSLPCCCSA-O N(2),N(7)-dimethylguanosine Chemical compound CNC=1NC(C=2[N+](=CN([C@H]3[C@H](O)[C@H](O)[C@@H](CO)O3)C=2N=1)C)=O ZBYRSRLCXTUFLJ-IOSLPCCCSA-O 0.000 description 3
- VQAYFKKCNSOZKM-IOSLPCCCSA-N N(6)-methyladenosine Chemical compound C1=NC=2C(NC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VQAYFKKCNSOZKM-IOSLPCCCSA-N 0.000 description 3
- 206010028851 Necrosis Diseases 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 108010029485 Protein Isoforms Proteins 0.000 description 3
- 102000001708 Protein Isoforms Human genes 0.000 description 3
- 229930185560 Pseudouridine Natural products 0.000 description 3
- PTJWIQPHWPFNBW-UHFFFAOYSA-N Pseudouridine C Natural products OC1C(O)C(CO)OC1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-UHFFFAOYSA-N 0.000 description 3
- 108091030071 RNAI Proteins 0.000 description 3
- 108020004459 Small interfering RNA Proteins 0.000 description 3
- 108091008605 VEGF receptors Proteins 0.000 description 3
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 3
- 101150084041 WT1 gene Proteins 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- WGDUUQDYDIIBKT-UHFFFAOYSA-N beta-Pseudouridine Natural products OC1OC(CN2C=CC(=O)NC2=O)C(O)C1O WGDUUQDYDIIBKT-UHFFFAOYSA-N 0.000 description 3
- 229910052796 boron Inorganic materials 0.000 description 3
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 3
- 229960001736 buprenorphine Drugs 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 125000002091 cationic group Chemical group 0.000 description 3
- 230000006037 cell lysis Effects 0.000 description 3
- 230000005754 cellular signaling Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 210000004351 coronary vessel Anatomy 0.000 description 3
- 238000007405 data analysis Methods 0.000 description 3
- MXHRCPNRJAMMIM-UHFFFAOYSA-N desoxyuridine Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-UHFFFAOYSA-N 0.000 description 3
- 230000007783 downstream signaling Effects 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 210000003038 endothelium Anatomy 0.000 description 3
- 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 3
- 230000005284 excitation Effects 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 230000009368 gene silencing by RNA Effects 0.000 description 3
- 230000035876 healing Effects 0.000 description 3
- 210000005119 human aortic smooth muscle cell Anatomy 0.000 description 3
- 230000036543 hypotension Effects 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 239000003978 infusion fluid Substances 0.000 description 3
- 230000015788 innate immune response Effects 0.000 description 3
- 230000000297 inotrophic effect Effects 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 210000005246 left atrium Anatomy 0.000 description 3
- 239000002479 lipoplex Substances 0.000 description 3
- 210000003141 lower extremity Anatomy 0.000 description 3
- 239000012139 lysis buffer Substances 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- CUHVIMMYOGQXCV-UHFFFAOYSA-N medetomidine Chemical compound C=1C=CC(C)=C(C)C=1C(C)C1=CNC=N1 CUHVIMMYOGQXCV-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000000386 microscopy Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 238000001543 one-way ANOVA Methods 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000002688 persistence Effects 0.000 description 3
- 229920000573 polyethylene Polymers 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- PTJWIQPHWPFNBW-GBNDHIKLSA-N pseudouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-GBNDHIKLSA-N 0.000 description 3
- DWRXFEITVBNRMK-JXOAFFINSA-N ribothymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 DWRXFEITVBNRMK-JXOAFFINSA-N 0.000 description 3
- 210000005245 right atrium Anatomy 0.000 description 3
- 210000005241 right ventricle Anatomy 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 230000001568 sexual effect Effects 0.000 description 3
- 239000007929 subcutaneous injection Substances 0.000 description 3
- 238000010254 subcutaneous injection Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000009261 transgenic effect Effects 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- 239000011534 wash buffer Substances 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
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 2
- UVBYMVOUBXYSFV-XUTVFYLZSA-N 1-methylpseudouridine Chemical compound O=C1NC(=O)N(C)C=C1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 UVBYMVOUBXYSFV-XUTVFYLZSA-N 0.000 description 2
- FPUGCISOLXNPPC-UHFFFAOYSA-N 2'-O-Methyladenosine Natural products COC1C(O)C(CO)OC1N1C2=NC=NC(N)=C2N=C1 FPUGCISOLXNPPC-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 2
- ZAYHVCMSTBRABG-UHFFFAOYSA-N 5-Methylcytidine Natural products O=C1N=C(N)C(C)=CN1C1C(O)C(O)C(CO)O1 ZAYHVCMSTBRABG-UHFFFAOYSA-N 0.000 description 2
- ZAYHVCMSTBRABG-JXOAFFINSA-N 5-methylcytidine Chemical compound O=C1N=C(N)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 ZAYHVCMSTBRABG-JXOAFFINSA-N 0.000 description 2
- 125000003345 AMP group Chemical group 0.000 description 2
- 208000008035 Back Pain Diseases 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 2
- 108090000331 Firefly luciferases Proteins 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 208000034693 Laceration Diseases 0.000 description 2
- 206010067125 Liver injury Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 108700026244 Open Reading Frames Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002873 Polyethylenimine Polymers 0.000 description 2
- 206010039897 Sedation Diseases 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 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 2
- 230000004075 alteration Effects 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 210000003484 anatomy Anatomy 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 238000009534 blood test Methods 0.000 description 2
- SIEYLFHKZGLBNX-UHFFFAOYSA-N bupivacaine hydrochloride (anhydrous) Chemical compound [Cl-].CCCC[NH+]1CCCCC1C(=O)NC1=C(C)C=CC=C1C SIEYLFHKZGLBNX-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 210000004413 cardiac myocyte Anatomy 0.000 description 2
- 230000037198 cardiovascular physiology Effects 0.000 description 2
- 210000001715 carotid artery Anatomy 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000003750 conditioning effect Effects 0.000 description 2
- 210000004748 cultured cell Anatomy 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 210000004207 dermis Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000013118 diabetic mouse model Methods 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 231100000294 dose-dependent toxicity Toxicity 0.000 description 2
- 210000001174 endocardium Anatomy 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229920006227 ethylene-grafted-maleic anhydride Polymers 0.000 description 2
- 238000013401 experimental design Methods 0.000 description 2
- 210000003722 extracellular fluid Anatomy 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- HZHFFEYYPYZMNU-UHFFFAOYSA-K gadodiamide Chemical compound [Gd+3].CNC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC(=O)NC HZHFFEYYPYZMNU-UHFFFAOYSA-K 0.000 description 2
- 229960005063 gadodiamide Drugs 0.000 description 2
- 238000002695 general anesthesia Methods 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 210000002064 heart cell Anatomy 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 231100000753 hepatic injury Toxicity 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 238000010191 image analysis Methods 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000003112 inhibitor Substances 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
- 230000003993 interaction Effects 0.000 description 2
- 230000003601 intercostal effect Effects 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 238000007914 intraventricular administration Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 210000001865 kupffer cell Anatomy 0.000 description 2
- 201000002364 leukopenia Diseases 0.000 description 2
- 231100001022 leukopenia Toxicity 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000003908 liver function Effects 0.000 description 2
- 229940106885 marcaine Drugs 0.000 description 2
- 210000004088 microvessel Anatomy 0.000 description 2
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 2
- 229960003793 midazolam Drugs 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 210000003643 myeloid progenitor cell Anatomy 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000000737 periodic effect Effects 0.000 description 2
- 208000030613 peripheral artery disease Diseases 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 229960004134 propofol Drugs 0.000 description 2
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 230000036280 sedation Effects 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 231100000057 systemic toxicity Toxicity 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- 206010043554 thrombocytopenia Diseases 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 239000002691 unilamellar liposome Substances 0.000 description 2
- 230000008728 vascular permeability Effects 0.000 description 2
- 230000007998 vessel formation Effects 0.000 description 2
- RFCQJGFZUQFYRF-UHFFFAOYSA-N 2'-O-Methylcytidine Natural products COC1C(O)C(CO)OC1N1C(=O)N=C(N)C=C1 RFCQJGFZUQFYRF-UHFFFAOYSA-N 0.000 description 1
- RFCQJGFZUQFYRF-ZOQUXTDFSA-N 2'-O-methylcytidine Chemical compound CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C=C1 RFCQJGFZUQFYRF-ZOQUXTDFSA-N 0.000 description 1
- 238000011265 2D-echocardiography Methods 0.000 description 1
- PCCVCJAQMHDWJY-UHFFFAOYSA-N 5-(2-ethyl-1,3-dihydroinden-2-yl)-1h-imidazole;hydrochloride Chemical compound Cl.C1C2=CC=CC=C2CC1(CC)C1=CN=CN1 PCCVCJAQMHDWJY-UHFFFAOYSA-N 0.000 description 1
- 238000008808 ABL800 Flex Methods 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- 239000012109 Alexa Fluor 568 Substances 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 108020005544 Antisense RNA Proteins 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 238000009020 BCA Protein Assay Kit Methods 0.000 description 1
- 238000009010 Bradford assay Methods 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 206010011985 Decubitus ulcer Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 208000000655 Distemper Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- 206010017711 Gangrene Diseases 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- 208000013875 Heart injury Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 101000991410 Homo sapiens Nucleolar and spindle-associated protein 1 Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010051792 Infusion related reaction Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- 241000254158 Lampyridae Species 0.000 description 1
- 108091026898 Leader sequence (mRNA) Proteins 0.000 description 1
- 206010049694 Left Ventricular Dysfunction Diseases 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 240000001307 Myosotis scorpioides Species 0.000 description 1
- 108020001621 Natriuretic Peptide Proteins 0.000 description 1
- 102000004571 Natriuretic peptide Human genes 0.000 description 1
- 102100030991 Nucleolar and spindle-associated protein 1 Human genes 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 108700022034 Opsonin Proteins Proteins 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108010069381 Platelet Endothelial Cell Adhesion Molecule-1 Proteins 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 230000026279 RNA modification Effects 0.000 description 1
- 101150084101 RNA2 gene Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- 239000011542 SDS running buffer Substances 0.000 description 1
- 101100353432 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) PRP2 gene Proteins 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- 108091036066 Three prime untranslated region Proteins 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000004987 Troponin T Human genes 0.000 description 1
- 108090001108 Troponin T Proteins 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- 208000032594 Vascular Remodeling Diseases 0.000 description 1
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 208000026448 Wilms tumor 1 Diseases 0.000 description 1
- 102100022748 Wilms tumor protein Human genes 0.000 description 1
- 101710127857 Wilms tumor protein Proteins 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- RMOKTVAFIHZJCV-GJSPRUFOSA-N [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C=NC=2C(N)=NC=NC12.CO[C@H]1[C@@H](O[C@@H]([C@H]1O)CO)N1C=NC=2C(N)=NC=NC12 Chemical compound [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C=NC=2C(N)=NC=NC12.CO[C@H]1[C@@H](O[C@@H]([C@H]1O)CO)N1C=NC=2C(N)=NC=NC12 RMOKTVAFIHZJCV-GJSPRUFOSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 238000010420 art technique Methods 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 229960001352 atipamezole hydrochloride Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 230000004071 biological effect 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
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 238000009530 blood pressure measurement Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 238000000339 bright-field microscopy Methods 0.000 description 1
- 229960001889 buprenorphine hydrochloride Drugs 0.000 description 1
- UAIXRPCCYXNJMQ-RZIPZOSSSA-N buprenorphine hydrochlorie Chemical compound [Cl-].C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)C[NH+]2CC1CC1 UAIXRPCCYXNJMQ-RZIPZOSSSA-N 0.000 description 1
- DEGAKNSWVGKMLS-UHFFFAOYSA-N calcein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(O)=O)CC(O)=O)=C(O)C=C1OC1=C2C=C(CN(CC(O)=O)CC(=O)O)C(O)=C1 DEGAKNSWVGKMLS-UHFFFAOYSA-N 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- MPBRYMWMMKKRGC-UHFFFAOYSA-M carbocyanin DBTC Chemical compound [Br-].C1=CC=CC2=C([N+](=C(C=C(C)C=C3N(C4=C5C=CC=CC5=CC=C4S3)CC)S3)CC)C3=CC=C21 MPBRYMWMMKKRGC-UHFFFAOYSA-M 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000013184 cardiac magnetic resonance imaging Methods 0.000 description 1
- 238000007675 cardiac surgery Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000002975 chemoattractant Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000003184 complementary RNA Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000008828 contractile function Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000010219 correlation analysis Methods 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000007950 delayed release tablet Substances 0.000 description 1
- 229940124447 delivery agent Drugs 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 201000009101 diabetic angiopathy Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 230000003205 diastolic effect Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- 230000035784 germination Effects 0.000 description 1
- 239000011544 gradient gel Substances 0.000 description 1
- 230000037313 granulation tissue formation Effects 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000018578 heart valve disease Diseases 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 230000001951 hemoperfusion Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000005934 immune activation Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229940039412 ketalar Drugs 0.000 description 1
- 102000005861 leptin receptors Human genes 0.000 description 1
- 108010019813 leptin receptors Proteins 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 208000002741 leukoplakia Diseases 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 230000008338 local blood flow Effects 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000000504 luminescence detection Methods 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 229960002140 medetomidine Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 230000010060 microvascular dysfunction Effects 0.000 description 1
- 230000004879 molecular function Effects 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- SQMWSBKSHWARHU-SDBHATRESA-N n6-cyclopentyladenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(NC3CCCC3)=C2N=C1 SQMWSBKSHWARHU-SDBHATRESA-N 0.000 description 1
- 239000000692 natriuretic peptide Substances 0.000 description 1
- 235000020925 non fasting Nutrition 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 229960002378 oftasceine Drugs 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- SSYDTHANSGMJTP-UHFFFAOYSA-N oxolane-3,4-diol Chemical compound OC1COCC1O SSYDTHANSGMJTP-UHFFFAOYSA-N 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 210000003540 papillary muscle Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000004713 phosphodiesters Chemical group 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002745 poly(ortho ester) Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229940048914 protamine Drugs 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 210000003492 pulmonary vein Anatomy 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000015909 regulation of biological process Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 208000012201 sexual and gender identity disease Diseases 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 239000002924 silencing RNA Substances 0.000 description 1
- 238000003307 slaughter Methods 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- AIDBEARHLBRLMO-UHFFFAOYSA-M sodium;dodecyl sulfate;2-morpholin-4-ylethanesulfonic acid Chemical compound [Na+].OS(=O)(=O)CCN1CCOCC1.CCCCCCCCCCCCOS([O-])(=O)=O AIDBEARHLBRLMO-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 206010042772 syncope Diseases 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 230000006492 vascular dysfunction Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
- C07K14/515—Angiogenesic factors; Angiogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7115—Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/712—Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1858—Platelet-derived growth factor [PDGF]
- A61K38/1866—Vascular endothelial growth factor [VEGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Dermatology (AREA)
- Molecular Biology (AREA)
- Vascular Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Urology & Nephrology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Toxicology (AREA)
- Immunology (AREA)
- Inorganic Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Biotechnology (AREA)
- Pulmonology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2021049671A JP7167226B2 (ja) | 2016-06-07 | 2021-03-24 | Ｖｅｇｆ－ａポリペプチドをコードする改変ｒｎａ、製剤、およびそれに関連する使用 |
| JP2022171389A JP2023011733A (ja) | 2016-06-07 | 2022-10-26 | Ｖｅｇｆ－ａポリペプチドをコードする改変ｒｎａ、製剤、およびそれに関連する使用 |
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662346979P | 2016-06-07 | 2016-06-07 | |
| US62/346,979 | 2016-06-07 | ||
| US201662411091P | 2016-10-21 | 2016-10-21 | |
| US62/411,091 | 2016-10-21 | ||
| US201662432005P | 2016-12-09 | 2016-12-09 | |
| US62/432,005 | 2016-12-09 | ||
| PCT/US2017/036188 WO2017214175A1 (en) | 2016-06-07 | 2017-06-06 | Modified rna encoding vegf-a polypeptides, formulations, and uses relating thereto |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2021049671A Division JP7167226B2 (ja) | 2016-06-07 | 2021-03-24 | Ｖｅｇｆ－ａポリペプチドをコードする改変ｒｎａ、製剤、およびそれに関連する使用 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2019521976A JP2019521976A (ja) | 2019-08-08 |
| JP2019521976A5 JP2019521976A5 (enExample) | 2020-10-01 |
| JP6859369B2 true JP6859369B2 (ja) | 2021-04-14 |
Family
ID=59270113
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2018564389A Active JP6859369B2 (ja) | 2016-06-07 | 2017-06-06 | Ｖｅｇｆ−ａポリペプチドをコードする改変ｒｎａ、製剤、およびそれに関連する使用 |
| JP2021049671A Active JP7167226B2 (ja) | 2016-06-07 | 2021-03-24 | Ｖｅｇｆ－ａポリペプチドをコードする改変ｒｎａ、製剤、およびそれに関連する使用 |
| JP2022171389A Pending JP2023011733A (ja) | 2016-06-07 | 2022-10-26 | Ｖｅｇｆ－ａポリペプチドをコードする改変ｒｎａ、製剤、およびそれに関連する使用 |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2021049671A Active JP7167226B2 (ja) | 2016-06-07 | 2021-03-24 | Ｖｅｇｆ－ａポリペプチドをコードする改変ｒｎａ、製剤、およびそれに関連する使用 |
| JP2022171389A Pending JP2023011733A (ja) | 2016-06-07 | 2022-10-26 | Ｖｅｇｆ－ａポリペプチドをコードする改変ｒｎａ、製剤、およびそれに関連する使用 |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US11866475B2 (enExample) |
| EP (2) | EP3971204A1 (enExample) |
| JP (3) | JP6859369B2 (enExample) |
| KR (4) | KR102494499B1 (enExample) |
| CN (2) | CN116606861A (enExample) |
| AU (2) | AU2017277277B2 (enExample) |
| CA (1) | CA3026500A1 (enExample) |
| CY (1) | CY1124667T1 (enExample) |
| DK (1) | DK3464338T3 (enExample) |
| ES (1) | ES2895421T3 (enExample) |
| HR (1) | HRP20211569T1 (enExample) |
| HU (1) | HUE056055T2 (enExample) |
| IL (1) | IL263370A (enExample) |
| LT (1) | LT3464338T (enExample) |
| MA (1) | MA45172B1 (enExample) |
| MX (1) | MX2018015110A (enExample) |
| PL (1) | PL3464338T3 (enExample) |
| PT (1) | PT3464338T (enExample) |
| RS (1) | RS62556B1 (enExample) |
| RU (1) | RU2756313C2 (enExample) |
| SG (2) | SG11201810816QA (enExample) |
| SI (1) | SI3464338T1 (enExample) |
| SM (1) | SMT202100586T1 (enExample) |
| TW (2) | TWI752036B (enExample) |
| WO (1) | WO2017214175A1 (enExample) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3971204A1 (en) | 2016-06-07 | 2022-03-23 | Modernatx, Inc. | Modified rna encoding vegf-a polypeptides, formulations, and uses relating thereto |
| US11628227B2 (en) * | 2017-07-05 | 2023-04-18 | Wisconsin Alumni Research Foundation | Mineral coated microparticles for gene delivery in chronic wound therapy |
| DK3703658T3 (da) | 2017-10-31 | 2022-07-18 | Astrazeneca Ab | Lipidnanopartikler til administration af modificeret rna, der koder for et vegf-a-polypeptid |
| US20220226243A1 (en) * | 2019-05-08 | 2022-07-21 | Astrazeneca Ab | Methods of using lipid nanoparticles for delivering modified rna encoding a vegf-a polypeptide and pharmaceutical compositions comprising the same |
| JP7345888B2 (ja) * | 2021-06-17 | 2023-09-19 | 株式会社ニューギン | 遊技機 |
| WO2023061985A2 (en) * | 2021-10-12 | 2023-04-20 | Modernatx, Inc. | Compositions comprising modified rna encoding vegf-a and methods of use |
| WO2023084013A1 (en) * | 2021-11-12 | 2023-05-19 | Modernatx, Inc. | Compositions comprising modified rna encoding vegf-a and methods of use |
Family Cites Families (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102004035227A1 (de) | 2004-07-21 | 2006-02-16 | Curevac Gmbh | mRNA-Gemisch zur Vakzinierung gegen Tumorerkrankungen |
| WO2006086798A2 (en) | 2005-02-08 | 2006-08-17 | Board Of Regents, The University Of Texas System | Compositions and methods involving mda-7 for the treatment of cancer |
| JP5705127B2 (ja) | 2008-12-03 | 2015-04-22 | アモーサイト インコーポレイテッド | 梗塞領域灌流改善組成物および血管損傷修復の方法 |
| MX2011005912A (es) * | 2008-12-04 | 2011-06-17 | Opko Curna Llc | Tratamiento de enfermedades relacionadas con factor de crecimiento endotelial vascular por inhibicion de transcrito antisentido natural para factor de crecimiento endotelial vascular. |
| WO2011069529A1 (en) * | 2009-12-09 | 2011-06-16 | Curevac Gmbh | Mannose-containing solution for lyophilization, transfection and/or injection of nucleic acids |
| WO2012103985A2 (en) | 2010-12-16 | 2012-08-09 | Steve Pascolo | Pharmaceutical composition consisting of rna having alkali metal as counter ion and formulated with dications |
| JP2014511687A (ja) | 2011-03-31 | 2014-05-19 | モデルナ セラピューティクス インコーポレイテッド | 工学操作された核酸の送達および製剤 |
| WO2012138453A1 (en) | 2011-04-03 | 2012-10-11 | The General Hospital Corporation | Efficient protein expression in vivo using modified rna (mod-rna) |
| HRP20220717T1 (hr) | 2011-12-16 | 2022-07-22 | Modernatx, Inc. | Modificirani pripravci mrna |
| RU2014129863A (ru) | 2011-12-21 | 2016-02-10 | Модерна Терапьютикс, Инк. | Способы повышения жизнеспособности или увеличения продолжительности жизни органа или экспланта органа |
| US20140275229A1 (en) * | 2012-04-02 | 2014-09-18 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding udp glucuronosyltransferase 1 family, polypeptide a1 |
| US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
| US10501513B2 (en) | 2012-04-02 | 2019-12-10 | Modernatx, Inc. | Modified polynucleotides for the production of oncology-related proteins and peptides |
| JP6189415B2 (ja) | 2012-04-02 | 2017-08-30 | モデルナティエックス インコーポレイテッドＭｏｄｅｒｎａＴＸ，Ｉｎｃ． | 細胞質および細胞骨格タンパク質の産生のための修飾ポリヌクレオチド |
| US9663564B2 (en) | 2013-03-15 | 2017-05-30 | The Regents Of The University Of California | Vectors and methods to treat ischemia |
| EP2971010B1 (en) * | 2013-03-14 | 2020-06-10 | ModernaTX, Inc. | Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions |
| KR102354389B1 (ko) * | 2013-08-21 | 2022-01-20 | 큐어백 아게 | Rna―암호화된 단백질의 발현을 증가시키는 방법 |
| EP3094647A1 (en) | 2014-01-15 | 2016-11-23 | F. Hoffmann-La Roche AG | Fc-region variants with modified fcrn- and maintained protein a-binding properties |
| WO2016118725A1 (en) | 2015-01-23 | 2016-07-28 | Moderna Therapeutics, Inc. | Lipid nanoparticle compositions |
| ES2969082T3 (es) | 2015-09-17 | 2024-05-16 | Modernatx Inc | Compuestos y composiciones para la administración intracelular de agentes terapéuticos |
| EP3971204A1 (en) | 2016-06-07 | 2022-03-23 | Modernatx, Inc. | Modified rna encoding vegf-a polypeptides, formulations, and uses relating thereto |
| US11542490B2 (en) | 2016-12-08 | 2023-01-03 | CureVac SE | RNAs for wound healing |
| MX389934B (es) | 2016-12-09 | 2025-03-20 | Desarrolladora Y Com De Tecnologias Biomedicas Decotecbio S A De C V | Composición coadyuvante de un factor de crecimiento y un neuropéptido para acelerar la cicatrización de heridas y la repitelización de órganos. |
| DK3703658T3 (da) | 2017-10-31 | 2022-07-18 | Astrazeneca Ab | Lipidnanopartikler til administration af modificeret rna, der koder for et vegf-a-polypeptid |
| EP3965797A1 (en) | 2019-05-08 | 2022-03-16 | AstraZeneca AB | Compositions for skin and wounds and methods of use thereof |
-
2017
- 2017-06-06 EP EP21186195.0A patent/EP3971204A1/en not_active Withdrawn
- 2017-06-06 RS RS20211280A patent/RS62556B1/sr unknown
- 2017-06-06 KR KR1020227008509A patent/KR102494499B1/ko active Active
- 2017-06-06 MX MX2018015110A patent/MX2018015110A/es unknown
- 2017-06-06 CN CN202310693718.2A patent/CN116606861A/zh active Pending
- 2017-06-06 EP EP17734885.1A patent/EP3464338B1/en active Active
- 2017-06-06 DK DK17734885.1T patent/DK3464338T3/da active
- 2017-06-06 PL PL17734885T patent/PL3464338T3/pl unknown
- 2017-06-06 HR HRP20211569TT patent/HRP20211569T1/hr unknown
- 2017-06-06 MA MA45172A patent/MA45172B1/fr unknown
- 2017-06-06 SI SI201730935T patent/SI3464338T1/sl unknown
- 2017-06-06 PT PT177348851T patent/PT3464338T/pt unknown
- 2017-06-06 AU AU2017277277A patent/AU2017277277B2/en not_active Ceased
- 2017-06-06 LT LTEPPCT/US2017/036188T patent/LT3464338T/lt unknown
- 2017-06-06 SG SG11201810816QA patent/SG11201810816QA/en unknown
- 2017-06-06 CN CN201780048447.8A patent/CN109790207B/zh active Active
- 2017-06-06 RU RU2018147229A patent/RU2756313C2/ru active
- 2017-06-06 KR KR1020197000227A patent/KR102376245B1/ko not_active Expired - Fee Related
- 2017-06-06 WO PCT/US2017/036188 patent/WO2017214175A1/en not_active Ceased
- 2017-06-06 ES ES17734885T patent/ES2895421T3/es active Active
- 2017-06-06 KR KR1020237003204A patent/KR102552543B1/ko active Active
- 2017-06-06 JP JP2018564389A patent/JP6859369B2/ja active Active
- 2017-06-06 CA CA3026500A patent/CA3026500A1/en active Pending
- 2017-06-06 HU HUE17734885A patent/HUE056055T2/hu unknown
- 2017-06-06 KR KR1020237022229A patent/KR20230107891A/ko not_active Ceased
- 2017-06-06 SM SM20210586T patent/SMT202100586T1/it unknown
- 2017-06-06 SG SG10202012175YA patent/SG10202012175YA/en unknown
- 2017-06-06 US US16/305,224 patent/US11866475B2/en active Active
- 2017-06-07 TW TW106118838A patent/TWI752036B/zh not_active IP Right Cessation
- 2017-06-07 TW TW110145699A patent/TWI818375B/zh not_active IP Right Cessation
-
2018
- 2018-11-29 IL IL263370A patent/IL263370A/en unknown
-
2021
- 2021-03-24 JP JP2021049671A patent/JP7167226B2/ja active Active
- 2021-10-14 CY CY20211100889T patent/CY1124667T1/el unknown
-
2022
- 2022-10-26 JP JP2022171389A patent/JP2023011733A/ja active Pending
-
2023
- 2023-07-28 AU AU2023208200A patent/AU2023208200A1/en not_active Abandoned
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6859369B2 (ja) | Ｖｅｇｆ−ａポリペプチドをコードする改変ｒｎａ、製剤、およびそれに関連する使用 | |
| Carlsson et al. | Biocompatible, purified VEGF-A mRNA improves cardiac function after intracardiac injection 1 week post-myocardial infarction in swine | |
| Fujii et al. | Ultrasound-targeted gene delivery induces angiogenesis after a myocardial infarction in mice | |
| JP2020143158A (ja) | 組織の修復及び再生の方法 | |
| WO2012006585A2 (en) | Use of interleukin-15 to treat cardiovascular diseases | |
| HK40070904A (en) | Modified rna encoding vegf-a polypeptides, formulations, and uses relating thereto | |
| Santiago-Vacas et al. | Effect of sildenafil on right ventricular performance in an experimental large-animal model of postcapillary pulmonary hypertension | |
| HK40007104B (en) | Modified rna encoding vegf-a polypeptides, formulations, and uses relating thereto | |
| CN107625781B (zh) | miRNA抑制子在制备防治心肌梗死药物中的应用 | |
| CN114632144B (zh) | Il-3在制备治疗或评估心脏损伤的产品中的应用 | |
| Kusmic et al. | Silencing Survivin: a Key Therapeutic strategy for cardiac hypertrophy | |
| WO2006062087A1 (ja) | 心筋障害又は心不全の治療もしくは予防組成物 | |
| Harris | Illuminating Molecular Regulators of Lymphatic Endothelial Cell Signaling and Identity | |
| CN115944738A (zh) | 补体c3裂解抑制剂在制备治疗糖尿病心肌病的药物中的应用 | |
| CN106692974A (zh) | 雌激素受体抑制剂在制备治疗缺血性疾病的药物中的应用 | |
| WO2023061985A2 (en) | Compositions comprising modified rna encoding vegf-a and methods of use | |
| CN116440163A (zh) | 一种用于哺乳动物骨骼和/或肌肉抗衰的生物制品及其制备方法和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200528 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20200528 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200820 |
|
| A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20200820 |
|
| A975 | Report on accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A971005 Effective date: 20200904 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200917 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20201217 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20210302 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210325 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6859369 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |