CN116531392A - 20S-O-Glc-DM在制备治疗和/或预防心血管疾病药物中的应用 - Google Patents
20S-O-Glc-DM在制备治疗和/或预防心血管疾病药物中的应用 Download PDFInfo
- Publication number
- CN116531392A CN116531392A CN202210085081.4A CN202210085081A CN116531392A CN 116531392 A CN116531392 A CN 116531392A CN 202210085081 A CN202210085081 A CN 202210085081A CN 116531392 A CN116531392 A CN 116531392A
- Authority
- CN
- China
- Prior art keywords
- glc
- myocardial
- iso
- group
- mice
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 40
- 208000024172 Cardiovascular disease Diseases 0.000 title claims abstract description 27
- 229940079593 drug Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 206010019280 Heart failures Diseases 0.000 claims description 17
- 230000002861 ventricular Effects 0.000 claims description 17
- 239000007924 injection Substances 0.000 claims description 16
- 238000002347 injection Methods 0.000 claims description 16
- 208000010125 myocardial infarction Diseases 0.000 claims description 11
- 239000003826 tablet Substances 0.000 claims description 9
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 6
- 206010003119 arrhythmia Diseases 0.000 claims description 6
- 230000006793 arrhythmia Effects 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 6
- 239000006187 pill Substances 0.000 claims description 6
- 206010002383 Angina Pectoris Diseases 0.000 claims description 5
- 206010052337 Diastolic dysfunction Diseases 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 5
- 208000029078 coronary artery disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- -1 enteric preparations Substances 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 4
- 239000000839 emulsion Substances 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 208000024891 symptom Diseases 0.000 claims description 3
- 239000006188 syrup Substances 0.000 claims description 3
- 235000020357 syrup Nutrition 0.000 claims description 3
- 239000004530 micro-emulsion Substances 0.000 claims description 2
- 239000006196 drop Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 15
- 229940089161 ginsenoside Drugs 0.000 abstract description 3
- 229930182494 ginsenoside Natural products 0.000 abstract description 3
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 98
- 229940039009 isoproterenol Drugs 0.000 description 87
- 241000699670 Mus sp. Species 0.000 description 59
- 230000002107 myocardial effect Effects 0.000 description 46
- 230000000694 effects Effects 0.000 description 45
- 210000004027 cell Anatomy 0.000 description 41
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 36
- 210000002966 serum Anatomy 0.000 description 36
- 210000004413 cardiac myocyte Anatomy 0.000 description 29
- 241001465754 Metazoa Species 0.000 description 27
- 238000002474 experimental method Methods 0.000 description 25
- 208000031225 myocardial ischemia Diseases 0.000 description 18
- 229960004679 doxorubicin Drugs 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- 208000037891 myocardial injury Diseases 0.000 description 16
- 230000001225 therapeutic effect Effects 0.000 description 16
- 206010021143 Hypoxia Diseases 0.000 description 15
- 239000000090 biomarker Substances 0.000 description 15
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 15
- 229960004166 diltiazem Drugs 0.000 description 15
- 206010020880 Hypertrophy Diseases 0.000 description 13
- 230000034994 death Effects 0.000 description 13
- 231100000517 death Toxicity 0.000 description 13
- 230000007954 hypoxia Effects 0.000 description 13
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 229960001317 isoprenaline Drugs 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 101800000407 Brain natriuretic peptide 32 Proteins 0.000 description 10
- 230000037149 energy metabolism Effects 0.000 description 10
- 230000001965 increasing effect Effects 0.000 description 10
- 230000004083 survival effect Effects 0.000 description 10
- 102400000667 Brain natriuretic peptide 32 Human genes 0.000 description 9
- 101800002247 Brain natriuretic peptide 45 Proteins 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 230000000747 cardiac effect Effects 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000011282 treatment Methods 0.000 description 9
- 230000000875 corresponding effect Effects 0.000 description 8
- 230000006378 damage Effects 0.000 description 8
- 230000000069 prophylactic effect Effects 0.000 description 8
- 206010048610 Cardiotoxicity Diseases 0.000 description 7
- 231100000259 cardiotoxicity Toxicity 0.000 description 7
- 239000013641 positive control Substances 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 238000013155 cardiography Methods 0.000 description 6
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 230000018109 developmental process Effects 0.000 description 6
- 210000005240 left ventricle Anatomy 0.000 description 6
- 238000000465 moulding Methods 0.000 description 6
- 210000004165 myocardium Anatomy 0.000 description 6
- 230000001575 pathological effect Effects 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 238000008157 ELISA kit Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000003833 cell viability Effects 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 238000002592 echocardiography Methods 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000003902 lesion Effects 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000007929 subcutaneous injection Substances 0.000 description 5
- 238000010254 subcutaneous injection Methods 0.000 description 5
- 230000002407 ATP formation Effects 0.000 description 4
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 4
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 4
- 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 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 206010028594 Myocardial fibrosis Diseases 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 208000033774 Ventricular Remodeling Diseases 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 230000003698 anagen phase Effects 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 4
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000003205 diastolic effect Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 230000002526 effect on cardiovascular system Effects 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 229960001031 glucose Drugs 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 208000014674 injury Diseases 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000002438 mitochondrial effect Effects 0.000 description 4
- 230000007170 pathology Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 3
- 238000011740 C57BL/6 mouse Methods 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 208000013875 Heart injury Diseases 0.000 description 3
- 238000012404 In vitro experiment Methods 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 231100001259 acute cardiotoxicity Toxicity 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960003624 creatine Drugs 0.000 description 3
- 239000006046 creatine Substances 0.000 description 3
- 229960000605 dexrazoxane Drugs 0.000 description 3
- 238000003304 gavage Methods 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 229960001855 mannitol Drugs 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000008065 myocardial cell damage Effects 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000007901 soft capsule Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 208000002381 Brain Hypoxia Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 208000006029 Cardiomegaly Diseases 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 206010013012 Dilatation ventricular Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 244000042430 Rhodiola rosea Species 0.000 description 2
- 235000003713 Rhodiola rosea Nutrition 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 102000004903 Troponin Human genes 0.000 description 2
- 108090001027 Troponin Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000001964 calcium overload Effects 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002662 enteric coated tablet Substances 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 238000007667 floating Methods 0.000 description 2
- 230000002414 glycolytic effect Effects 0.000 description 2
- 210000004209 hair Anatomy 0.000 description 2
- 210000005003 heart tissue Anatomy 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 230000003680 myocardial damage Effects 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000036284 oxygen consumption Effects 0.000 description 2
- 208000008494 pericarditis Diseases 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 239000008299 semisolid dosage form Substances 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000004904 shortening Methods 0.000 description 2
- VSIVTUIKYVGDCX-UHFFFAOYSA-M sodium;4-[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].COC1=CC([N+]([O-])=O)=CC=C1[N+]1=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=NN1C1=CC=C([N+]([O-])=O)C=C1 VSIVTUIKYVGDCX-UHFFFAOYSA-M 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- MNULEGDCPYONBU-WMBHJXFZSA-N (1r,4s,5e,5'r,6'r,7e,10s,11r,12s,14r,15s,16s,18r,19s,20r,21e,25s,26r,27s,29s)-4-ethyl-11,12,15,19-tetrahydroxy-6'-[(2s)-2-hydroxypropyl]-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trio Polymers O([C@@H]1CC[C@@H](/C=C/C=C/C[C@H](C)[C@@H](O)[C@](C)(O)C(=O)[C@H](C)[C@@H](O)[C@H](C)C(=O)[C@H](C)[C@@H](O)[C@H](C)/C=C/C(=O)O[C@H]([C@H]2C)[C@H]1C)CC)[C@]12CC[C@@H](C)[C@@H](C[C@H](C)O)O1 MNULEGDCPYONBU-WMBHJXFZSA-N 0.000 description 1
- MNULEGDCPYONBU-DJRUDOHVSA-N (1s,4r,5z,5'r,6'r,7e,10s,11r,12s,14r,15s,18r,19r,20s,21e,26r,27s)-4-ethyl-11,12,15,19-tetrahydroxy-6'-(2-hydroxypropyl)-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione Polymers O([C@H]1CC[C@H](\C=C/C=C/C[C@H](C)[C@@H](O)[C@](C)(O)C(=O)[C@H](C)[C@@H](O)C(C)C(=O)[C@H](C)[C@H](O)[C@@H](C)/C=C/C(=O)OC([C@H]2C)C1C)CC)[C@]12CC[C@@H](C)[C@@H](CC(C)O)O1 MNULEGDCPYONBU-DJRUDOHVSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- MNULEGDCPYONBU-YNZHUHFTSA-N (4Z,18Z,20Z)-22-ethyl-7,11,14,15-tetrahydroxy-6'-(2-hydroxypropyl)-5',6,8,10,12,14,16,28,29-nonamethylspiro[2,26-dioxabicyclo[23.3.1]nonacosa-4,18,20-triene-27,2'-oxane]-3,9,13-trione Polymers CC1C(C2C)OC(=O)\C=C/C(C)C(O)C(C)C(=O)C(C)C(O)C(C)C(=O)C(C)(O)C(O)C(C)C\C=C/C=C\C(CC)CCC2OC21CCC(C)C(CC(C)O)O2 MNULEGDCPYONBU-YNZHUHFTSA-N 0.000 description 1
- MNULEGDCPYONBU-VVXVDZGXSA-N (5e,5'r,7e,10s,11r,12s,14s,15r,16r,18r,19s,20r,21e,26r,29s)-4-ethyl-11,12,15,19-tetrahydroxy-6'-[(2s)-2-hydroxypropyl]-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione Polymers C([C@H](C)[C@@H](O)[C@](C)(O)C(=O)[C@@H](C)[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@H](C)/C=C/C(=O)OC([C@H]1C)[C@H]2C)\C=C\C=C\C(CC)CCC2OC21CC[C@@H](C)C(C[C@H](C)O)O2 MNULEGDCPYONBU-VVXVDZGXSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- WGYFINWERLNPHR-UHFFFAOYSA-N 3-nitroanisole Chemical compound COC1=CC=CC([N+]([O-])=O)=C1 WGYFINWERLNPHR-UHFFFAOYSA-N 0.000 description 1
- MNULEGDCPYONBU-UHFFFAOYSA-N 4-ethyl-11,12,15,19-tetrahydroxy-6'-(2-hydroxypropyl)-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione Polymers CC1C(C2C)OC(=O)C=CC(C)C(O)C(C)C(=O)C(C)C(O)C(C)C(=O)C(C)(O)C(O)C(C)CC=CC=CC(CC)CCC2OC21CCC(C)C(CC(C)O)O2 MNULEGDCPYONBU-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010003225 Arteriospasm coronary Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- BMZRVOVNUMQTIN-UHFFFAOYSA-N Carbonyl Cyanide para-Trifluoromethoxyphenylhydrazone Chemical compound FC(F)(F)OC1=CC=C(NN=C(C#N)C#N)C=C1 BMZRVOVNUMQTIN-UHFFFAOYSA-N 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 1
- 208000003890 Coronary Vasospasm Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 108020005199 Dehydrogenases Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 201000010046 Dilated cardiomyopathy Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 235000011201 Ginkgo Nutrition 0.000 description 1
- 235000008100 Ginkgo biloba Nutrition 0.000 description 1
- 244000194101 Ginkgo biloba Species 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- 241001559542 Hippocampus hippocampus Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 208000029549 Muscle injury Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 108020001621 Natriuretic Peptide Proteins 0.000 description 1
- 102000004571 Natriuretic peptide Human genes 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000031662 Noncommunicable disease Diseases 0.000 description 1
- 244000131316 Panax pseudoginseng Species 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 235000017276 Salvia Nutrition 0.000 description 1
- 240000007164 Salvia officinalis Species 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 206010042434 Sudden death Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000004987 Troponin T Human genes 0.000 description 1
- 108090001108 Troponin T Proteins 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000037328 acute stress Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229940095672 calcium sulfate Drugs 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000001054 cardiac fibroblast Anatomy 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 230000036996 cardiovascular health Effects 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000009091 contractile dysfunction Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 201000011634 coronary artery vasospasm Diseases 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 230000007946 glucose deprivation Effects 0.000 description 1
- 230000034659 glycolysis Effects 0.000 description 1
- 239000005337 ground glass Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000011702 heart failure animal model Methods 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 238000007489 histopathology method Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000036723 left ventricular dilatation Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- 230000006540 mitochondrial respiration Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 239000000692 natriuretic peptide Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 208000013435 necrotic lesion Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229930191479 oligomycin Natural products 0.000 description 1
- MNULEGDCPYONBU-AWJDAWNUSA-N oligomycin A Polymers O([C@H]1CC[C@H](/C=C/C=C/C[C@@H](C)[C@H](O)[C@@](C)(O)C(=O)[C@@H](C)[C@H](O)[C@@H](C)C(=O)[C@@H](C)[C@H](O)[C@@H](C)/C=C/C(=O)O[C@@H]([C@@H]2C)[C@@H]1C)CC)[C@@]12CC[C@H](C)[C@H](C[C@@H](C)O)O1 MNULEGDCPYONBU-AWJDAWNUSA-N 0.000 description 1
- RFUBTTPMWSKEIW-UHFFFAOYSA-N omecamtiv mecarbil Chemical compound C1CN(C(=O)OC)CCN1CC1=CC=CC(NC(=O)NC=2C=NC(C)=CC=2)=C1F RFUBTTPMWSKEIW-UHFFFAOYSA-N 0.000 description 1
- 229950001617 omecamtiv mecarbil Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000008807 pathological lesion Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 210000001567 regular cardiac muscle cell of ventricle Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000035806 respiratory chain Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000011506 response to oxidative stress Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- JUVIOZPCNVVQFO-UHFFFAOYSA-N rotenone Natural products O1C2=C3CC(C(C)=C)OC3=CC=C2C(=O)C2C1COC1=C2C=C(OC)C(OC)=C1 JUVIOZPCNVVQFO-UHFFFAOYSA-N 0.000 description 1
- 229940080817 rotenone Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000001013 sinoatrial node Anatomy 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
- HUAUNKAZQWMVFY-UHFFFAOYSA-M sodium;oxocalcium;hydroxide Chemical compound [OH-].[Na+].[Ca]=O HUAUNKAZQWMVFY-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229940126680 traditional chinese medicines Drugs 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明属于医药技术领域,公开了式I所示的人参皂苷类化合物20S‑O‑Glc‑DM及其药学上可接受的盐、含有20S‑O‑Glc‑DM的药物组合物在制备治疗和/或预防心血管疾病药物中的用途。
Description
技术领域
本发明涉及医药技术领域,涉及稀有人参皂苷20S-O-Glc-DM的新医药用途,其具体为20S-O-Glc-DM在制备治疗和/或预防心血管疾病药物中的用途。
背景技术
心血管疾病(CVD)是全球导致死亡的主要原因,其致死人数占全世界死亡人数的31.5%,占非传染性疾病致死人数的45.0%。根据《中国心血管健康与疾病报告2020》统计,我国心血管疾病患病率处于持续上升阶段,心血管疾病死亡率仍占我国城乡居民死亡原因首位,每5例死亡中即有2例死于心血管疾病,目前心血管疾病患者人数为3.3亿,约占总人口的23%,其中脑卒中1300万,冠心病1139万,心力衰竭890万,高血压2.45亿,且发病年龄逐渐年轻化。心脑血管疾病住院总费用逐年增加,平均增速远高于国民生产总值增速。
近40年来,关于心血管疾病治疗药物的研究有了很大进展,包括β受体阻滞剂、钙通道阻滞剂、利尿剂、肾素-血管紧张素-醛固酮系统药物、调脂药、血管扩张剂、窦房结通道阻滞剂、改善心肌代谢药及丹参片、速效救心丸、银杏叶制剂等中成药。但近年来,该领域治疗药物研发遇到瓶颈,除了在老药新用(如恩格列净)和少数的新作用靶点候选药物(Vericiguat和Omecamtiv Mecarbil)的研发取得一定进展,整体研发明显落后于肿瘤药物和自身免疫性疾病药物,现有药物不能满足临床需要,迫切需要开发新的药物疗法。同时目前的标准治疗仍然存在心血管风险,接受二级预防的患者,仍会存在相当大的残留心血管风险,主要不良心血管事件的风险仍有4~12%。
以中药与天然产物为资源发现和研发创新药物,一直是新药创制的重要途径,其可通过抑制氧化应激和炎症反应、抑制心肌细胞凋亡、调节代谢等,在心血管疾病方面发挥重要作用。人参作为补益心肺的名优中药,其心血管治疗活性的研发一直是热点。20S-O-Glc-DM是基于合成生物学技术获得的非天然人参皂苷,已有研究显示其具有抗肿瘤活性。在本发明中我们提出20S-O-Glc-DM在心血管疾病药物方面的应用前景。
发明内容
本发明提供了20S-O-β-D-吡喃葡萄糖基-达玛-24-烯-3β,20S-二醇(20S-O-β-D-glucopyranosyl-dammar-24-ene-3β,20S-diol,简称为20S-O-Glc-DM)、含有20S-O-Glc-DM的药物组合物在制备治疗和/或预防心血管疾病药物中的应用。
本发明技术方案的第一方面提供了20S-O-Glc-DM或其药学上可接受的盐在制备治疗和/或预防心血管疾病药物中的应用,该化合物结构如下:
所述心血管疾病包括左心室舒张功能障碍、冠心病、高血压、心力衰竭、心肌病、心律失常、心肌梗死、心绞痛。
为验证本发明的技术方案,本发明提供了体内外相关实验。
本发明的体内实验之一为利用异丙肾上腺素(Isoproterenol,ISO)诱导的小鼠心肌缺血模型。在心血管疾病中,心肌缺血性心脏病是心血管疾病中的焦点,可导致心肌肥厚、左心室扩大,逐渐发展为心肌纤维化、心绞痛、心肌梗死、心力衰竭,是全球范围内致残和致死的主要原因。切实有效的减轻因心肌缺血引起的损伤已成为当今医药界面临的一个热点问题。ISO在实验动物中能诱导一个心脏病理学谱,可根据造模剂量的不同诱导心肌缺血损伤、心肌纤维化及心力衰竭动物模型,其皮下注射诱导的心肌缺血模型在模拟心肌缺血后心室重构和心肌纤维化方面具有明显优势,是冠状动脉粥样硬化性心脏病防治研究常用的心肌缺血模型,该模型是一种无创且简便易行的经典动物模型,被广泛应用于药理及机制研究。ISO是一个强的β受体兴奋剂,能通过加快心率、增强心肌收缩力等环节增加心肌耗氧量,造成心脏负荷过重缺血缺氧、心肌微循环障碍、冠状动脉痉挛、心肌梗死样变化、心肌坏死、甚至猝死。这些病理损伤可能与干扰线粒体能量代谢和呼吸链功能、诱导氧化应激、诱导心肌细胞凋亡、引起心肌钙超载等有关。本发明利用该模型评价20S-O-Glc-DM对心肌缺血、心肌肥厚的防治作用。
本发明的体内实验之二为利用阿霉素(Doxorubicin,DOX)诱导的小鼠急性心脏毒性模型。阿霉素是治疗多种恶性肿瘤疾病的临床一线化疗药物,但同时存在严重的心脏毒性,症状包括血管扩张、心律失常、心包炎-心包炎综合症、扩张型心肌病,可发展成为左心室收缩功能障碍和心力衰竭。阿霉素在动物模型上可引起急性心脏毒性、亚慢性心脏毒性和慢性心脏毒性,与临床发病相似。其诱导心脏毒性的机制复杂,线粒体是其主要毒性靶器官,同时氧化应激、自噬、钙超载和凋亡等参与阿霉素诱导的心脏毒性过程。本发明利用该模型考察20S-O-Glc-DM对阿霉素引起急性心脏毒性的防治作用。
本发明的体内实验之三为小鼠耐常压缺氧模型。该模型是一种以测定小鼠缺氧存活时间为指标的实验方法,是急性应激复合模型,为筛选抗心脑缺血药的常用方法之一,能够考察整体动物在缺氧条件下的生存能力。本发明利用常压缺氧小鼠模型考察20S-O-Glc-DM耐心脑缺氧的作用。
本发明的体外实验之一为CCK8细胞增殖与活性检测实验。CCK8细胞增殖与活性检测实验是一种基于WST-8(2-(2-甲氧基-4硝基苯)-3-(4-硝基苯)-5-(2,4-二磺基苯)-2H-四唑单钠盐)的细胞活力检测方法,WST-8在电子耦合试剂存在的情况下,可以被线粒体内的一些脱氢酶还原生成橙黄色水溶性的甲臜染料。对于同样的细胞,生成甲臜物的数量与活细胞的数量成正比,颜色的深浅和细胞数目呈线性关系。利用氧糖剥夺缺氧复氧损伤心肌细胞和过氧化氢(H2O2)损伤心肌细胞,用该方法来检测H9C2心肌细胞的存活率,考察20S-O-Glc-DM对缺氧复氧损伤心肌细胞及氧化损伤心肌细胞的保护作用。
本发明的体外实验之二为心肌细胞肥大实验。心室重构是心衰的基本病理机制,其主要特征包括病理性心肌肥大、心肌细胞凋亡、心脏成纤维细胞增殖与心肌间质纤维化。心肌细胞肥大是心室重构的起点,极易导致心肌缺血、心律失常的发生,最终可发展为心力衰竭。长时间高水平的β肾上腺素能受体刺激是诱发心肌细胞肥大的重要因素。从β肾上腺素能受体角度阐明药物对心肌细胞肥大的影响对开发有效药物具有重大意义。异丙肾上腺素(Isoproterenol,ISO)是强的β受体激动剂,用ISO作用于心肌H9C2细胞,制作心肌细胞肥大模型,通过分析软件分析单个心肌细胞表面积。本发明利用该方法考察20S-O-Glc-DM对心肌细胞肥大的防治作用。
本发明的体外实验之三为心肌细胞能量代谢实验。心脏是人体代谢最为活跃的器官之一,ATP是心脏利用能源的形式,心脏每天消耗的ATP量达到5kg,但心肌储存的ATP很少,必须及时合成。Seahorse XF技术是强大的实时活细胞能量代谢分析技术,可实时评价活细胞的线粒体功能和产生ATP量。本发明利用该方法考察20S-O-Glc-DM对受损心肌细胞能量代谢的影响。
本发明利用上述实验方法评价了20S-O-Glc-DM作为防治心血管疾病药物的活性。
本发明技术方案的第二方面提供含有第一方面所述的20S-O-Glc-DM的药物组合物在制备治疗和/或预防心血管疾病药物中的应用。所述心血管疾病包括左心室舒张功能障碍、冠心病、高血压、心力衰竭、心肌病、心律失常、心肌梗死、心绞痛。
该药物组合物可根据本领域公知的方法制备。可通过将本化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.001-95%重量。
本发明技术方案的第三方面所述药物组合物包括片剂、胶囊剂、颗粒剂、丸剂、滴丸剂、预乳剂、微乳剂、混悬剂、糖浆剂、肠溶制剂、注射剂。
本化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道给药或非肠道给药,如口服、静脉注射、肌肉注射、皮下注射、鼻腔给药、口腔粘膜给药、眼给药、肺和呼吸道给药、皮肤给药、阴道给药、直肠给药等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本申请的化合物可以制成普通制剂,也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;润湿剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分20S-O-Glc-DM与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可以将有效成分20S-O-Glc-DM先与稀释剂、粘合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备20S-O-Glc-DM片剂的各稀释剂、粘合剂、润湿剂、崩解剂、助流剂品种也可用于制备20S-O-Glc-DM的胶囊剂。
为将本化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向所述制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的,增强治疗效果,本申请的化合物或其药学上可接受的盐或其药物组合物可用任何公知的给药方法给药。
本申请的化合物或其药学上可接受的盐或其药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。一般来讲,本申请的化合物合适的每日剂量范围为0.001-150mg/kg体重,优选为0.1-100mg/kg体重,更优选为1-60mg/kg体重,最优选为2-30mg/kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本申请的化合物或其药学上可接受的盐或其药物组合物可单独服用,或与其它治疗药物或对症药物合并使用。当本申请的化合物或其药学上可接受的盐或其药物组合物与其它治疗药物存在协同作用时,应根据实际情况调整其剂量。
有益技术效果:
1.本发明提供了20S-O-Glc-DM在治疗或预防心血管疾病方面的新用途。
2.证明本发明所述的化合物在药理上具有以下显著活性:显著改善左心室舒张功能,改善心肌缺血,减轻心肌肥厚和心室重构状态,降低心肌耗氧,改善能量代谢,减轻心肌损伤及心肌炎症,改善心脏病理损伤,阻逆心肌纤维化,降低心衰动物死亡率,延长缺氧条件下动物的存活时间,同时显著改善不同原因引起的体外心肌细胞损伤,抑制心肌细胞肥大。
综合,在本发明中,体内、体外实验结果证实了20S-O-Glc-DM具有潜在的抗心血管疾病药物的开发价值。
附图说明
图1 20S-O-Glc-DM对异丙肾上腺素(ISO)诱导的心肌缺血小鼠死亡率的影响。
图2 20S-O-Glc-DM对异丙肾上腺素(ISO)诱导心肌缺血小鼠血清心肌酶CK-MB的影响(n=7-10)。(***P<0.001与空白对照组比较;#P<0.05,##P<0.01与模型组比较)
图3各组小鼠超声心动图检查心脏长轴M-Mode图。
图4 20S-O-Glc-DM对异丙肾上腺素(ISO)诱导急性期心肌缺血小鼠超声心动图各指标的影响(n=5)。(**P<0.01,***P<0.001与空白对照组比较;#P<0.05,##P<0.01,###P<0.001与模型组比较)
图5 20S-O-Glc-DM对异丙肾上腺素(ISO)诱导心肌缺血小鼠左心室质量的影响(n=5)。(*P<0.05与空白对照组比较;#P<0.05与模型组比较)
图6 20S-O-Glc-DM对异丙肾上腺素(ISO)诱导心肌缺血小鼠心脏病理改善作用的代表性照片。
图7 20S-O-Glc-DM预防性给药对异丙肾上腺素(ISO)诱导心肌损伤小鼠超声心动图舒张期主要指标的影响(n=5)。(*P<0.05,**P<0.01与空白对照组比较;#P<0.05,##P<0.01与模型组比较)
图8 20S-O-Glc-DM对阿霉素(DOX)诱导心脏毒性小鼠心脏指数的影响(n=10)。(***P<0.001与空白对照组比较;#P<0.05,##P<0.01与模型组比较)
图9 20S-O-Glc-DM对异丙肾上腺素(ISO)诱导心肌细胞肥大损伤抑制作用的代表性图片。
图10 20S-O-Glc-DM对损伤心肌细胞能量代谢线粒体呼吸产生ATP的影响。(***P<0.001与空白对照组比较;##P<0.01,###P<0.001与模型组比较)
图11 20S-O-Glc-DM对损伤心肌细胞能量代谢糖酵解的影响。(*P<0.05与空白对照组比较;###P<0.01与模型组比较)
具体实施方式
下面的实施例及药理活性实验仅用于进一步说明本发明,但这并不意味着对本发明的任何限制。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
下述实施例中,部分物质相应的中文名称如下:
Control:空白对照
Model:模型对照
ISO:异丙肾上腺素
DOX:阿霉素
CK-MB:肌酸激酶-同工酶
cTn-T:肌钙蛋白T
BNP:B型钠尿肽
ANP:心钠肽
下述实施例中所述室温如本领域常规所述,一般指15~25℃。
下面结合实施例和附图对本发明做进一步说明,但本发明不受下述实施例限制。本领域技术人员应该理解,对本申请技术特征所作的等同替换或相应的改进,仍属于本申请的保护范围之内。除特别说明的以外,以下实施例采用的试剂均为市售产品,溶液的配制可以采用本领域常规技术。
实施例1 20S-O-Glc-DM(I)的制备
参照文章Green Chemistry,2019,21(12):3286-3299中的方法制备得到20S-O-Glc-DM。
实验例1 20S-O-Glc-DM在异丙肾上腺素(ISO)诱导的小鼠心肌缺血模型中的活性测试
实验方法:
雄性C57BL/6小鼠(由北京华阜康生物科技股份有限公司提供)适应环境后随机分为7组,分别为空白对照组、ISO模型组、ISO+地尔硫卓20mg/kg阳性对照组、ISO+3β-O-Glc-DM(3β-O-D-吡喃葡萄糖基-达玛-24-烯-3β,20S-二醇)3mg/kg组、ISO+3β-O-Glc-DM 6mg/kg组、ISO+20S-O-Glc-DM 3mg/kg组及ISO+20S-O-Glc-DM 6mg/kg组。给药组小鼠均每天灌胃给药相应剂量药物1次,地尔硫卓组每天腹腔注射给药1次,空白对照组及模型组小鼠给予相同量的溶剂(0.5%CMC-Na溶剂),给药量均为10mL/kg,连续给药12天。给药第6~12天,空白对照组皮下注射生理盐水,其余各组小鼠皮下注射异丙肾上腺素(ISO)40mg/kg(均在给药后2h造模),最后一天造模1h后处理动物。实验过程中记录动物体重及动物状态。
心脏超声心动图检查:在造模第6天,小鼠皮下注射ISO后2h,每组随机选取5只小鼠,麻醉后固定于37℃恒温加热板上,剃除胸毛,于胸部涂少量耦合剂。采用Vevo770Imaging System小动物超声实时影像系统进行超声心动图检查,测量收缩期、舒张期心室厚度、心室内径及左心室射血分数、短轴缩短率、左心室质量等指标。所有指标均连续测量3个心动周期,取平均值。
心肌损伤生物标志物心肌酶检测:在实验结束时小鼠眼眶取血,室温静置2h,3500rpm离心20min分离血清,按ELISA试剂盒说明书测定血清CK-MB含量。
心肌组织病理学分析:心脏经冰生理盐水清洗并用吸水纸拭干,横向切成两半,靠近心尖的一半固定于4%多聚甲醛溶液中,经梯度乙醇脱水,二甲苯透明,然后放入溶解的石蜡中浸透3次进行包埋,每次30min,包埋好后进行连续切片(厚度约为4μm)。常规苏木紫-伊红(H.E.)染色。在光学显微镜下观察心肌组织病理状态并照相。
实验结果:
动物一般状态及死亡率:
结果见图1,ISO 40mg/kg连续皮下注射7次,动物出现死亡,死亡率为30%,20S-O-Glc-DM 3mg/kg、6mg/kg剂量提前给药5天,在注射ISO的同时再连续给药7天,能显著减少动物的死亡率,到实验结束,动物无死亡。20S-O-Glc-DM结构类似物3β-O-Glc-DM在3mg/kg时动物仍有11%的死亡率,在相同剂量下,20S-O-Glc-DM活性优于3β-O-Glc-DM。
心肌酶结果:
血清肌酸激酶-同工酶(CK-MB)是判断心肌坏死的临床特异性和敏感性指标。结果见图2,ISO能引起小鼠血清CK-MB活性显著升高,与空白对照组比较有统计学差异。20S-O-Glc-DM 3mg/kg、6mg/kg剂量显著降低由ISO升高的血清CK-MB水平,与空白对照组有统计学差异,与地尔硫卓20mg/kg活性相当。3β-O-Glc-DM 3mg/kg剂量仅有降低CK-MB活性的趋势,与空白对照组相比无统计学差异,在3mg/kg剂量下,20S-O-Glc-DM活性优于结构类似物3β-O-Glc-DM。
超声心动图检查结果:
小动物超声心动图技术是一种操作简便、重复性好的评估小鼠心功能技术。结果见图3-图5。ISO 40mg/kg皮下注射小鼠每天一次,连续7天,在末次给药后2h监测心动图,动物表现明显的心肌肥厚现象,表现在收缩期及舒张期前壁厚度、后壁厚度、左心室质量均明显或显著增加,同时心脏处于ISO注射后2h肾上腺素受体强烈激动导致的收缩剧烈、射血分数显著升高的状态。20S-O-Glc-DM 3mg/kg、6mg/kg剂量显著降低舒张期后壁厚度、收缩期前壁厚度、收缩期后壁厚度,改善ISO连续给药诱导小鼠心肌肥厚现象,同时显著增加收缩期左心室内径及容量,降低射血分数和短轴缩短率,对ISO注射后小鼠心脏的急性病理性反应有明确调节作用。20S-O-Glc-DM 3mg/kg、6mg/kg剂量亦能显著降低小鼠左心室质量,改善心肌缺血导致的心脏肥大状态。20S-O-Glc-DM活性与阳性对照药地尔硫卓相当,对超声心动图各指标的改善作用活性优于结构类似物3β-O-Glc-DM。
心脏病理结果:
结果见图6,空白对照组小鼠心肌组织结构完整,心肌细胞排列整齐,无炎症浸润现象。异丙肾上腺素(ISO)模型组小鼠心肌组织出现大量炎症细胞浸润,心肌纤维断裂,心室肌细胞排列紊乱,心肌细胞坏死。20S-O-Glc-DM 3mg/kg、6mg/kg对ISO引起的心肌组织病理损伤均具有显著改善作用,炎症浸润情况显著改善,心肌纤维断裂状况修复,炎症/坏死病变累及面积缩小。心脏病变程度评分结果见表1,20S-O-Glc-DM 3mg/kg和6mg/kg均显著降低心脏组织病变评分,与模型组比较有统计学差异。20S-O-Glc-DM对心脏组织病理的改善作用略优于地尔硫卓。
表1 20S-O-Glc-DM对异丙肾上腺素(ISO)诱导心肌缺血小鼠心脏组织病理评分的影响(n=7-9)
***P<0.001与空白对照组比较;#P<0.05,##P<0.01与模型组比较。
实验例2 20S-O-Glc-DM在异丙肾上腺素(ISO)诱导的小鼠心肌损伤不同阶段的防治作用测试
实验方法:
雄性C57BL/6小鼠(由北京华阜康生物科技股份有限公司提供)适应环境后随机分为6组,分别为空白对照组、ISO模型组、ISO+地尔硫卓20mg/kg阳性对照药组、ISO+20S-O-Glc-DM 3mg/kg、ISO+20S-O-Glc-DM 6mg/kg组及ISO+20S-O-Glc-DM 10mg/kg组。给药组小鼠均每天灌胃给药相应剂量的20S-O-Glc-DM 1次,地尔硫卓组每天腹腔注射给药1次,空白对照组及模型组小鼠给予相同量的溶剂(0.5%CMC-Na溶剂),给药量均为10mL/kg,连续给药18天。给药第4~10天进行ISO造模,空白对照组皮下注射生理盐水,其余各组小鼠皮下注射ISO 40mg/kg(均在给药后2h造模),共7次。实验过程中记录动物体重及动物状态。
超声心动图检测:给药第9天(ISO造模6次),小鼠皮下注射ISO 4h后每组随机选取5只,麻醉后固定于37℃恒温加热板,剃除胸毛,于胸部涂少量耦合剂。采用Vevo770Imaging System小动物超声实时影像系统进行超声心动图检查,所有动物心动图指标均连续测量3个心动周期,取平均值。
心肌损伤生物标志物心肌酶检测:在给药第10天(提前给药3天,然后与ISO一起给药连续7天),每组随机取5只小鼠眼静脉丛取血,室温静置2h,3500rpm离心20min分离血清,按ELISA试剂盒说明书测定血清CK-MB、cTn-T含量。在给药第18天(ISO造模后第8天),所有动物摘眼球取血,室温静置2h,3500rpm离心20min分离血清,按ELISA试剂盒说明书测定血清CK-MB、cTn-T含量。
心力衰竭生物标志物检测:在给药第18天(ISO停止注射后第8天),所有动物摘眼球取血,室温静置2h,3500rpm离心20min分离血清,按ELISA试剂盒说明书测定血清BNP、ANP含量。
实验结果:
心肌损伤生物标志物cTn-T结果:
心肌坏死时,心肌内含有的一些蛋白质类物质会从心肌组织内释放出来,并出现在外周循环血中,可作为心肌损伤的判断性指标。肌钙蛋白(Tn)是心肌组织收缩的调节蛋白,心肌肌钙蛋白(cTn)与骨骼肌中的Tn在分子结构和免疫学上是不同的,因此是心肌所独有,是判断心肌坏死最特异和敏感的首选标志物。cTn有三个亚型:cTn-T、cTn-I和cTn-C。cTn-T对早期和晚期心肌坏死均具有很高的诊断价值。
预防性给药结果见表2。ISO连续皮下注射小鼠7天,在注射ISO前三天开始预防性给药,连续给药10天。模型组小鼠血清心肌损伤生物标志物cTn-T与空白对照组相比显著升高,20S-O-Glc-DM 3mg/kg、6mg/kg、10mg/kg剂量预防性给药,均能降低血清cTn-T水平,其中20S-O-Glc-DM 6mg/kg、10mg/kg剂量血清cTn-T水平与模型组比较有统计学差异。20S-O-Glc-DM 6mg/kg预防性给药效果与地尔硫卓20mg/kg相当。
表2 20S-O-Glc-DM预防性给药对异丙肾上腺素(ISO)诱导心肌损伤小鼠血清心肌损伤生物标志物cTn-T的影响(n=5)
***P<0.001与空白对照组比较;#P<0.05,###P<0.001与模型组比较。
ISO连续皮下注射7次后,停止注射,动物继续每天灌胃给予20S-O-Glc-DM,进行治疗性给药8天。血清cTn-T结果见表3。ISO停止损伤小鼠7天后,小鼠血清心肌损伤生物标志物cTn-T水平仍较空白对照组显著升高,提示心脏损伤仍然存在。20S-O-Glc-DM 3mg/kg、6mg/kg剂量治疗性给药,均能显著降低血清cTn-T水平,20S-O-Glc-DM 3mg/kg治疗活性与地尔硫卓20mg/kg相当,20S-O-Glc-DM 6mg/kg治疗活性优于地尔硫卓20mg/kg。
表3 20S-O-Glc-DM治疗性给药对异丙肾上腺素(ISO)诱导心肌损伤小鼠血清心肌损伤生物标志物cTn-T的影响(n=6-8)
*P<0.05与空白对照组比较;#P<0.05,##P<0.01,###P<0.001与模型组比较。
心肌酶结果:
血清肌酸激酶-同工酶(CK-MB)是判断心肌坏死的另一个临床特异性和敏感性指标。
预防性给药结果见表4。ISO连续皮下注射小鼠7天,在注射ISO前三天开始预防性给药,连续给药10天。模型组小鼠血清CK-MB水平与空白对照组相比有升高趋势,20S-O-Glc-DM 3mg/kg、6mg/kg、10mg/kg剂量均能降低血清CK-MB水平,20S-O-Glc-DM 6mg/kg降低血清心肌酶的能力优于地尔硫卓20mg/kg。
表4 20S-O-Glc-DM预防性给药对异丙肾上腺素(ISO)诱导心肌损伤小鼠血清心肌酶CK-MB含量的影响(n=5)
治疗性给药结果见表5。ISO连续皮下注射7次后,停止注射,动物继续每天灌胃给予20S-O-Glc-DM,连续治疗性给药7天。ISO停止刺激小鼠7天后,小鼠血清心肌损伤生物标志物CK-MB水平与空白对照组显著升高,提示心脏损伤在停止ISO刺激后7天仍然存在。20S-O-Glc-DM 3mg/kg、6mg/kg、10mg/kg剂量治疗性给药,均能显著降低血清CK-MB水平,20S-O-Glc-DM 3mg/kg治疗活性与地尔硫卓20mg/kg相当,20S-O-Glc-DM 6mg/kg、10mg/kg治疗活性优于地尔硫卓20mg/kg。
表5 20S-O-Glc-DM治疗性给药对异丙肾上腺素(ISO)诱导心肌损伤小鼠血清心肌酶CK-MB含量的影响(n=6-8)
*P<0.05与空白对照组比较;#P<0.05,##P<0.01,###P<0.001与模型组比较。
心力衰竭生物标志物结果:
血清脑钠肽BNP是心力衰竭早期诊断的生物标志物,其水平降低也是药物治疗有效的有力证据。心钠肽ANP是另一个心力衰竭的血清敏感生物标志物,目前研究亦显示,BNP和ANP水平与心肌肥厚程度呈正相关,可作为心肌肥厚的生物标志物。
在停止ISO刺激,动物继续每天灌胃给予20S-O-Glc-DM进行治疗性给药8天后,利用ELISA试剂盒检测血清BNP和ANP水平,结果见表6。模型组动物血清BNP水平及ANP水平较空白对照组均显著升高,提示心脏损伤严重,有心衰可能,且存在心肌肥厚病征。20S-O-Glc-DM 3mg/kg、6mg/kg和10mg/kg均能够降低血清血清BNP水平,其中20S-O-Glc-DM 10mg/kg降低BNP的作用与模型组比较有统计学差异。20S-O-Glc-DM 3mg/kg、6mg/kg和10mg/kg亦能够明显降低血清ANP水平,其中20S-O-Glc-DM 3mg/kg、6mg/kg对ANP的降低作用与模型组比较有统计学差异。20S-O-Glc-DM对心力衰竭生物标志物的降低作用优于阳性对照药地尔硫卓。
表6 20S-O-Glc-DM治疗性给药对异丙肾上腺素(ISO)诱导心肌缺血小鼠血清心力衰竭生物标志物BNP、ANP含量的影响(n=6-8)
***P<0.001与空白对照组比较;##P<0.01与模型组比较。
超声心动图检查结果:
连续ISO给药导致的心肌损伤,主要是引起左心室心内膜病变,增加左心室僵硬度,引起左心室舒张功能异常,降低左心室膨胀度。
小鼠心脏超声心动图检查部分指标统计结果见图7,连续ISO给药引起的心肌损伤导致显著的心肌肥厚现象,舒张期前壁厚度和后壁厚度均明显或显著升高,同时舒张期左心室内径和舒张期左心室容量均显著降低。20S-O-Glc-DM 3mg/kg显著降低舒张期前壁厚度,改善心肌肥厚,同时显著升高舒张期左心室内径和舒张期左心室容量,改善左心室舒张期功能,与模型组比较有统计学差异。20S-O-Glc-DM 3mg/kg对左心室舒张功能的改善活性优于阳性药地尔硫卓20mg/kg。
实验例3 20S-O-Glc-DM在阿霉素(DOX)诱导的小鼠心肌损伤模型中的活性测试
实验方法:
雄性C57BL/6小鼠(由北京华阜康生物科技股份有限公司提供)适应环境后随机分为5组,分别为空白对照组、阿霉素模型组、右丙亚胺100mg/kg阳性对照药组、阿霉素+20S-O-Glc-DM 3mg/kg组及阿霉素+20S-O-Glc-DM 6mg/kg组。给药组小鼠每天灌胃给药相应剂量的20S-O-Glc-DM 1次,空白对照组及模型组小鼠给予相同量的溶剂(0.5%CMC-Na溶剂),给药量均为10mL/kg,连续7天,右丙亚胺阳性对照组于造模前1h给药,共两次。给药第4~5天,空白对照组皮下注射生理盐水,其余各组小鼠腹腔注射阿霉素10mg/kg,第7天,处死小鼠,取心脏称重。
实验结果:
结果见图8,阿霉素10mg/kg腹腔注射小鼠2次,小鼠心脏明显变小萎缩,出现显著的心脏毒性,心脏指数与空白对照组比较显著降低。20S-O-Glc-DM 3mg/kg、6mg/kg均显著升高心脏指数,活性与右丙亚胺100mg/kg相当。
实验例4 20S-O-Glc-DM在常压耐氧诱导的小鼠缺氧模型中的活性测试
实验方法:
SPF级雄性CD-1(ICR)(由北京华阜康生物科技股份有限公司提供)小鼠适应环境后随机分为4组,分别为空白对照组、红景天600mg/kg阳性对照药组、20S-O-Glc-DM 3mg/kg组和20S-O-Glc-DM 6mg/kg组。给药组小鼠每天灌胃给药相应剂量的20S-O-Glc-DM 1次,空白对照组给予相同量的溶剂(0.5%CMC-Na溶剂),给药量均为10mL/kg,连续4天,于末次给药1h后,小鼠进行常压耐缺氧实验。将小鼠放进250mL的密封性好的磨口玻璃瓶内,每瓶1只小鼠,瓶内用纱布包15g钠石灰。将小鼠放入瓶内后立即用封口膜密封盖紧,以小鼠挣扎抽搐后突然瘫软,且胸部不再起伏,呼吸停止为死亡依据,记录各组小鼠从密封至死亡的时间。
实验结果:
小鼠存活时间结果见表7。20S-O-Glc-DM 3mg/kg、6mg/kg提前给药4天,均能延长小鼠的常压缺氧情况下的存活时间,存活时间较空白对照组动物分别延长9.22%和5.60%,表现耐心脑缺氧活性。20S-O-Glc-DM耐缺氧活性优于红景天600mg/kg。
表7 20S-O-Glc-DM在常压缺氧模型对小鼠生存时间的影响(n=10)
实验例5 20S-O-Glc-DM在缺氧复氧诱导的心肌细胞损伤模型中的活性测试
实验方法:
取对数生长期H9C2心肌细胞8×104个/mL接种于96孔板中,每孔100μL,分为空白对照组、缺氧复氧(H/R)组、H/R+20S-O-Glc-DM 2μM组、H/R+20S-O-Glc-DM 10μM组,每组5个平行孔。培养24h后,将H/R组、H/R+20S-O-Glc-DM 2μM组和H/R+20S-O-Glc-DM 10μM组的H9C2心肌细胞培养液更换为不含血清的无糖DMEM培养基,置于37℃,95%N2,5%CO2的培养箱中缺氧处理6h。去除培养基,H/R组加入含血清含糖的完全DMEM培养基,H/R+20S-O-Glc-DM组加入含相应药物的完全培养基,在37℃,95%O2,5%CO2培养箱中复氧培养12h。去除上清液,PBS洗涤(pH7.4),每孔加入100μL CCK8溶液(CCK8体积占DMEM培养液体积的10%),细胞培养箱中孵育1h,置于酶标仪450nm处测定吸光度。计算细胞存活率。细胞存活率=(实验孔-空白孔)/(对照孔-空白孔)×100%。
实验结果:
结果见表8,氧糖剥夺后复氧,导致心肌细胞显著损伤,细胞存活率仅为54.09%,20S-O-Glc-DM 2μM和10μM显著提高缺氧复氧损伤心肌细胞的存活率,与模型组比较有统计学差异,表现出良好的抗缺血再灌注损伤活性。
表8 20S-O-Glc-DM对缺氧复氧损伤心肌细胞的保护作用(n=3)
/>
***P<0.001与空白对照组比较;###P<0.001与模型组比较。
实验例6 20S-O-Glc-DM在过氧化氢诱导的心肌细胞损伤模型中的活性测试
实验方法:
将对数生长期的H9C2心肌细胞按8×104个/mL接种于96孔板中,每孔100μL,分为空白对照组、过氧化氢(H2O2)模型组、H2O2+20S-O-Glc-DM 2μM组、H2O2+20S-O-Glc-DM 10μM组。细胞培养24h后,H2O2模型组、H2O2+20S-O-Glc-DM 2μM组和H2O2+20S-O-Glc-DM 10μM组分别加入200μM H2O2,H2O2+20S-O-Glc-DM 2μM组同时加入2μM的20S-O-Glc-DM,H2O2+20S-O-Glc-DM 10μM组同时加入10μM的20S-O-Glc-DM,空白对照组加入等体积DMSO,继续培养24h。吸出原有培养液,用PBS洗涤(pH7.4),每孔加入100μL CCK8溶液(CCK8体积占DMEM培养液体积的10%),细胞培养箱中孵育1h,置于酶标仪450nm处测定吸光度。计算细胞存活率。细胞存活率=(实验孔-空白孔)/(对照孔-空白孔)×100%。
实验结果:
结果见表9,与空白对照组相比,过氧化氢(H2O2)作用后可显著降低H9C2心肌细胞的存活率。与模型对照组比较,20S-O-Glc-DM 2μM能够显著提高过氧化氢损伤心肌细胞的存活率,20S-O-Glc-DM 10μM对过氧化氢损伤心肌细胞亦表现保护活性。
表9 20S-O-Glc-DM对过氧化氢(H2O2)损伤心肌细胞的保护作用(n=3)
**P<0.01与空白对照组比较;#P<0.05与模型组比较。
实验例7 20S-O-Glc-DM在异丙肾上腺素(ISO)诱导的心肌细胞肥大损伤模型中的活性测试
实验方法:
将对数生长期的大鼠H9C2心肌细胞按8×104个/mL接种于96孔板中,每孔100μL,分为空白对照组、ISO模型组、ISO+20S-O-Glc-DM 2μM组、ISO+20S-O-Glc-DM 10μM组。培养24h后,ISO模型组和ISO+20S-O-Glc-DM分别加入600μM ISO,ISO+20S-O-Glc-DM 2μM组和ISO+20S-O-Glc-DM 10μM组同时加入不同浓度的20S-O-Glc-DM,空白对照组加入等体积DMSO,继续培养24h。弃掉培养液,用PBS洗3次(pH7.4)。倒置显微镜下观察,每孔随机选取视野拍照。采用Image J软件测量视野内所有心肌细胞的表面积之和,同时计数视野内细胞数,单个心肌细胞表面积=视野内所有心肌细胞表面积和/视野内心肌细胞数,获得每一个心肌细胞表面积。
实验结果:
如图9所示,ISO作用H9C2细胞24h,与空白对照组相比,模型组细胞数量明显减少,且心肌细胞体积显著增大,部分细胞膜边界不明显并发生融合,出现心肌细胞肥大现象,同时细胞出现死亡,漂浮细胞显著增多。20S-O-Glc-DM 2μM和20S-O-Glc-DM 10μM均显著改善ISO引起的心肌细胞肥大损伤现象,同时改善细胞数下降和细胞漂浮情况,细胞膜边界与模型组相比也较清晰,细胞融合情况明显减少。
单个心肌细胞表面积统计数据见表10,模型组心肌细胞随机选取的视野内单个心肌细胞表面积均增大,与空白对照组比较有统计学差异。20S-O-Glc-DM 2μM和20S-O-Glc-DM 10μM显著改善ISO引起的心肌细胞肥大损伤,单个心肌细胞表面积与模型组比较显著降低。
表10 20S-O-Glc-DM对异丙肾上腺素(ISO)诱导心肌细胞肥大损伤心肌细胞表面积(μM2)的作用(x±s,n=3)
***P<0.001与空白对照组比较;#P<0.05与模型组比较。
实验例8 20S-O-Glc-DM对损伤心肌细胞线粒体能量代谢影响的活性测试
实验方法:
根据安捷伦公司SeahorseXF细胞线粒体压力测试试剂盒(批号:103015-100)说明进行实验,取对数生长期H9C2细胞接种于除特质细胞培养板A1、A12、H1、H12孔以外的孔中,每孔80μL,同时A1、A12、H1、H12孔加入80μL完全培养基,超净台静置1h后移入37℃,5%CO2培养箱中培养4h。A1、A12、H1、H12孔补加80μL完全DMEM培养基,剩余孔设置空白对照组、模型组和20S-O-Glc-DM 2μM、10μM作用组,除空白对照组,其它各组同时加入500μM ISO,空白对照孔加入相应的DMSO溶剂。继续培养20h。润洗细胞,每孔依次加入Oligomycin 1.0μM、FCCP 1μM、Rotenone/antimycinA 0.5μM(终浓度)。进行上机检测。检测完毕后,去除孔中液体并清洗,每孔加入100μL含蛋白酶抑制剂和磷酸酶抑制剂的RIPA裂解液,冰上裂解20min,BCA法测定每孔蛋白浓度,根据蛋白浓度对上机结果进行统一化处理。
实验结果:
如图10和图11所示,异丙肾上腺素(ISO)显著抑制线粒体能量代谢,ATP产生显著减少,同时糖酵解能力显著降低。20S-O-Glc-DM 2μM、10μM显著改善心肌细胞能量代谢状态,显著升高ATP产生量,同时显著提高受损心肌细胞的糖酵解能力。
Claims (5)
1.如式I所示的20S-O-Glc-DM或其药学上可接受的盐在制备治疗和/或预防心血管疾病及其相关病症的药物中的应用,
2.根据权利要求1的应用,其特征在于,所述心血管疾病选自于以下中的一种或多种:左心室舒张功能障碍、冠心病、高血压、心力衰竭、心肌病、心律失常、心肌梗死、心绞痛。
3.一种药物组合物在制备治疗和/或预防心血管疾病及其相关病症的药物中的应用,其特征在于,所述的药物组合物包含式I所示的20S-O-Glc-DM或其药学上可接受的盐和药学上可接受的载体或赋形剂,
4.根据权利要求3的应用,其特征在于,所述药物组合物包括片剂、胶囊剂、颗粒剂、丸剂、滴丸剂、预乳剂、微乳剂、混悬剂、糖浆剂、肠溶制剂、注射剂。
5.根据权利要求3或4的应用,其特征在于,所述心血管疾病选自于以下中的一种或多种:左心室舒张功能障碍、冠心病、高血压、心力衰竭、心肌病、心律失常、心肌梗死、心绞痛。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210085081.4A CN116531392A (zh) | 2022-01-25 | 2022-01-25 | 20S-O-Glc-DM在制备治疗和/或预防心血管疾病药物中的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210085081.4A CN116531392A (zh) | 2022-01-25 | 2022-01-25 | 20S-O-Glc-DM在制备治疗和/或预防心血管疾病药物中的应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116531392A true CN116531392A (zh) | 2023-08-04 |
Family
ID=87456497
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210085081.4A Pending CN116531392A (zh) | 2022-01-25 | 2022-01-25 | 20S-O-Glc-DM在制备治疗和/或预防心血管疾病药物中的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116531392A (zh) |
-
2022
- 2022-01-25 CN CN202210085081.4A patent/CN116531392A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20080153827A1 (en) | Method for the Treatment or Prevention of Cardiac Hypertrophy | |
CN117323323A (zh) | 奇楠成分对ampk的激活作用 | |
CN111840112B (zh) | 鼠尾草酸或其衍生物在制备治疗糖尿病并发症药物中的应用 | |
US20120004188A1 (en) | Use of ranolazine for treating pulmonary hypertension | |
TWI464147B (zh) | 吲哚氫胺酸和吲哚啉氫胺酸於治療心臟衰竭或神經損傷的用途 | |
CN116531392A (zh) | 20S-O-Glc-DM在制备治疗和/或预防心血管疾病药物中的应用 | |
CN104523676A (zh) | 京尼平用于预防或治疗缺血性脑损伤的用途 | |
CN116531363A (zh) | 甲基麦冬黄酮a在制备治疗心血管疾病药物中的应用 | |
US5684007A (en) | Methods for inhibiting cardiac fibroblast growth and cardiac fibrosis | |
WO2017157248A1 (zh) | 三乙酰基-3-羟基苯基腺苷在制备治疗动脉粥样硬化药物中的应用 | |
CN107913273A (zh) | 中乌宁碱的应用 | |
WO2021252630A1 (en) | Methods for treating or preventing chronic kidney disease | |
CN111494606B (zh) | 神经肽y的新应用 | |
CN116115601A (zh) | 戈米辛e在制备心血管疾病药物中的应用 | |
WO2024027521A1 (zh) | 甲基麦冬黄酮a类衍生物及其制备和应用 | |
CN117442624A (zh) | 源自岳桦的一种达玛烯三醇在防治心血管疾病中的用途 | |
CN113662930B (zh) | 二蒽酮类化合物在制备预防和/或治疗心肌缺血性疾病及其相关病症的药物中的应用 | |
CN102247392A (zh) | 甘草酸治疗扩张型心肌病心脏重构和心功能障碍的用途 | |
CN104873482B (zh) | 一种抗慢性心力衰竭的药物组合物 | |
CN110934864A (zh) | 4-甲基-6,7-二甲氧基香豆素在制备防治糖尿病肾病的药物中的应用 | |
CN117045767A (zh) | 一类甘草中的化合物和其药物组合物在防治心衰中的应用 | |
CN112826820B (zh) | Nlrp3抑制剂及其应用 | |
WO2020228477A1 (zh) | 一种用于预防、缓解和/或治疗纤维化的药物、组合产品及其应用 | |
CN112773789B (zh) | 山莴苣苦素在制备预防和治疗心力衰竭和病理性心脏重构药物中的应用 | |
JPH11116472A (ja) | 心不全の治療法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication |