WO2018152996A1 - Utilisation du nadph dans la préparation d'un médicament destiné à traiter l'hypertrophie cardiaque et l'insuffisance cardiaque - Google Patents
Utilisation du nadph dans la préparation d'un médicament destiné à traiter l'hypertrophie cardiaque et l'insuffisance cardiaque Download PDFInfo
- Publication number
- WO2018152996A1 WO2018152996A1 PCT/CN2017/090157 CN2017090157W WO2018152996A1 WO 2018152996 A1 WO2018152996 A1 WO 2018152996A1 CN 2017090157 W CN2017090157 W CN 2017090157W WO 2018152996 A1 WO2018152996 A1 WO 2018152996A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- nadph
- heart failure
- heart
- iso
- cardiac
- Prior art date
Links
- 206010007572 Cardiac hypertrophy Diseases 0.000 title claims abstract description 35
- 208000006029 Cardiomegaly Diseases 0.000 title claims abstract description 34
- 239000003814 drug Substances 0.000 title claims abstract description 24
- 206010019280 Heart failures Diseases 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- ACFIXJIJDZMPPO-NCHANQSKSA-N nadph Chemical compound C1=CCC(C(=O)N)=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](COP(O)(=O)OP(O)(=O)OC[C@H]2[C@@H]([C@H](OP(O)(O)=O)[C@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NCHANQSKSA-N 0.000 title 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 claims abstract description 101
- 238000011282 treatment Methods 0.000 claims abstract description 11
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000002504 physiological saline solution Substances 0.000 claims description 3
- 239000006188 syrup Substances 0.000 claims description 3
- 235000020357 syrup Nutrition 0.000 claims description 3
- 239000000443 aerosol Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000012153 distilled water Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000011505 plaster Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 238000005507 spraying Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 29
- 230000036772 blood pressure Effects 0.000 abstract description 17
- 206010067484 Adverse reaction Diseases 0.000 abstract description 3
- 230000006838 adverse reaction Effects 0.000 abstract description 3
- 102000004190 Enzymes Human genes 0.000 abstract 3
- 108090000790 Enzymes Proteins 0.000 abstract 3
- 210000004165 myocardium Anatomy 0.000 abstract 1
- XJLXINKUBYWONI-NNYOXOHSSA-N NADP zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-N 0.000 description 94
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 43
- 229940039009 isoproterenol Drugs 0.000 description 43
- 241000699670 Mus sp. Species 0.000 description 26
- 230000000747 cardiac effect Effects 0.000 description 26
- 230000002107 myocardial effect Effects 0.000 description 14
- 241000700159 Rattus Species 0.000 description 12
- 230000002861 ventricular Effects 0.000 description 12
- 239000011575 calcium Substances 0.000 description 11
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 9
- 230000004217 heart function Effects 0.000 description 9
- 208000007177 Left Ventricular Hypertrophy Diseases 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 108091006112 ATPases Proteins 0.000 description 6
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 6
- 206010007558 Cardiac failure chronic Diseases 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 238000011065 in-situ storage Methods 0.000 description 6
- 239000013641 positive control Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 229960003180 glutathione Drugs 0.000 description 5
- 230000003834 intracellular effect Effects 0.000 description 5
- 210000005240 left ventricle Anatomy 0.000 description 5
- 206010007556 Cardiac failure acute Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 210000000709 aorta Anatomy 0.000 description 3
- 210000004413 cardiac myocyte Anatomy 0.000 description 3
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 3
- 229960002327 chloral hydrate Drugs 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 230000000116 mitigating 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
- 230000035806 respiratory chain Effects 0.000 description 3
- 238000009423 ventilation Methods 0.000 description 3
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 2
- 108010064733 Angiotensins Proteins 0.000 description 2
- 102000015427 Angiotensins Human genes 0.000 description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 description 2
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 2
- 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 2
- 108010053070 Glutathione Disulfide Proteins 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 206010020880 Hypertrophy Diseases 0.000 description 2
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 2
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 2
- 229960000830 captopril Drugs 0.000 description 2
- 210000000038 chest Anatomy 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000001447 compensatory effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000035487 diastolic blood pressure Effects 0.000 description 2
- 230000003205 diastolic effect Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- YPZRWBKMTBYPTK-BJDJZHNGSA-N glutathione disulfide Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@H](C(=O)NCC(O)=O)CSSC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O YPZRWBKMTBYPTK-BJDJZHNGSA-N 0.000 description 2
- -1 hydrogen ions Chemical class 0.000 description 2
- 229940124975 inotropic drug Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000000955 neuroendocrine Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 231100000915 pathological change Toxicity 0.000 description 2
- 230000036285 pathological change Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000036316 preload Effects 0.000 description 2
- 238000000718 qrs complex Methods 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000007634 remodeling Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000004904 shortening Methods 0.000 description 2
- 230000035488 systolic blood pressure Effects 0.000 description 2
- 210000001364 upper extremity Anatomy 0.000 description 2
- 210000001631 vena cava inferior Anatomy 0.000 description 2
- 206010001029 Acute pulmonary oedema Diseases 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010052337 Diastolic dysfunction Diseases 0.000 description 1
- 241000208011 Digitalis Species 0.000 description 1
- 206010016803 Fluid overload Diseases 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 206010058558 Hypoperfusion Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 102000012011 Isocitrate Dehydrogenase Human genes 0.000 description 1
- 108010075869 Isocitrate Dehydrogenase Proteins 0.000 description 1
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 description 1
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 1
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 1
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 1
- 206010028594 Myocardial fibrosis Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 206010042434 Sudden death Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000000808 adrenergic beta-agonist Substances 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940125388 beta agonist Drugs 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000004094 calcium homeostasis Effects 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 206010007625 cardiogenic shock Diseases 0.000 description 1
- 230000006567 cellular energy metabolism Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000037326 chronic stress Effects 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 230000007322 compensatory function Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000002592 echocardiography Methods 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 210000003617 erythrocyte membrane Anatomy 0.000 description 1
- 230000010222 extracellular calcium influx Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 230000010247 heart contraction Effects 0.000 description 1
- 210000001308 heart ventricle Anatomy 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000019948 ion homeostasis Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- ODBLHEXUDAPZAU-UHFFFAOYSA-N isocitric acid Chemical compound OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- YPZRWBKMTBYPTK-UHFFFAOYSA-N oxidized gamma-L-glutamyl-L-cysteinylglycine Natural products OC(=O)C(N)CCC(=O)NC(C(=O)NCC(O)=O)CSSCC(C(=O)NCC(O)=O)NC(=O)CCC(N)C(O)=O YPZRWBKMTBYPTK-UHFFFAOYSA-N 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 210000003540 papillary muscle Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000004108 pentose phosphate pathway Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000003805 potassium influx Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000004088 pulmonary circulation Effects 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 230000035485 pulse pressure Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000005241 right ventricle Anatomy 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 210000001908 sarcoplasmic reticulum Anatomy 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 206010042772 syncope Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000012285 ultrasound imaging Methods 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Images
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
- A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
Definitions
- the invention belongs to the field of medicines, and particularly relates to the application of NADPH in preparing medicines for treating cardiac hypertrophy and heart failure.
- NADPH reduced nicotinamide adenine dinucleotide phosphate
- PPP pentose phosphate pathway
- GSH glutathione
- GSH is an important antioxidant in the cell, which protects some thiol-containing proteins, fats and proteases from oxidants, especially in maintaining the integrity of erythrocyte membranes.
- NADPH is also involved in the hydroxylation of the body and the biotransformation of drugs, poisons and certain hormones; for example, NADPH can utilize the electron donor of detoxified cells.
- the metabolism of the organism is reduced by metabolism in the body, and the balance of redox is maintained, which plays an important role in the oxidation defense system.
- NADPH can also enter the respiratory chain by means of isocitrate shuttle to produce ATP: due to the low permeability of the mitochondrial inner membrane to the substance, the NADPH produced by the mitochondria in vitro cannot be directly oxidized into the respiratory chain.
- H on NADPH can be delivered to NAD+ under the action of isocitrate dehydrogenase, and then energy is generated by NAD+ entering the respiratory chain.
- ROS reactive oxygen species
- Cardiac hypertrophy is the target organ response of the heart to chronic stress or volume overload. There are about 266 million patients with hypertension in China, and one-third of them with hypertension can be associated with LVH. Cardiac hypertrophy is an extremely important cardiovascular risk factor, which can increase the risk of sudden death such as coronary heart disease, congestive heart failure, stroke or transient ischemic heart attack; more importantly, cardiac hypertrophy is also chronic heart failure.
- Heart failure refers to a syndrome in which circulatory disorders are predominant due to the absolute or relative decrease in cardiac output during normal venous return. Clinically, pulmonary circulation and/or systemic blood stasis and tissue hypoperfusion are the main features. According to the development of heart failure, acute heart failure and chronic heart failure can be divided into acute heart failure. Acute heart failure refers to acute cardiac output in a short period of time.
- Chronic heart failure also known as congestive heart failure or chronic heart failure
- the disease-causing factors cause the heart to be under stress and/or over-loading for a long time, causing the heart to be exhausted and gradually losing compensatory function.
- the cardiac output is absolutely or relatively insufficient to maintain the body's metabolic needs.
- the causes of heart failure are multiple and complex, mainly including myocardial contraction and / or diastolic dysfunction and long-term cardiac load and ventricular filling limitation.
- Heart failure is actually the result of cardiac function from compensation to decompensation; In depletion, especially in chronic heart failure, the compensatory response of the body to prevent the reduction of cardiac output includes neuroendocrine reflex and myocardial configuration reconstruction.
- Cardiac hypertrophy is the main manifestation of cardiac reconstruction. Early cardiac hypertrophy has a certain compensatory significance for cardiac function; however, in the late stage of cardiac hypertrophy, pathological cardiac hypertrophy is accompanied by cardiomyocyte apoptosis, myocardial fibroblast proliferation and myocardial fibrosis interstitial hyperplasia, which promotes cardiac function gradually. The compensation is decompensated and participates in the occurrence and development of heart failure.
- angiotensin conversion Enzyme inhibitors ACEIs
- angiotensin II receptor I blockers ARBs
- Diuretics the mechanism of action is: by eliminating excess water in the body, reducing effective circulating blood volume, reducing cardiac preload, eliminating interstitial edema or pulmonary edema, aldosterone receptors such as spironolactone Antagonists can also resist the cardiac remodeling of aldosterone
- calcium antagonists the mechanism of action is: inhibition of extracellular Ca 2+ influx, decrease intracellular free Ca 2+ concentration, relax blood vessels, lower blood pressure
- the above-mentioned drugs (1)-(4) alleviate or reverse cardiac hypertrophy and gradually improve cardiac function, and are suitable for long-term treatment of cardiac hypertrophy or chronic heart failure, but because they do not have a cardiac effect, the development of cardiac hypertrophy to heart failure
- the decompensation period is generally effective and cannot be used for the treatment of acute heart failure; while the category (5) drugs have more serious adverse reactions in clinical application, such as increasing the risk of arrhythmia and even increasing heart failure. mortality rate.
- the present invention proposes the use of NADPH in the preparation of a medicament for the treatment of cardiac hypertrophy and heart failure.
- the present invention provides the use of NADPH for the preparation of a medicament for the treatment of cardiac hypertrophy.
- the present invention also provides the use of NADPH for the preparation of a medicament for treating heart failure.
- the medicament comprises a pharmaceutically effective amount of NADPH and a pharmaceutically acceptable carrier.
- the carrier is selected from the group consisting of commonly used pharmaceutical excipients, or physiological saline, or distilled water.
- the drug is NADPH according to a conventional process, and a conventional excipient is added to prepare a clinically acceptable tablet, capsule, powder, mixture, pill, granule, syrup, plaster, suppository. , aerosol, ointment or injection.
- the administration mode of the drug is at least one selected from the group consisting of oral administration, injection administration, sublingual administration, rectal administration, transdermal administration, and spray inhalation.
- the present invention has found that NADPH not only has a significant cardiac effect, but also has a mitigating effect on cardiac hypertrophy, and thus can be used as a drug for treating cardiac hypertrophy and heart failure;
- NADPH can increase the activity of Na + -K + -ATPase, Ca 2+ -Mg 2+ -ATPase and total ATPase in myocardial tissue of mice, suggesting that NADPH may pass
- the above mechanism exerts a mitigating effect on cardiac hypertrophy
- NADPH has no significant effect on the blood pressure of normal rats, and the adverse reactions in the treatment of cardiac hypertrophy and heart failure are small.
- Fig. 1(a) shows the effect of NADPH on the cardiac contractile force of the in situ frog heart in Experimental Example 1, and the numerical value indicates the percentage of contractile force compared with normal;
- Fig. 1(b) shows the experimental example 1.
- Fig. 1(c) shows the effect of NADPH on the heart rate of in situ frog heart in experimental example 1;
- Fig. 2(a) shows the effect of NADPH on ISO-induced cardiac hypertrophy in Experimental Example 2
- Figure 2(b) shows the HE staining map of each group of mice in Experimental Example 2
- N (L) is NADPH 1mg/kg
- N(M) represents NADPH 2mg/kg
- N(H) represents NADPH 4mg/kg
- Fig. 3(a) shows the electrocardiogram of each group of mice in Experimental Example 2
- Fig. 3(b) shows the effect of NADPH on the R wave amplitude of the electrocardiogram of ISO-induced mice in Experimental Example 2; Standard deviation; compared with the control group, ### P ⁇ 0.001
- N(L) indicates NADPH 1 mg/kg
- N(M) indicates NADPH 2 mg/kg
- N(H) indicates NADPH 4 mg/kg.
- Figure 4 is the effect of NADPH on cardiac function in mice in Experimental Example 2; N(L) indicates NADPH 1 mg/kg, N(M) indicates NADPH 2 mg/kg, and N(H) indicates NADPH 4 mg/kg. Kg;
- Figure 5 is a graph showing the effect of NADPH on the ATPase content in myocardial tissue of mice in Experimental Example 2; N(L) indicates NADPH 1 mg/kg, and N(M) indicates NADPH 2 mg/kg, and N(H) indicates For NADPH 4mg/kg;
- Figure 6 is the effect of NADPH on the blood pressure of normal rats in Experimental Example 3; NS indicates normal saline, SBP indicates systolic blood pressure, DBP indicates diastolic blood pressure, MBP indicates mean arterial pressure, mean ⁇ standard difference.
- Animal feeding environment room temperature 22 ° C, humidity 50-60%, good ventilation, artificial day and night (12h / 12h), free access to food and water;
- the source of exogenous NADPH drugs can be obtained by artificial synthesis, semi-synthesis, and biological extraction;
- the medulla was fixed on the frog plate, the left and right aorta and inferior vena cava were separated, the inferior vena cava was inserted into the venous cannula, the left aorta was inserted into the arterial cannula, and the right aorta was ligated with Ren's solution (1000 mL: NaCl 6.5 g).
- KCl 0.14g, CaCl 2 0.12g, NaHCO 3 0.2g, NaH 2 PO 4 0.01g, glucose 1g, double distilled water rinse the heart, frog heart clamps the apex, connect the Medlab operating system through the tension transducer, record Normal frog heart beat curve, heart rate and cardiac output, switch into the same amount of low calcium Ren's solution (CaCl 2 content is 1/2 of Ren's solution) to perfuse the heart, when the heart contraction is significantly weakened, add NADPH to the venous cannula (Purity >97%, Roche, 10621706001), recording changes in heart beat curve, heart rate, and cardiac output.
- Fig. 1(a), 1(b), 1(c), and 1(d) that the heart deficiencies are significantly reduced and the cardiac output is decreased after perfusion of the low-calcium solution.
- the contraction amplitude of the isolated frog heart can be significantly increased, the cardiac output is increased, but the heart rate has no significant effect; after 20 minutes of administration, the cardiac effect begins to appear. , the maintenance time is up to 2h.
- NADPH can significantly increase the contraction amplitude of the isolated frog heart and increase the cardiac output, but has no significant effect on the heart rate; that is, NADPH has a significant cardiac effect.
- Animal feeding environment room temperature 22 ° C, humidity 50-60%, good ventilation, artificial day and night (12h / 12h), free access to food and water;
- the source of exogenous NADPH drugs can be obtained by artificial synthesis, semi-synthesis, and biological extraction;
- ATPase kit (A070-6), purchased from Nanjing Jiancheng Bioengineering Research Institute;
- Isoproterenol (ISO) and captopril (Cap) were purchased from Shanghai Maclean Biochemical Technology Co., Ltd.;
- Chloral hydrate is purchased from Sinopharm Chemical Reagent Co., Ltd.;
- Electrocardiograph Kenz, ECG-103.
- Isoproterenol is a non-selective beta-adrenergic receptor agonist. Long-dose administration can increase myocardial contractility and oxygen consumption, and promote intracellular cyclic adenosine monophosphate (cAMP) and sugar. The original synthesis increases the synthesis of total protein and non-shrinking protein in cardiomyocytes, causing cardiac hypertrophy, especially left ventricular hypertrophy.
- cAMP cyclic adenosine monophosphate
- ICR mice were randomly divided into 6 groups: normal control group, model control group - ISO group, positive control group - ISO + Captopril (Cap) 100 mg / kg, ISO + NADPH 1 mg / kg group, ISO + NADPH 2 mg /kg group, ISO+NADPH 4mg/kg group.
- each group was injected subcutaneously (sc) with equal volume of normal saline daily; other groups were injected subcutaneously (sc) ISO twice times, each time 1 mg/kg, 2 times interval 8 h, ISO+ The NADPH 1 mg/kg group, the ISO+NADPH 2 mg/kg group, and the ISO+NADPH 4 mg/kg group were sc ISO every morning. After 4 hours, the corresponding dose of NADPH was intraperitoneally injected. The positive control group was sc ISO every morning, and the corresponding dose was intraperitoneally injected 4 hours later. Cap, model control group was intraperitoneally injected with equal volume of normal saline; continuous administration for 14 days.
- mice were intraperitoneally injected with 4% chloral hydrate 10 mg/kg to remove the chest hair of the mice.
- the high-resolution small animal ultrasound imaging system (VISU ⁇ LSONICS, VEVO2100) was used.
- the probe frequency was 8 MHz, placed on the left side of the sternum, and the standard left was selected.
- the short-axis and long-axis sections of the papillary muscle were combined with M-mode and Doppler ultrasound to measure the ejection fraction (EF) and left ventricular short-axis shortening (FS) of the systolic and diastolic phases of the mouse, respectively.
- the indoor diameter (LVID), left ventricular posterior wall thickness (LVPW), left ventricular anterior wall thickness (LVAW), and left ventricular volume (LVvol) were averaged over three consecutive cardiac cycles.
- mice were intraperitoneally injected with 4% chloral hydrate 10 mL/kg anesthetized, and the needle electrode red was connected with (R) right upper limb, yellow (L) left upper limb, green (LF) left lower limb, black (RF) right lower limb, and electrocardiogram was used.
- the instrument detects the II lead electrocardiogram with a frequency of 50 Hz and a paper speed of 25 mm/s.
- mice After 14 days of administration, the body weight (BW) of the mice was measured, the anesthesia was sacrificed, the heart was opened by chest, the residual blood was washed with physiological saline, the filter paper was blotted and photographed, and the heart weight (HW) and left were weighed.
- the left ventricular tissue of the apex was fixed in 4% neutral formaldehyde solution, dehydrated with gradient ethanol, embedded in paraffin, sectioned, and stained with HE. The photograph was taken under an optical microscope.
- the supernatant of the left ventricular tissue of the mice was taken, and the levels of Na + -K + , Ca 2+ -Mg 2+ and T-ATPase in the myocardial tissue were determined by a kit.
- the heart of the model control group was significantly larger than the normal control group, the positive control group, the ISO+NADPH 1 mg/kg group, the ISO+NADPH 2 mg/kg group, and the ISO+NADPH 4 mg/kg group heart. It has been reduced.
- Fig. 2(b) the pathological examination showed that the myocardial cells of the model control group were hypertrophied by HE staining, the nuclei were deeply stained, and the cell spacing became larger; ISO+NADPH 1 mg/kg group, ISO+NADPH 2 mg/kg group In the ISO+NADPH 4mg/kg group, the decrease of myocardial cell hypertrophy was more obvious with the increase of NADPH dose; this indicates that NADPH can alleviate the pathological changes of ISO-induced mouse cardiomyocyte hypertrophy.
- the heart HWI and LVWI of the model control group increased significantly after ISO treatment for 2 weeks; compared with the model control group, the positive control group, ISO+NADPH 1 mg/kg group, ISO+NADPH 2 mg/kg Heart HWI and LVWI were significantly lower in the group and ISO+NADPH 4 mg/kg group; this indicates that NADPH can effectively alleviate ISO-induced cardiac hypertrophy in mice.
- the QRS complex reflects the changes in potential and time during the depolarization of the left and right ventricles. In the left ventricular hypertrophy, the QRS complex voltage increased in the electrocardiogram and the wave group time prolonged.
- the effect of NADPH on ISO-induced changes in electrocardiogram in mice is shown in Figures 3(a) and 3(b).
- the QRS amplitude of the model control group was significantly higher than that of the normal control group, indicating that the left ventricular hypertrophy occurred in the mice; the positive control group, ISO+NADPH 1 mg/kg group, ISO+NADPH 2 mg The QRS wave voltage of the mice in the /kg group and the ISO+NADPH 4 mg/kg group decreased; this indicates that NADPH has ameliorating effect on cardiac hypertrophy.
- systolic left ventricular diameter LVIDs
- diastolic left ventricular diameter LVIDd
- left ventricular end systolic volume LV Vols
- the left ventricular end-diastolic volume (LV Vold) was significantly increased, while the ejection fraction (EF) and left ventricular short-axis shortening rate (FS) were significantly reduced; this indicates that the model control group developed left ventricular hypertrophy and heart.
- Na+-K+-ATPase relies on ATP to allow Na + efflux and K + influx to maintain Na + and K + levels inside and outside the cell;
- Ca 2+ -Mg 2+ -ATPase relies on ATP to pump intracellular Ca 2+ to The sarcoplasmic reticulum or extracellular to maintain intracellular calcium homeostasis.
- the effect of NADPH on ATPase content in myocardial tissue of mice is shown in Figure 5.
- NADPH can alleviate the pathological changes of myocardial hypertrophy in mice and alleviate cardiac hypertrophy; (2) NADPH can increase Na + -K + -ATPase and Ca 2+ -Mg 2 in myocardial tissue of mice + -ATPase and total ATPase activity to maintain intracellular ionic homeostasis.
- Animal feeding environment room temperature 22 ° C, humidity 50-60%, good ventilation, artificial day and night (12h / 12h), free access to food and water;
- Non-invasive blood pressure detection system Karl Scientific, CODA20496.
- the blood pressure of non-invasive tail artery was measured in rats.
- the blood pressure of awake rats was measured by volumetric pressure recording sensor.
- the rats were kept for 2 days.
- the blood pressure of the rats was measured by non-invasive blood pressure detection system.
- the experimental environment was quiet and constant, and the adaptive training started 3 days later.
- Formal experiment. Divided into two groups: saline group; NADPH 10mg/kg group. Two rats were tested in each experiment.
- the baseline blood pressure was measured first. After the basal blood pressure was stable, one intravenous saline was injected at 2 mL/kg, and the other intravenously was administered with 0.5% NADPH 2 mL/kg.
- the intravenous drug was recorded for 30 min, 60 min. Blood pressure after 90 min and 120 min.
- NADPH had no significant effect on blood pressure in normal rats.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne l'utilisation du NADPH dans la préparation d'un médicament destiné à traiter l'hypertrophie cardiaque et l'insuffisance cardiaque. Le NADPH permet d'améliorer l'activité d'une enzyme Na+-K+-ATP, d'une enzyme Ca2+-Mg2+-ATP et d'une enzyme ATP totale dans le tissu myocardique murin ; en outre, le NADPH n'a pas d'influence flagrante sur la tension artérielle chez le rat normal, et provoque moins de réactions secondaires pendant le traitement de l'insuffisance cardiaque et de l'hypertrophie cardiaque.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710093339.4A CN106902131A (zh) | 2017-02-21 | 2017-02-21 | Nadph在制备治疗心肌肥厚与心力衰竭的药物中的应用 |
CN201710093339.4 | 2017-02-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2018152996A1 true WO2018152996A1 (fr) | 2018-08-30 |
Family
ID=59208816
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2017/090157 WO2018152996A1 (fr) | 2017-02-21 | 2017-06-27 | Utilisation du nadph dans la préparation d'un médicament destiné à traiter l'hypertrophie cardiaque et l'insuffisance cardiaque |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN106902131A (fr) |
WO (1) | WO2018152996A1 (fr) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111202745B (zh) * | 2020-03-06 | 2021-09-10 | 广东药科大学 | Fad在制备抑制或治疗心血管系统疾病药物中的应用 |
CN113917156A (zh) * | 2021-09-30 | 2022-01-11 | 复旦大学附属中山医院 | Hint2在制备治疗或诊断心力衰竭药物中的用途 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104840479A (zh) * | 2015-02-17 | 2015-08-19 | 苏州人本药业有限公司 | Nadph在制备治疗心脏疾病药物中的应用 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110190373A1 (en) * | 2008-05-05 | 2011-08-04 | University Of Rochester | Methods and compositions for the treatment or prevention of pathological cardiac remodeling and heart failure |
-
2017
- 2017-02-21 CN CN201710093339.4A patent/CN106902131A/zh active Pending
- 2017-06-27 WO PCT/CN2017/090157 patent/WO2018152996A1/fr active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104840479A (zh) * | 2015-02-17 | 2015-08-19 | 苏州人本药业有限公司 | Nadph在制备治疗心脏疾病药物中的应用 |
Also Published As
Publication number | Publication date |
---|---|
CN106902131A (zh) | 2017-06-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Ferrannini et al. | Metabolic and hemodynamic effects of insulin on human hearts | |
Forfia et al. | Acute phosphodiesterase 5 inhibition mimics hemodynamic effects of B-type natriuretic peptide and potentiates B-type natriuretic peptide effects in failing but not normal canine heart | |
Cheng et al. | Increase of myocardial performance by Rhodiola–ethanol extract in diabetic rats | |
CN108348481A (zh) | 贝壳杉烷类化合物在治疗心肌肥厚和肺动脉高压的药物应用 | |
JP2022523821A (ja) | 急性心不全(ahf)の治療のためのイスタロキシム含有静脈用製剤 | |
WO2018152996A1 (fr) | Utilisation du nadph dans la préparation d'un médicament destiné à traiter l'hypertrophie cardiaque et l'insuffisance cardiaque | |
Qiu et al. | Therapeutic effect of astragaloside-IV on bradycardia is involved in up-regulating klotho expression | |
He et al. | Protective effects of hydroxysafflor yellow A on acute and chronic congestive cardiac failure mediated by reducing ET-1, NOS and oxidative stress in rats | |
CN110876798A (zh) | 卡泊芬净在制备治疗缺血/再灌注损伤药物中的应用 | |
CN106176703A (zh) | 丹酚酸a在制备预防和/或治疗肺动脉高压中的药物用途 | |
Schmieder et al. | OS 12-03 SGLT-2-inhibition with dapagliflozin reduces tissue sodium content | |
Lin et al. | Ginseng is useful to enhance cardiac contractility in animals | |
CN101070338A (zh) | 丹参酮ⅱa磺酸钾用于制备预防和治疗心肌缺血缺氧、脑缺血缺氧的药物 | |
CN117257803A (zh) | 鲁拉西酮在制备治疗或预防缺血/再灌注损伤的药物和细胞保护药物中的应用 | |
WO2016131320A1 (fr) | Utilisation de nadph pour la préparation d'un médicament indiqué pour le traitement de maladies cardiaques | |
CN109010797B (zh) | 一种Tat-SPK2肽防治心肌肥厚或心力衰竭的应用 | |
CN101991573A (zh) | 去氢钩藤碱及其异构体在制备药物中的用途 | |
CN106214680A (zh) | 一种血管紧张素受体拮抗剂和左西孟旦的复合物及其用途 | |
CN108524484A (zh) | 乙酸橙花酯在制备抗高血压心肌纤维化药物中的应用 | |
CN102218134A (zh) | 左型精氨酸-葡萄糖-胰岛素-氯化钾组合物及其应用 | |
CN107056877A (zh) | 一种甾体类化合物及其用途 | |
CN116919943A (zh) | 葛根素晶v型物质用于预防治疗糖尿病心肌病的用途 | |
CN1330311C (zh) | 3,4’,5-三羟基茋-3-β-D-葡萄糖甙在抗心肌缺血药物制备中的用途 | |
Kagota et al. | PS-BPB09-4: ARTERIAL SITES AND SEX DIFFERENCES IN ENHANCING VASORELAXATION RESPONSE BY PERIVASCU-LAR ADIPOSE TISSUE IN METABOLIC SYNDROME RATS | |
Miheeva et al. | Treatment of portal hypertensia by beta-blockers and ACE-inhibitors in patients sick of cirrhosis and arterial hypertension |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 17897985 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 17897985 Country of ref document: EP Kind code of ref document: A1 |