CN114699401A - Application of isorhamnetin in preparation of thoracic aorta vasodilation drugs - Google Patents
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- CN114699401A CN114699401A CN202210292311.4A CN202210292311A CN114699401A CN 114699401 A CN114699401 A CN 114699401A CN 202210292311 A CN202210292311 A CN 202210292311A CN 114699401 A CN114699401 A CN 114699401A
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- 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
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- 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
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- 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
- A61P9/08—Vasodilators for multiple indications
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- 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
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- 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
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- 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
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Abstract
The invention provides an application of isorhamnetin in preparing a thoracic aorta vasodilation medicament and a corresponding medicament composition, in particular an application in treating cardiovascular and cerebrovascular diseases accompanied with endothelial injury, such as angina pectoris and hypertension. The invention discloses that isorhamnetin applied to isolated thoracic aortic annulus of PE pre-contracted rat has obvious expansion effect. The isorhamnetin serving as a thoracic aorta vasodilator has the characteristics of high efficiency, low toxicity and the like, and can be particularly used for preventing and treating cardiovascular and cerebrovascular diseases such as angina, general hypertension, heart failure and the like.
Description
Technical Field
The invention relates to a new application of a compound isorhamnetin, and particularly provides an application of isorhamnetin in preparation of a thoracic aorta vasodilator and a corresponding pharmaceutical composition.
Background
Chronic diseases with great harm to human health are called main chronic diseases, including cardiovascular and cerebrovascular diseases, malignant tumors, chronic respiratory diseases and diabetes. Cardiovascular and cerebrovascular diseases are the general names of cardiovascular and cerebrovascular diseases, which generally refer to ischemic or hemorrhagic diseases of heart, brain and systemic tissues caused by hyperlipidemia, blood viscosity, atherosclerosis, hypertension, etc., and mainly include coronary heart diseases, such as sudden death of coronary heart disease, myocardial infarction, angina pectoris, and coronary insufficiency; cerebrovascular diseases, such as ischemic stroke, hemorrhagic stroke, and transient cerebral ischemia. Cardiovascular and cerebrovascular diseases are common diseases seriously threatening the health of human beings, especially the middle-aged and old people over 50 years old, have the characteristics of high morbidity, high disability rate and high mortality rate, and live at the first position of various causes of death. The national health and health committee indicates that the annual average treatment cost of the cardiovascular and cerebrovascular diseases in China is up to 6000 billions of yuan, and the cardiovascular and cerebrovascular diseases become the main disease burden of residents in China. Therefore, it is very important to find a convenient and easily available medicament with low price for effectively treating cardiovascular and cerebrovascular diseases.
The thoracic aorta is a main channel for pumping blood out of the heart, the contraction, stenosis and lesion of the thoracic aorta are important causes of diseases such as pulmonary hypertension, general hypertension, cerebral arterial thrombosis and the like, the use of the thoracic aorta vasodilator is also an important method for treating the diseases, the conventional thoracic aorta vasodilators such as calcium ion antagonist, prostacyclin and the like have defects in drug effect and side effect, and the need of developing novel high-efficiency and low-toxicity thoracic aorta vasodilators and medical related diseases, particularly angina pectoris, general hypertension and heart failure, is existed in the field.
There are two major calcium channels in vascular smooth muscle, receptor-operated calcium channel (ROC) voltage-dependent calcium channel (VDC), which are activated by PE and KC1 at high concentration, respectively, to allow the influx of extracellular calcium ions, resulting in vasoconstriction. KC1 allows the influx of extracellular calcium ions by activating voltage-dependent calcium channels, thereby contracting blood vessels. PE causes the influx of extracellular calcium ions and the release of intracellular calcium ions by activating receptor-operated calcium channels, thereby contracting blood vessels.
At present, drugs for dilating blood vessels are classified into endothelium-dependent drugs and endothelium-independent drugs, and the clinically commonly used drugs are all endothelium-dependent vasodilators, such as Angiotensin Converting Enzyme Inhibitors (ACEI), HMG-COA reductase inhibitors, angiotensin II receptor blockers (ARB), Endothelin Receptor Antagonists (ERA), l-arginine, receptor blockers, etc., which have poor therapeutic effects on cardiovascular diseases patients with impaired vascular endothelial function. Therefore, the search for non-endothelium dependent vasodilators is of great clinical interest.
The mechanism of action of the endothelium-independent drugs is mainly associated with k+Channel correlation, k+The channels play an important role in regulating the processes of relaxation and contraction of vascular smooth muscle. After potassium channels are activated, hyperpolarization of the cell membrane is induced, resulting in Ca2+The channels are closed and Ca is reduced2+Influx, thereby dilating the blood vessel.
Isorhamnetin (Isorhamnetin, Iso, systematic name is 3,5, 7-trihydroxy-2- (4-hydroxy-3-methoxyphenyl) benzopyran-4-ketone) is a flavonoid compound separated and purified from medicinal plants such as ginkgo, sea buckthorn and the like, and is also widely present in flowers, fruits and leaves of other various plants. Most studies show that isorhamnetin can play a role in protecting the cardiovascular system and the liver, and whether the function of protecting the cardiovascular system is related to vasodilation or not is not reported.
Disclosure of Invention
In one aspect, the application provides the use of isorhamnetin in the preparation of a thoracic aortic vasodilation medicament
Further, the thoracic aorta vasodilator is a drug for treating angina.
Further, the thoracic aorta vasodilator is a drug for treating hypertension.
Further, the thoracic aortic vasodilator is a drug for dilating thoracic aortic blood vessels.
Furthermore, the medicine is used for treating cardiovascular and cerebrovascular diseases.
In another aspect, the invention also provides a thoracic aorta vasodilator drug, which comprises isorhamnetin as an active ingredient.
Further, the medicament is used for treating angina pectoris, hypertension, or for thoracic aortic vasodilation.
Further, the isorhamnetin in the medicine is an endothelial dependent medicine and an endothelial independent medicine.
Further, the medicine is a medicine for treating cardiovascular and cerebrovascular diseases accompanied with endothelial injury.
The isorhamnetin has the effect of endothelium-independent vasodilatation, has high sensitivity, has excellent curative effect on cardiovascular and cerebrovascular diseases accompanied with endothelium injury, and has important clinical significance for treating the cardiovascular and cerebrovascular diseases.
Further, the medicine is in an oral or injection dosage form.
Further, the medicine also comprises pharmaceutic adjuvants.
The available dosage forms of the application include but are not limited to injections such as injection, powder injection and the like, oral preparations such as tablets, capsules, oral liquid and the like, throat or nasal sprays, external preparations such as ointments, sprays, patches and the like; preferably injection and oral preparation. The medicine can also contain other medicines for dilating thoracic aorta blood vessel, treating angina pectoris and ischemic cerebral apoplexy, or be combined with these medicines; that is, different drugs in other therapeutic combinations can be prepared into the same formulation; may also be provided in the same package in the same or different dosage forms; or in the same or different dosage forms in separate packages.
Those skilled in the art can select suitable excipients for the drugs to which this application relates based on general knowledge in the pharmaceutical arts, and the classes of excipients that can be used include, but are not limited to, solvents, cosolvents, stabilizers, dispersants, viscosity modifiers, antioxidants, sweeteners, binders, gas generants, and the like.
The chemical name of isorhamnetin described in this application is 3,5, 7-trihydroxy-2- (4-hydroxy-3-methoxyphenyl) chromen-4-one.
Advantageous effects
The invention firstly indicates that isorhamnetin can obviously expand a thoracic aorta vascular ring, and firstly proposes that the relaxation of the isorhamnetin is endothelium-independent with concentration dependence. The invention provides clues for the isorhamnetin to develop a new medicine for treating cardiovascular and cerebrovascular diseases.
Secondly, the existing chest aorta vasodilators such as calcium ion antagonist, prostacyclin and the like have defects in drug effect and side effect, and the isorhamnetin serving as the chest aorta vasodilator has the characteristics of high efficiency, low toxicity and the like, and can be particularly used for preventing and treating cardiovascular and cerebrovascular diseases such as angina, general hypertension, heart failure and the like.
Drawings
FIG. 1: effects of Iso on the basal tension endothelial intact thoracic aortic vascular ring.
FIG. 2: effect of Iso on PE pre-contracted endothelial intact thoracic aortic vascular ring.
FIG. 3: the effect of Iso on PE pre-constriction to remove the endothelial thoracic aortic vascular ring.
Detailed Description
The present invention will be further specifically described below in connection with animal experiments.
Experimental materials:
animals: SPF Sprague Dawley (SD) rats, male, with a body weight of 220-330g, provided by Ningxia university of medicine animal center, animal qualification number: SCXK 2015-0001. Animals are kept in an environment with proper temperature and humidity, and can freely take food and drink water.
Drugs and reagents:
isorhamnetin (English, Isorhamnetin, Shanghai leaf Biotech Co., Ltd., CAS: 480-19-3), phenylephrine (English, PE, Shanghai Hefeng pharmaceutical Co., Ltd., batch No. 07150801); acetylcholine chloride (English, ACh, Beijing Solebao science and technology Co., Ltd., batch No. 601H 013); sodium bicarbonate (approval No. XK 13-011 and 00027 from Dache chemical reagent factory, Tianjin); potassium chloride (Hangzhou national pharmaceutical Co., Ltd., approval No. H33021574); glucose (approval number: XK 13-201-; calcium chloride (mao chemical reagent, penguin, Tianjin); monopotassium phosphate (Beichen Zhengji reagent factory, Tianjin City, lot number: 20150626); magnesium sulfate heptahydrate (mao chemical reagent factory, Tianjin, enterprise logo); sodium chloride (approval No. XK 13-011-; the water is double distilled water.
Preparing K-H nutrient solution by adding 0.35g KCl and 0.29g MgSO into 1000ml double distilled water respectively4·7H2O、0.28g CaCl2、0.16g KH2PO42.0g glucose, 6.92g NaCl, 2.21g NaHCO3In a beaker, stir until the drug is completely dissolved. Prepared just before use by using 10mmol L-1Adjusting the pH value to 7.4 by NaOH, and storing in a constant-temperature water bath at 37 ℃ for later use.
The instrument comprises the following steps:
HV1403 constant temperature perfusion system of isolated tissue organs (Chengtai Union software Co., Ltd.); BL-420S biological function experimental system (Chengdutai union software Co., Ltd.); model HW-500 super constant temperature water bath (Gengtai alliance software Co., Ltd.).
Example 1 preparation of isolated rat thoracic aortic vascular Ring
Taking an SPF healthy SD male rat with the weight of 220-2+5％CO2) Carefully removing fat and connective tissues around blood vessels from K-H liquid of the mixed gas, and shearing the blood vessels into blood vessel rings with the length of 3-4 mm. And preparing a part of the vascular ring into an endothelial removal model by adopting a method of rubbing the inner surface of the vascular ring with a cotton swab. Suspending the vascular ring in a bath containing K-H solution preheated at 37 deg.CIn the groove, one end is fixed, the other end connects the tension transducer with the biological signal acquisition system, and the tension transducer is continuously communicated with 95 percent of O2And 5% CO2Mixing gas, adjusting base tension to 2.0g, stabilizing for 60 min, changing solution 1 time every 20 min, and administering KCl (60 mmol. L)-1) Stimulating to reach peak value, flushing with K-H solution for 3 times, and allowing the blood vessel ring to reach maximum contraction amplitude. Warp PE (10)-6mol·L-1) After the tension of the preshrinked vascular ring is stabilized, Ach (10 mu mol/L) is added, and if the vasodilation reaches more than 80 percent, the endothelium can be considered to be complete. If the vasodilation is less than 10%, de-endothelialization may be considered.
Example 2 methods of observation and study
Observing the influence of isorhamnetin on the vascular ring tension of the basic state:
an endothelial intact vascular ring was taken and divided into a blank control group and an Iso administration group. After stabilization, add Iso cumulatively every 5min to increase the final concentration to 1 × 10-4、1.9×10-4、3.98×10-4、7.9×10-4、1.5×10-3mol/L; the blank control group was added with an equal volume of DMSO solution, and the change in the tension thereof was observed, and the relaxation rate (%) was calculated as the vasodilation amplitude of the blood vessel ring after liquiritin was added/the maximum ring contraction amplitude of PE-induced blood vessel x 100%. The effect of cumulative administration of Iso on the base tension vascular ring was explored.
Observe the effect of isorhamnetin on PE pre-systolic vascular ring tension:
an endothelial intact vascular ring was taken and divided into a blank control group and an Iso administration group. Warp PE (10)-6mol/L) after the pre-shrinkage is stable, adding Iso cumulatively every 5min to increase the final concentration to 1 × 10-4、1.9×10-4、3.98×10-4、7.9×10-4、1.5×10-3mol/L; the blank control group is added with an equal volume of DMSO solution, the change of the tension is observed, and the relaxation rate is calculated by the same method. The effect of cumulative administration of Iso on PE pre-contractile endothelial integrity was explored.
Endothelial vascular rings were removed and divided into blank control and Iso dosing groups. Warp PE (10)-6mol/L) after the pre-shrinkage is stable, adding Iso cumulatively every 5min to make the final concentration graduallyIncreased to 1 × 10-4、1.9×10-4、3.98×10-4、7.9×10-4、1.5×10-3mol/L; the blank control group was added with an equal volume of DMSO solution, and the change in the tension was observed to calculate the diastolic rate, which was calculated as above. The effect of cumulative administration of Iso on PE pre-contracting the de-endothelialised vascular ring was explored.
Example 3 results of the experiment
Experimental data are expressed as mean ± standard deviation and analyzed using SPSS26.0 statistical software. The comparison between the two groups was performed using independent samples t test, and P <0.05 indicated that the difference was statistically significant.
Effect of accumulated concentration of Iso on basal state vascular ring tone:
FIG. 1 shows that Iso is at the base state, 1X 10-4-1.5×10-3The tension of the thoracic aorta vascular ring with complete endothelium is not obviously affected within the mol/L concentration range, P is more than 0.05, and the difference has no statistical significance.
Effect of cumulative concentrations of LQ on PE pre-systolic vascular ring tone:
FIG. 2 shows that Iso is at 1X 10-4-1.5×10-3The dilating effect on the endothelial intact PE preshrinked thoracic aorta vascular ring is achieved within the mol/L concentration range, and the dilating effect is remarkably different from that of a control group, wherein P is less than 0.05.
FIG. 3 shows that Iso is at 1X 10-4-1.5×10-3The blood vessel ring of the thoracic aorta pre-contracted by the PE with the endothelium removed has the relaxation effect within the mol/L concentration range, and has obvious difference compared with a control group, wherein P is less than 0.05.
Claims (12)
1. The application of isorhamnetin in preparing thoracic aorta vasodilation medicines is disclosed, wherein the molecular structural formula of the isorhamnetin is shown as a formula (I):
2. the use according to claim 1, wherein the thoracic aortic vasodilator drug is a drug for the treatment of angina.
3. The use of claim 1, wherein the thoracic aortic vasodilator drug is a drug for the treatment of hypertension.
4. The use of claim 1, wherein the thoracic aortic vasodilator drug is a drug that dilates thoracic aortic vessels.
5. The use according to any one of claims 1 to 4, wherein the medicament is a medicament for the treatment of cardiovascular and cerebrovascular diseases.
6. The use according to claim 5, wherein the medicament is a medicament for treating cardiovascular and cerebrovascular diseases accompanied by endothelial injury.
7. The use according to any one of claims 1 to 6, wherein the cardiovascular and cerebrovascular disease is angina pectoris, heart failure, pulmonary hypertension, coronary heart disease, cerebral stroke and/or peripheral vasospastic disease.
8. A thoracic aortic vasodilator comprising isorhamnetin as an active ingredient.
9. The medicament according to claim 8, wherein the medicament is for the treatment of angina pectoris, heart failure, or for chest aortic vasodilation, preferably accompanied by endothelial damage.
10. The medicament of claim 8 or 9, wherein isorhamnetin in the medicament is capable of relaxing the vascular ring pre-contracted by PE or KCl.
11. The medicament or use according to any one of claims 1 to 10, wherein the medicament is in an oral or injectable dosage form.
12. The medicament or use according to claim 11, wherein the medicament further comprises a pharmaceutical excipient.
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| CN202210292311.4A CN114699401A (en) | 2022-03-22 | 2022-03-22 | Application of isorhamnetin in preparation of thoracic aorta vasodilation drugs |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024032710A1 (en) * | 2022-08-11 | 2024-02-15 | Ubi Pharma Inc. | Method against snake envenomation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103239436A (en) * | 2013-04-24 | 2013-08-14 | 中国医学科学院药用植物研究所 | Application of isorhamnetin to preparing drugs for adriamycin adjuvant therapy |
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- 2022-03-22 CN CN202210292311.4A patent/CN114699401A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103239436A (en) * | 2013-04-24 | 2013-08-14 | 中国医学科学院药用植物研究所 | Application of isorhamnetin to preparing drugs for adriamycin adjuvant therapy |
Non-Patent Citations (1)
| Title |
|---|
| 赵增光等: "异鼠李素对大鼠主动脉环的舒张作用", 《泸州医学院学报》, vol. 33, no. 5, pages 494 - 497 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024032710A1 (en) * | 2022-08-11 | 2024-02-15 | Ubi Pharma Inc. | Method against snake envenomation |
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