CN111759830A - Medicine for treating atherosclerosis and protecting blood vessel, preparation method and application - Google Patents
Medicine for treating atherosclerosis and protecting blood vessel, preparation method and application Download PDFInfo
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- CN111759830A CN111759830A CN202010798705.8A CN202010798705A CN111759830A CN 111759830 A CN111759830 A CN 111759830A CN 202010798705 A CN202010798705 A CN 202010798705A CN 111759830 A CN111759830 A CN 111759830A
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- zedoarondiol
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/906—Zingiberaceae (Ginger family)
- A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
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Abstract
The invention discloses a medicament for preventing and treating atherosclerosis and protecting blood vessels, which takes guaiane type sesquiterpene medicament Zedoarondiol extracted from traditional Chinese medicine zedoary (Curcuma zedoaria/Christm.Rosc) or artificially synthesized as an effective component and has a definite chemical molecular structural formula. The invention adopts modern technology, has stable quality and high content, is completely made of natural plants, protects the environment, and has no toxic or side effect on human body after continuous use. The medicine is guaiane type sesquiterpene natural product easy to be absorbed by human body, is suitable for treating dyslipidaemia and atherosclerosis, and treating vascular endothelial disorder caused by atherosclerosis, and has effects of regulating lipid metabolism, stabilizing plaque, and preventing and treating coronary heart disease.
Description
Technical Field
The invention relates to the field of anti-atherosclerosis medicines, in particular to a medicine for treating atherosclerosis and protecting blood vessels, a preparation method and application thereof.
Background
The related documents report that the incidence of ischemic heart disease and cerebral apoplexy of urban and rural people is obviously increased, which indicates that the incidence of ischemic cardiovascular diseases (including coronary heart disease and ischemic cerebral apoplexy) based on atherosclerosis is increased year by year. Cardiovascular diseases become the first cause of death of urban and rural people in China, the cardiovascular diseases in China are characterized by low incidence of coronary heart disease due to high stroke, but the incidence and mortality of coronary heart disease gradually rise in more than 20 years, and the queue research in China shows that the rise of serum Total Cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) is one of the independent risk factors of coronary heart disease and ischemic stroke.
Traditional Chinese medicine does not have corresponding disease names of atherosclerosis, and generally belongs to the categories of chest stuffiness, cardiodynia, angina pectoris, stroke and the like, and the basic pathogenesis is mainly phlegm, stasis and deficiency. Modern medical research shows that the formation and development process of atheromatous plaques is always accompanied by inflammatory reaction, and the inflammatory reaction is closely related to phlegm, stasis and deficiency in traditional Chinese medicine. The existence of healthy qi in the interior, failure of pathogenic qi to dry, deficiency, which is the basis of the occurrence of inflammatory reaction, is not able to bulge out normally due to the failure of healthy qi to promote and lift the body and the inability to promote and lift the body.
Rhizoma Curcumae (Rhizoma Curcumae) is dried rhizome of Curcuma zedoaria (Curcuma zedoaria) Val. of the family Monocotyledon, Curcuma zedoaria (Curcuma zedoaria) C.wenyujin Y.H.Chen et C.Ling, and Curcuma kwangsiensis C.kwangsiensis S.lee et C.F.Liang. Has the effects of breaking blood, promoting qi circulation, removing blood stasis and relieving pain.
In the related art, the extract in the zedoary is used for preventing and treating vascular restenosis, but a plurality of compounds in a specific ratio in the extract need to be combined, and a vascular stent is needed to ensure that the medicament can directly enter human circulation from menstrual blood to achieve the effect. In contrast, if gastrointestinal administration is used, it is likely that a good effect of preventing and treating vascular restenosis cannot be achieved because absorption is required as compared with blood administration. In addition, at present, the compound in the zedoary has not been reported to be used as an anti-atherosclerosis oral preparation.
Disclosure of Invention
The invention aims to provide a medicament for treating atherosclerosis and protecting blood vessels, a preparation method and application thereof, which can be orally taken and have good effects of resisting atherosclerosis and improving endothelial functions.
In order to solve the above problems, in a first aspect, an embodiment of the present invention provides an agent for treating atherosclerosis and protecting blood vessels, wherein the agent comprises Zedoarondiol as an active ingredient, and the molecular formula of the agent is:
further, the animal dosage of the Zedoarondiol is 10 mg/kg-d to 50 mg/kg-d.
Further, the animal dose of Zedoarondiol is 20 mg/kg. d.
In a second aspect, the present invention provides the use of the guaiane-type sesquiterpene compound Zedoarondiol for the preparation of a medicament for the treatment of atherosclerosis and for the protection of blood vessels.
Further, the preparation prepared from the guaiane type sesquiterpene compound Zedoarondiol is tablets, sustained-release tablets, dropping pills, oral liquid, granules, capsules, soft capsules, granules or soft extracts.
Further, in the application, the animal dosage of the Zedoarondiol is 10 mg/kg-d to 50 mg/kg-d.
Further, in the application, the animal dosage of the Zedoarondiol is 20 mg/kg-d.
In a third aspect, the embodiments of the present invention provide a method for preparing the above medicament for treating atherosclerosis and protecting blood vessels, including:
(1) firstly, extracting curcuma zedoary powder in water bath, and centrifuging an extraction sample liquid pipeline to obtain a centrifugal extracting solution;
(2) then, carrying out ultrafiltration separation on the centrifugal extracting solution to obtain ultrafiltration permeating liquid and ultrafiltration trapped fluid;
(3) then carrying out nanofiltration concentration on the ultrafiltration permeating liquid to obtain nanofiltration liquid;
(4) and finally, carrying out chromatographic purity analysis and nuclear magnetic resonance structure comparison on the nanofiltration solution to obtain the guaiane type sesquiterpene compound Zedoarondiol serving as the effective component of the medicament for treating atherosclerosis and protecting blood vessels.
Through comparative research on a plurality of effective components of curcuma zedoary, the inventor finds that the guaiane type sesquiterpene compound Zedoarondiol serving as the effective component of the medicament for treating atherosclerosis and protecting blood vessels not only reduces the formation of porridge plaques, but also protects the endothelial function of the blood vessels, improves the movement rate of leukocytes in microcirculation, the adhesion of leukocytes and the endothelium and other inflammatory states, and confirms that the composition has good effects of resisting porridge and improving the endothelial function. The active ingredients are single, complex compatibility and proportion are not needed, and the components are simplified while good absorption effect and treatment effect are still maintained.
Drawings
FIG. 1 is a chromatogram for preparing Zedoarondiol as guaiane-type sesquiterpene compound in the medicine provided by the embodiment of the invention;
FIG. 2 is a diagram of the molecular formula of Zedoarondiol as a guaiane sesquiterpene compound;
FIG. 3 is a graph showing the results of the effect of groups on the number of full aortic plaques in mice;
FIG. 4 is a graph showing the results of the effect of groups on the formation of plaques in the aortic root of mice;
FIG. 5 is a graph showing the results of the effect of groups on the rate of leukocyte movement and leukocyte-endothelial adhesion in mice;
FIG. 6 is a graph showing the results of the effect of groups on the vasodilatory function of mouse blood vessels.
Detailed Description
The principles and spirit of the present invention will be described with reference to a number of exemplary embodiments shown in the drawings. It should be understood that these embodiments are described only to enable those skilled in the art to better understand and to implement the present invention, and are not intended to limit the scope of the present invention in any way.
1. Preparation of zedoary turmeric guaiane type sesquiterpene medicine-P3
1.1 extraction of the extract of Zedoariae rhizoma
The preparation and extraction are carried out by weighing 2kg of curcuma zedoary block-shaped powder and extracting in two batches. Adding 10L of the extract 1kg each time, rotating in 95 deg.C water bath for 2 hr, and extracting for 3 times. The extracted samples were combined, centrifuged through a tube at about 43.5L, and 50mL of each sample was analyzed.
Ultrafiltering, adding 43.5L of centrifugal extractive solution into No. 4 stock solution tank of membrane separation apparatus, and ultrafiltering (hollow fiber membrane UF, model PS06, membrane area 4.0M)2Number 09-0114), obtaining about 43L of ultrafiltration permeating liquid (because water is not discharged before ultrafiltration), and respectively taking 50mL of ultrafiltration trapped fluid 3.5L and analyzing.
Nanofiltration concentration, nanofiltration (200MW), alcohol-resistant roll-type membrane, number: 8156426. adding 43L of ultrafiltrate permeate into a nanofiltration instrument, adjusting the frequency to 20Hz and the pressure of a liquid outlet to 0.5MPa to obtain 3.9L of nanofiltration retentate and 40.1L of nanofiltration permeate, and respectively taking 50mL of retentate and analyzing.
1.2 preparation of Curcumane sesquiterpene drugs
Preparative chromatography # 4, column: X1-Z01, 480g, column size: 50X 400mm, column volume of about 500mL, number 4#, flow rate of 125mL/min, every 2 minutes collect 1 bottle.
Activating: 95% ethanol, 3 times of column volume, namely 1500mL, needs 12min, and the pressure is 2.7 MPa;
balancing: water, 2 times the column volume, i.e. 1000 mL/l, requires 8min and the pressure is 2.2 MPa;
③ sample loading: the nanofiltration solution is 1.9L, which needs 25min, the pressure is very high, and the membrane is frequently changed (when the second needle is prepared, the nanofiltration solution is filtered by a microporous filter membrane (0.45) and then is loaded).
Leaching: 20% ethanol, 3 times column volume, namely 1500mL, requires 12min, the pressure is 3.2MPa, and the numbers are F13-F18.
1.3 Peak P3 preparation (F16 sample)
Sample preparation: 350mg of zedoary F16 sample is dissolved in 20mL of water with the concentration of about 17mg/mL, and water membrane filtration is carried out.
Preparation conditions, chromatographic column: c18HC (20X 250mm, 10m, 12041901A); flow rate: 20 mL/min.
A detector: 275nm, 240nm, sample size: 1mL, see Table 1.
TABLE 1 Peak P3 preparative elution conditions
Purity analysis and structural characterization of P3
1.4.1 chromatographic purity analysis
The instrument comprises the following steps: alliance 6; a chromatographic column: c18TDE (4.6X 150mm, 5m, 110517-5), flow rate at 30 ℃ of 1 mL/min; detectors, 275nm, 240 nm; sample introduction amount: 50L; elution conditions: gradient elution. See table 2.
TABLE 2 preparative elution conditions for chromatographic purity analysis
1.4.2 structural characterization of P3
Finally, 25.5mg of P3 was obtained. Relative peak area purity analysis results, see table 3.
Compared with the nuclear magnetic data in the literature, the compound is guaiane type sesquiterpene, the P3 is Zedoarondiol, the purity analysis result of the relative peak area shows that the purity of the P3 is 98.44%, the result is shown in figure 1, and the structural formula is shown in figure 2.
TABLE 3 chromatogram of P3
2. Experimental study on curcuma zedoary guaiane type sesquiterpene drug-P3
2.1 Experimental animals
SPF class, male, ApoE-/-Gene-deficient mice, C57BL/6 (normal) mice, 6-8 weeks of age, body mass (18-20) g, animal certification: SCXK (Jing) 2019-.
After 1 week of adaptive feeding, mice were randomized into three groups: model control group (model group); ② a positive control group (atorvastatin calcium tablet group); ③ observe the drug group (group P3); each group comprises 12; another 12 normal C57BL/6 mice were used as normal control groups (normal group).
The normal control group was given ordinary feed, and the other groups were given high-fat feed (Beijing Huafukang biotech GmbH, formulation: 78.6% basal feed, 10% lard, 1% cholesterol, 10% yolk powder, 0.4% bile salt), to establish an atherosclerosis model. According to the literature method, the high-fat feed is generally fed for more than 4 weeks, and the success of the model modeling of the high-fat model is determined by taking the standard that the serum TG, TC and HDL-C levels of the model group are remarkably different from corresponding indexes of a normal control group which is fed with common feed at the same time (P < 0.05). After the molding is successful, the corresponding medicine is administered to each group, the control group is administered with normal saline according to the volume of 1ml/100, the administration of the medicine group is observed to be 20mg/kg, 1 time per day, and the administration is continuously carried out for 8 weeks.
2.2 index selection and detection
2.2.1 mouse blood lipid level detection
The mice are fasted for 12h, blood is taken from the canthus in the eyes after anesthesia, the mixture is kept still for 30min at room temperature, centrifuged for 10min at 3000rpm, and the supernatant is separated and subpackaged for storage at minus 80 ℃ for later use. Serum cholesterol (TG), Triglyceride (TC), high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL) levels were measured separately according to kit instructions.
2.2.2 mouse aorta full-length separation and aorta root frozen section pathological observation
After a mouse is fasted for 12 hours and is subjected to intragastric administration for 1 hour, pentobarbital sodium (50mg/kg) is injected into the abdominal cavity for anesthesia, a small opening is cut at the root of an inferior vena cava, then physiological saline solution is slowly perfused from a left ventricle (about 1-2 ml/min), residual blood in a cardiac blood vessel is washed clean, then 4% paraformaldehyde is replaced to slowly perfuse 10ml from the left ventricle, and a microsurgical instrument is used for stripping fat tissues to separate a heart and an aorta under a body microscope. The following experimental procedures and treatments were carried out following the ethical requirements of the department of science and technology and experimental animals in Beijing.
Fixing the heart embedded with the OCT on a freezing microtome for slicing, continuously slicing by 8 mu m until the valve disappears when the aortic valvular is just appeared by microscopic observation, continuously adsorbing the slices on 8 glass slides, taking out the aortic blood vessel preserved in 20% sucrose solution, rinsing by PBS solution, and trimming to remove the adipose tissue of the blood vessel. Preparing 0.5% oil red O stock solution by using isopropanol, filtering by using a filter membrane, mixing with purified water, and mixing the mixture in a ratio of 3: mixing at ratio of 2, and filtering again. A1 cm ruler is added beside the blood vessel, and a Nikon D5100 camera takes pictures and stores the pictures.
2.2.3 mice aortic root oil Red O staining
Preparing 0.5% oil red O stock solution by using isopropanol, filtering by using a filter membrane, mixing with purified water, and mixing the mixture in a ratio of 3: mixing at ratio of 2, and filtering again. The frozen section of the aortic root is taken out, and 8 aortas are placed in oil red O working solution for staining for 4-6h at room temperature. And (4) counterstaining with hematoxylin for 1-2 min, washing with tap water, and returning to blue. And (5) airing the slices at room temperature, sealing the slices with glycerol gelatin, performing microscopic examination, and taking a picture for recording.
2.2.4 detection of vascular endothelial function in mice
After the mice are anesthetized by pentobarbital sodium, the mice are fixed in a supine position, the abdominal cavity is opened along the median line, the mesenteric vascular bed is separated, the mesenteric vascular bed is placed in PSS buffer solution which is pre-oxygenated for 20 minutes, and a section of three-order mesenteric arteriole with the length of about 3mm is carefully separated under a stereoscopic microscope. Observation of 2M Phenylephrine (PE) pre-contraction followed by 10-10～10-5Vasodilatation reaction caused by M acetylcholine (Ach), and evaluation of the effect of the drug on the function of the vascular endothelium.
The diastolic response to Ach following PE presystraction is expressed as the percentage increase in the outer diameter of the blood vessel: % Relay ═ LD1-LD2)/(LD3-LD2)×100。(LD1For post-vasodilation diameter, LD, after administration of different concentrations of Ach or SNP2To give the PE a pre-contracted vessel diameter, LD3Representing the maximum diastolic diameter of the vessel without any added stimulant).
2.2.5 measurement of leukocyte movement Rate and adhesion amount
Pentobarbital sodium is injected into the abdominal cavity of the mouse for anesthesia, and 3% Rhodamine-6G 100 mu l of fluorescence labeled leucocyte is injected into the sublingual vein. A dynamic visualization microvascular study system (Gene & I-SMC 1) ToupView software was used to collect a 1min leucocyte movement video of each vessel segment. The rate of leukocyte movement and the amount of leukocyte-endothelial cell adhesion reflect the inflammatory status of the blood vessels and are early markers of endothelial dysfunction.
The leucocyte movement rate (the leucocyte movement rate is slow, the inflammatory reaction is generated in the reaction vessel, the leucocyte movement rate is observed after the corresponding medicine is given, and the inhibition effect of the medicine on the inflammatory reaction is reflected), and the leucocyte-endothelial cell adhesion quantity (the leucocyte adhesion quantity is increased, the inflammatory reaction in the vessel is aggravated, and the endothelial dysfunction can be caused).
2.3 statistical treatment
The pictures were analyzed using Image J, Image-Pro Plus software, the area of oil red O stained plaques was in area percent (% Lesion area), and the results of the experiment were expressed as-x + -SEM. T-student tests were performed using Graphpadprism software, and one way-ANOVA parametric analysis of variance or non-parametric LSD-t tests were performed for differences between groups. P <0.05 indicates a statistical difference, and P <0.01 is significantly different.
2.4 results of the experiment
2.4.1 Total aortic plaque number in mice
Experimental study found that P administration3The (20mg/kg) group significantly reduced the full-length aortic plaque area in mice.
The results of the study confirmed that P3Significant reduction of ApoE after 8 weeks of administration-/-Arterial plaque formation in mice was observed in FIG. 3. In FIG. 3, A is the normal group; b is a model group; c is atorvastatin calcium tablet group; d is P3 group, note: p compared to normal group<0.01; comparison with model group, # P<0.01。
2.4.2 mouse aortic root plaque formation
Experimental study on ApoE-/-The aortic root of the heart of the mouse is observed by adopting frozen section oil red O staining, the distribution of a large number of plaques around the aortic root valve of the mouse in the model group is found, and P is given3After 20mg/kg, the plaque area at the valve is obviously reduced, and only a small amount of plaque is accumulated around the valve. The results of the study demonstrated a significant reduction of ApoE 8 weeks after P3 administration-/-Plaques form in the aortic root of the mice, and the results are shown in FIG. 4.
In FIG. 4, A is the normal group; b is a model group; c is atorvastatin calcium tablet group; d is P3 group, note: p <0.01 compared to normal group; compared to the model group, # # P < 0.01.
2.4.3 leukocyte movement Rate and leukocyte-endothelial adhesion
Study focus observation P3Whether a reduction in the number of arterial plaque is associated with a reduction in the intravascular inflammatory response. Therefore, we performed leukocyte movement rate and leukocyte-endothelial adhesion assays, and the results in FIG. 5 show that P3 can increase ApoE-/-The movement rate of the white blood cells in the mesenteric venules of the mice reduces the adhesion quantity of the white blood cells and endothelial cells. The results of the study demonstrate that P3 reduces aortic plaque formation potentially reducing inflammatory response correlation.
In FIG. 5, A is the normal group; b is a model group; c is atorvastatin calcium tablet group; d is P3 group, 1 is leukocyte movement rate; 2. is leukocyte-endothelial adhesion. Note: p <0.01 compared to normal group; compared to the model group, # # P < 0.01.
2.4.4 vasodilation of vascular endothelium
The present invention also observes whether P3 decreased the number of arterial plaque numbers correlates with its improved vasodilation function of the blood vessels. Therefore, the results of the endothelial relaxation function test show that 8 weeks after the administration, the vasodilation degree of the mesenteric small artery endothelium of the model mouse is obviously lower than that of the normal group under the action of different concentrations of Ach (Ach concentration of 10) compared with that of the normal group-8mol/L, the difference between the two is the most significant (P)<0.05); compared with the model group, P3(20mg/kg) has the function of obviously improving the vasodilation function of the vascular endothelium, and is shown in Ach<10-7Degree of relaxation at mol/L and model setThe ratio is significantly different (P)<0.05), the results are shown in fig. 6.
In FIG. 6, A is the normal group; b is a model group; c is atorvastatin calcium tablet group; d is P3 group, note: p <0.01 compared to normal group; compared to the model group, # # P < 0.01.
2.5 conclusion of the experiment
In experimental research of the curcuma zedoary guaiane type sesquiterpene drug-P3, P3 not only reduces the formation of congee plaques, but also can protect the vascular endothelial function, improve the leucocyte movement rate in microcirculation, the adhesion of leucocytes and endothelium and other inflammatory states, and confirm that P3 has good effects of resisting congee and improving the endothelial function.
The invention discloses a medicament for preventing and treating atherosclerosis and protecting blood vessels, which is a guaiane type sesquiterpene medicament-P3 extracted from traditional Chinese medicine curcuma zedoaria/Christm. The invention adopts modern technology, has stable quality and high content, and is completely made of natural plants; also can be artificially synthesized, has high yield, protects the environment, and has no toxic or side effect on human body after continuous use. The medicine is a guaiane type sesquiterpene natural product easily absorbed by human body, is suitable for treating atherosclerosis and dyslipidemia of human body, and treating vascular endothelial disorder caused by atherosclerosis, and has effects of removing blood stasis, promoting qi circulation, relieving pain, regulating lipid metabolism, stabilizing plaque, and preventing and treating coronary heart disease.
The zedoary turmeric guaiane type sesquiterpene drug P3 for treating atherosclerosis and protecting blood vessel can be made into tablet, sustained release tablet, dripping pill, oral liquid, granule, capsule, soft capsule, granule or soft extract.
The inventive concept is explained in detail herein using specific examples, which are given only to aid in understanding the core concepts of the invention. It should be understood that any obvious modifications, equivalents and other improvements made by those skilled in the art without departing from the spirit of the present invention are included in the scope of the present invention.
Claims (6)
1. A medicament for treating atherosclerosis and protecting blood vessels, which comprises Zedoarondiol as an active ingredient, and has a molecular formula as follows:
2. the agent for treating atherosclerosis and protecting blood vessels of claim 1, wherein the animal dose of Zedoarondiol is 10 mg/kg-d to 50 mg/kg-d.
3. The agent for the treatment of atherosclerosis and the protection of blood vessels of claim 2, wherein the animal dose of Zedoarondiol is 20 mg/kg-d.
4. Use of the guaiane type sesquiterpene compound Zedoarondiol in the preparation of a medicament for treating atherosclerosis and protecting blood vessels.
5. The use according to claim 4, wherein the formulation of Zedoarondiol, the guaiane-type sesquiterpene compound, is in the form of a tablet, a sustained release tablet, a drop pill, an oral liquid, a granule, a capsule, a soft capsule, a granule or a soft extract.
6. A method of preparing a medicament for treating atherosclerosis and protecting blood vessels as claimed in claim 1, comprising:
(1) firstly, extracting curcuma zedoary powder in water bath, and centrifuging an extraction sample liquid pipeline to obtain a centrifugal extracting solution;
(2) then, carrying out ultrafiltration separation on the centrifugal extracting solution to obtain ultrafiltration permeating liquid and ultrafiltration trapped fluid;
(3) then carrying out nanofiltration concentration on the ultrafiltration permeating liquid to obtain nanofiltration liquid;
(4) and finally, carrying out chromatographic purity analysis and nuclear magnetic resonance structure comparison on the nanofiltration solution to obtain the guaiane type sesquiterpene compound Zedoarondiol serving as the effective component of the medicament for treating atherosclerosis and protecting blood vessels.
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| CN104188957A (en) * | 2014-05-28 | 2014-12-10 | 中国中医科学院西苑医院 | Medicine for preventing and curing restenosis, and preparation method and using method thereof |
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| CN104188957A (en) * | 2014-05-28 | 2014-12-10 | 中国中医科学院西苑医院 | Medicine for preventing and curing restenosis, and preparation method and using method thereof |
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