CN102091139A - Application of traditional Chinese medicinal composition to preparation of medicaments for improving hypercholesterolemia-induced cardiac dysfunction - Google Patents
Application of traditional Chinese medicinal composition to preparation of medicaments for improving hypercholesterolemia-induced cardiac dysfunction Download PDFInfo
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Abstract
The invention discloses application of a traditional Chinese medicinal composition to preparation of medicaments for improving hypercholesterolemia-induced cardiac dysfunction. The traditional Chinese medicinal composition comprises ginseng, leech, centipede, scorpion, ground beetle, cicada slough, red paeony root, borneol and the like and has the effects of tonifying qi and promoting blood circulation and removing blood stasis and meridian obstruction. A test proves that the traditional Chinese medicinal composition can reduce blood lipid level of a hypercholesterolemia patient, can improve endothelium-dependent vascular dilatation function and vascular flexibility, can enhance application of blood supply capacity from artery to cardiac muscular tissue, can enhance expression of vascular endothelial growth factor (VEGF) genes and protein, and can inhibit angiogenesis of atheromatous plaques so as to effectively improve the hypercholesterolemia-induced cardiac dysfunction.
Description
Technical field
The present invention relates to a kind of new purposes of Chinese medicine composition, particularly, the present invention relates to a kind of Chinese medicine composition and improve application in the cardiac dysfunction medicine that hypercholesterolemia brings out, belong to the Chinese medicine application in preparation.
Background technology
Coronary heart disease has become the major causes of death of the U.S. and other main developed countries at present.Coronary heart disease main hazard factor comprises advanced age, male, hypertension, smoking, diabetes, hypercholesterolemia and family history etc.As everyone knows, atherosclerosis is the main pathologic basis that development takes place coronary heart disease, and as important independent hazard factor, hypercholesterolemia can be brought out atherosclerosis, and can explain the pathogenetic risk of nearly 50% coronary disease.
The first road barrier as blood vessel wall, blood vessel endothelium plays a significant role in keeping the normal blood vessels inner equilibrium by secretion nitric oxide (NO) and Angiotensin II isoreactivity material, but also becomes the main target organ of many atherogenicity risk factor injured blood vessels simultaneously.Previously studies show that chronic hyperlipemia not only can cause the deposition of lipid at artery medicated porridge sample injury region, but also can cause the damage of blood vessel endothelium, thereby promote the atherosclerosis process.In addition, acute myocardial infarction ischemical reperfusion injury and Left Ventricular Remodeling take place mainly owing to microvascular destruction, and microvascular lesions that hypercholesterolemia is brought out and non-narrow property coronary heart disease left ventricular dysfunction are closely related.
Hypercholesterolemia is the most important reason that causes atherosclerosis to take place, and the blood fat reducing treatment has been proved to be the method that the most effective, most economical and safest minimizing coronary heart disease risk and cardiovascular event take place, and to be known as be the pathogenetic basis of prevention coronary disease.Though obtained impressive progress on the understanding of people to vascular endothelium dysfunction and vascular conditions dependency at present, lacked corresponding treatment medicine or means.Traditional medicine has been used several thousand in some country, such as America seal ground peace or China, so herbal mixture is used to improve cardiovascular functional disorder, has special advantages.
The present invention is the improvement invention of carrying out on the basis of No. 01131203.3 and No. 200410048292.2 patent, quotes in full the content of this two patent documents record at this.The application of unexposed this Chinese medicine composition of above-mentioned two patents in improving the cardiac dysfunction that hypercholesterolemia brings out.
Summary of the invention
The object of the invention provides a kind of Chinese medicine composition and improves application in the cardiac dysfunction medicine that hypercholesterolemia brings out in preparation;
Preferably, the present invention also provides the application of this Chinese medicine composition in preparation reduction hypercholesterolemiapatients patients blood lipid level medicine;
Also provide this Chinese medicine composition to improve application in hypercholesterolemiapatients patients endothelium-dependent relaxation vasodilation function and the blood vessel elasticity medicine in preparation;
The application of this Chinese medicine composition in preparation enhancing hypercholesterolemiapatients patients VEGF (VEGF) gene and protein expression medicine also is provided;
The application in the angiogenesis medicament in preparation suppresses the hypercholesterolemiapatients patients atheromatous plaque of this Chinese medicine composition also is provided.
Described Chinese medicine composition is made by following bulk drugs:
Radix Ginseng 3-10 Hirudo 3-11 Eupolyphaga Seu Steleophaga 5-10 Olibanum (system) 1-5 Radix Paeoniae Rubra 3-9 Lignum Dalbergiae Odoriferae 1-5
Lignum Santali Albi 1-5 Scorpio 3-9 Periostracum Cicadae 3-12 Scolopendra 1-3 Borneolum Syntheticum 1-7 Semen Ziziphi Spinosae (stir-fry) 3-10;
Preferably, this Chinese medicine composition is made by following bulk drugs:
Radix Ginseng 6 Hirudo 10 Eupolyphaga Seu Steleophagas, 7 Olibanums (system) 2 Radix Paeoniae Rubra 5 Lignum Dalbergiae Odoriferaes 2
Lignum Santali Albi 2 Scorpios 7 Periostracum Cicadaes 7 Scolopendra 1 Borneolum Syntheticum, 5 Semen Ziziphi Spinosaes (stir-fry) 5;
Or:
Radix Ginseng 10 Hirudo 8 Eupolyphaga Seu Steleophagas, 7 Olibanums (system) 2 Radix Paeoniae Rubra 5 Lignum Dalbergiae Odoriferaes 2
Lignum Santali Albi 2 Scorpios 9 Periostracum Cicadaes 7 Scolopendra 1 Borneolum Syntheticum, 5 Semen Ziziphi Spinosaes (stir-fry) 5;
Or:
Radix Ginseng 6 Hirudo 11 Eupolyphaga Seu Steleophagas, 7 Olibanums (system) 2 Radix Paeoniae Rubra 5 Lignum Dalbergiae Odoriferaes 2
Lignum Santali Albi 2 Scorpios 3 Periostracum Cicadaes 7 Scolopendra 1 Borneolum Syntheticum, 5 Semen Ziziphi Spinosaes (stir-fry) 5;
The active component of above-mentioned Chinese medicine composition is made up of following ingredients:
The a mean diameter is less than Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga, Periostracum Cicadae and the Olibanum (processed) medicated powder of 100 μ m;
B Borneolum Syntheticum medicated powder;
The volatile oil that c is extracted by Lignum Dalbergiae Odoriferae and Lignum Santali Albi;
The alcohol-extracted extract of the alcohol extract of d Radix Ginseng after after concentrating with ethanol extraction;
The water extracted immersing paste that is condensed into behind the water extract after the Lignum Dalbergiae Odoriferae behind the e extraction composition c and water extract, Radix Paeoniae Rubra and the Semen Ziziphi Spinosae (parched) of Lignum Santali Albi medicinal residues decoct with water and the water extract filtration of the medicine residues of Radix Ginseng after the extraction ingredient d, the mixing.
In the Chinese medicine composition of the present invention, as the latin name of the crude drug of active component and processing method thereof from " Chinese medicine voluminous dictionary " (in July, 1977, front page, Shanghai science tech publishing house) and " Chinese pharmacopoeia (version in 2005, Chemical Industry Press).
The invention also discloses that to contain above-mentioned Chinese medicine composition be capsule, tablet, granule, powder, oral liquid or pill as the pharmaceutical preparation of active component.
For above-mentioned dosage form can be realized, need when these dosage forms of preparation, to add the pharmacy acceptable auxiliary, for example: filler, disintegrating agent, lubricant, suspending agent, binding agent, sweeting agent, correctives, antiseptic, substrate etc.Filler comprises: starch, pregelatinized Starch, lactose, mannitol, chitin, microcrystalline Cellulose, sucrose etc.; Disintegrating agent comprises: starch, pregelatinized Starch, microcrystalline Cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose etc.; Lubricant comprises: magnesium stearate, sodium lauryl sulphate, Pulvis Talci, silicon dioxide etc.; Suspending agent comprises: polyvinylpyrrolidone, microcrystalline Cellulose, sucrose, agar, hydroxypropyl emthylcellulose etc.; Binding agent comprises, starch slurry, polyvinylpyrrolidone, hydroxypropyl emthylcellulose etc.; Sweeting agent comprises: saccharin sodium, Aspartane, sucrose, cyclamate, enoxolone etc.; Correctives comprises: sweeting agent and various essence; Antiseptic comprises: parabens, benzoic acid, sodium benzoate, sorbic acid and its esters, benzalkonium bromide, fixed, the Folium eucalypti globueli (Eucalyptus globulus Labill.) wet goods of acetic acid chloroethene; Substrate comprises: PEG6000, PEG4000, insect wax etc.
Capsule of the present invention is preferably made by following preparation method: five kinds of Chinese medicine such as the Hirudo of said ratio, Scorpio, Periostracum Cicadae, Eupolyphaga Seu Steleophaga, Scolopendra cleaned, and oven drying at low temperature, standby; Lignum Santali Albi, Lignum Dalbergiae Odoriferae extract volatile oil, and medicinal residues and aqueous solution are standby; Radix Ginseng extracts secondary with 70% alcohol heating reflux, and 3 hours for the first time, 2 hours for the second time, merge extractive liquid, reclaimed ethanol to there not being the alcohol flavor; The medicinal residues of medicine residues of Radix Ginseng and Lignum Santali Albi, Lignum Dalbergiae Odoriferae merge with aqueous solution, add Radix Paeoniae Rubra, Semen Ziziphi Spinosae (stir-fry), decoct with water secondary, 3 hours for the first time, 2 hours for the second time, collecting decoction filters, and filtrate is concentrated into the clear paste that relative density is 1.20-1.25 (60 ℃), add above-mentioned panaxynol extract, mixing, cold drying is ground into fine powder; The five tastes such as Olibanum (system) and Hirudo are ground into fine powder altogether; The Borneolum Syntheticum porphyrize, with above-mentioned fine powder facing-up, mixing sprays into volatile oil respectively, and mixing incapsulates, promptly.
Perhaps, capsule of the present invention is preferably made by following preparation method:
A) weight ratio of crude drug is: Radix Ginseng 3-10 part, Hirudo 3-11 part, Eupolyphaga Seu Steleophaga 5-10 part, Olibanum (processed) 1-5 part, Radix Paeoniae Rubra 3-9 part, Lignum Dalbergiae Odoriferae 1-5 part, Lignum Santali Albi 1-5 part, Scorpio 3-9 part, Periostracum Cicadae 3-12 part, Scolopendra 1-3 part, Borneolum Syntheticum 1-7 part, Semen Ziziphi Spinosae (parched) 3-10 part;
B) pulverizing medicinal materials technology:
Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga and five kinds of worm medicines of Periostracum Cicadae are prepared burden by prescription through the Olibanum (processed) that cleans, washes after handling the back and cleaning the process of preparing Chinese medicine, pulverized by pulverizer, the medicated powder fineness reaches more than 80 orders; Medicated powder behind the coarse powder carries out micronizing through various superfine communication techniques, makes the medicated powder mean diameter less than 100 μ m; Medical material to be pulverized is prepared burden after the cleaning, drying sterilization;
C) extract concentrated and drying process:
Reuse water extraction behind Lignum Dalbergiae Odoriferae and the Lignum Santali Albi elder generation extracting in water volatile oil, Radix Paeoniae Rubra and Semen Ziziphi Spinosae decoct with water, after the water extract filters, extractum to be condensed into; Radix Ginseng with ethanol extraction after, reuse water extraction, alcohol extract are condensed into alcohol-extracted extract after reclaiming ethanol, the water extract filter with all water extract mixings after be condensed into the water extracted immersing paste;
D) preparation process:
In Fluidbedgranulatingdrier, add the superfine powder flour, again the step c) gained is extracted extractum and spray into granulation; The granule made through granulate, is added the Borneolum Syntheticum fine powder, spray into the volatile oil that extracts by Lignum Dalbergiae Odoriferae and Lignum Santali Albi, by the capsule filler filling, make capsule behind the mixing.
Perhaps, capsule of the present invention is preferably made by following preparation method:
A) weight ratio of crude drug is: Radix Ginseng 3-10 part, Hirudo 3-11 part, Eupolyphaga Seu Steleophaga 5-10 part, Olibanum (system) 1-5 part, Radix Paeoniae Rubra 3-9 part, Lignum Dalbergiae Odoriferae 1-5 part, Lignum Santali Albi 1-5 part, Scorpio 3-9 part, Periostracum Cicadae 3-12 part, Scolopendra 1-3 part, Borneolum Syntheticum 1-7 part, Semen Ziziphi Spinosae (parched) 3-10 part;
B) pulverizing medicinal materials technology:
Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga and five kinds of worm medicines of Periostracum Cicadae are prepared burden by prescription through the Olibanum (processed) that cleans, washes after handling the back and cleaning the process of preparing Chinese medicine, pulverized by pulverizer, the medicated powder fineness reaches more than 80 orders; Medicated powder behind the coarse powder carries out micronizing through various superfine communication techniques, makes the medicated powder mean diameter less than 100 μ m; Medical material to be pulverized is prepared burden after the cleaning, drying sterilization;
C) extract concentrated and drying process:
Reuse water extraction behind Lignum Dalbergiae Odoriferae and the Lignum Santali Albi elder generation extracting in water volatile oil, Radix Paeoniae Rubra and Semen Ziziphi Spinosae decoct with water, after the water extract filters, extractum to be condensed into; Radix Ginseng with ethanol extraction after, reuse water extraction, alcohol extract are condensed into alcohol-extracted extract after reclaiming ethanol, the water extract filter with all water extract mixings after be condensed into the water extracted immersing paste, extractum directly is spray dried to spray powder;
D) preparation process:
The superfine powder flour is added in the Fluidbedgranulatingdrier with step c) gained spray drying powder, sprays solvent again and make granule; The granule made through granulate, is added the Borneolum Syntheticum fine powder, spray into the volatile oil that extracts by Lignum Dalbergiae Odoriferae and Lignum Santali Albi, by the capsule filler filling, make capsule behind the mixing.
The consumption of pharmaceutical composition of the present invention is converted to the weight of raw medicinal material, is each 0.8-3 gram, and take 2-4 every day, is preferably each 1.11-2.22 and restrains, and takes every day three times.
Description of drawings
Fig. 1: Tongxinluo to ApoE-/-influence of mice serum blood glucose and blood lipid level, with matched group relatively, * * P＜0.01; Compare #P＜0.05 with model group.
Fig. 2: aortic annulus endothelium-dependent relaxation diastolic rate changes under the variable concentrations acetylcholine-induced, compares * * P＜0.01 with matched group; Compare #P＜0.05 with model group.
Fig. 3: each organizes mouse aorta PSV and MFV compares, and compares ##P＜0.01 with model group.
Fig. 4: VEGF gel images scanning back optical density value analysis, compare #P＜0.01 with model group.
Fig. 5: VEGF mRNA expression ratio compares ##P＜0.05 with model group.
Fig. 6: each organizes mouse aorta 1 all interior new vessels length relatively, compares * * P＜0.01 with matched group; Compare ##P＜0.01 with model group.
Experimental example:
Improve the activity of the cardiac dysfunction that hypercholesterolemia brings out for illustrating Chinese medicine composition of the present invention, carried out following test proving its curative effect with the capsule that makes by above-described embodiment 1 method (to call medicine of the present invention in the following text), but it can not consist of any restriction to scope of the present invention.
1 materials and methods
1.1 animal used as test
16 12 monthly age ApoE-/-mouse (28-32g) is purchased from Texas ,Usa university Houston medical college iaboratory animal medicine and protection center, is divided at random model group and medicine group of the present invention, 8 every group. The wild type C57BL/6J mouse of 8 characteristic matching is organized in contrast. After the experiment beginning, medicine group mouse of the present invention gives 0.5% sodium carboxymethylcellulose (CMC-Na) and annotates outstanding medicine of the present invention (oral administration gavage (0.1ml/10g body weight) of 1.52g crude drug/kg/d), every day 1 time; Model group and control group mice are raised the CMC-Na oral administration gavage with Isodose, every day 1 time. Experiment amounted to for 8 weeks.
1.2 blood specimen collection
Eye socket is gathered peripheral blood and conventional separation of serum before the sacrifice of animal. T-CHOL, HDL-C (HDL), C-VLDL (VLDL), triglyceride and blood-sugar content are detected in Texas heart association experimental center.
1.3 echocardiography
Before all sacrifice of animal, (Veterinary Anesthesia Systems, America) row echocardiography (Visualsonics Vevo 770system, Canada) behind isoflurane anesthesia, frequency probe 40MHz. Gather the parameters such as heart rate (HR), LVED (LVDED), left chamber end systolic diameter (LVSED). With reference to the past document, calculate the indexs such as Left Ventricular Ejection Fraction (LVEF), stroke output (SV), cardiac output (CO) and left LVSF (LVFS) to estimate the mouse core function. In addition, measure mouse aorta pectoralis peak systolic flow velocity (PSV), end-diastolic VPV (EDV) and TAV (MFV), calculate PI (PI) and drag index (RI) to estimate blood vessel elasticity and compliance. [PI=(PSV-EDV)/MFV; RI=(PSV-EDV)/PSV]
1.4 endothelium-dependent vasodilatation function detects
With reference to the past document, adopt acetylcholine-induced aortic annulus stretching reaction method evaluation Endotheli-um-dependent Vasodilatation. Behind the animal via isoflurane anesthesia, separate rapidly sustainer and place 4 ℃ of precoolings, oxygen presaturation Kerb ' s-Henseleit (K-H) liquid (NaCl 118mmol/L, KCl 4.7mmol/L, CaCl22.5mmol/L, MgCl2 1.2mmol/L, KH2PO4 1.2mmol/L, NaHCO3 25mmol/L, Glucose 11mmol/L is after the preparation, at fully logical 95%O2With 5%CO2Behind the mist, transfer pH value to 7.4) in, fat and connective tissue around careful the separation, use clipper for surgical use under the arch of aorta, to be trimmed to 4 sections aortic annuluses that about 3mm is long successively, be individually fixed in subsequently on the stainless pin of DMT myograph (ADinstruments, Australia), in 30min, be pulled to 1g tension force, and balance 1h (if tension force changes, at any time adjusting). Potassium chloride (final concentration is 80mmol/L) pre-stimulation vascular circle reaches maximum shrinkage amplitude, and with the flushing of K-H liquid, 1 time/5min, continuous 3 times, vascular circle is returned to stimulates front state. The dropping final concentration is that the norepinephrine of 10 μ tmmol/L makes vascular circle reach 70% maximum collapse, applies respectively the acetylcholine-induced vascular circle diastole that final concentration is 1nM, 3nM, 10nM, 30nM, 100nM, 300nM, 1 μ M, 3 μ M and 10 μ M every 5min subsequently. Adopt PowerLab 8/30Data Recording ﹠Analysis System (ADinstruments, Australia) collection signal and analysis. Stimulate the Assessment of Changes endothelial function of lower vascular circle diastolic rate by calculating the variable concentrations acetylcholine.
1.5 the newborn experiment of extracorporeal blood vessel
Each organizes mouse after anesthesia, cuts skin and exposes the thoracic cavity along the chest median line. Excision atrium dextrum, left ventricle continue to inject PBS liquid (1.25% penicillin, 1.25% streptomysin, 10U/ml heparin) and clean the residual blood of sustainer. Careful peeling outer layer fiber and adipose tissue separate sustainer and are cut into equal portions, place Room 2 to cultivate capsule 3-D PEG fibrin gel surface by blood vessel proximal part to distal end order, 3 sections of every cells, and every animal amounts to 6 sections sustainers and is used for experimental analysis. Gather neovascularization growth image in 1 week, adopt Photoshop CS4. that the image of gathering is carried out Macro or mass analysis, ImageJ software (Nation-al Institute of Health, America) calculates 5 new vessels length mean values the longest.
1.6 myocardium CD34 immunohistochemistry detects
Take out immediately cardiac muscle after mouse is put to death and be fixed in 4% paraformaldehyde solution, Gradient elution using ethanol is also used FFPE. Slicer (Leica, Germany) serial section (4 μ m) also is fixed on the slide. The dimethylbenzene dewaxing, 3% hydrogen peroxide sealing cardiac muscle section 10min cleans and the microwave antigen retrieval. 10% normal goats serum sealing 20min, PBS dilution (contain 4% skimmed milk power, 0.1%Tween 20) rabbit polyclonal CD34 antibody (Santa Cruz biotechnology, 1: 50) is hatched section, 4 ℃, spends the night. The anti-rabbit igg antibody of artifact elementization (Vector Labs, 1: 100) is hatched 30min. Adopting VectastainABC-AP kit (Vector Labs) to detect immune complex expresses, method with reference to people such as Weidner is cut into slices at the lower complete observation of low-power field (* 100 times) earlier, to determine that the nascent blood vessel density highest point is that new vessels forms active region in the cardiac muscle; Again under high power field (* 400 times), the blood vessel number of every section random observation 5 high power fields of numeration (* 400 times), each visual field is counted (double-blind study) simultaneously by two researchers, and asking at last its mean value is microvessel density (MVD).
1.7 western blot analysis
Cardiac muscular tissue's VEGF (VEGF) protein expression level is measured the western blot analysis method that adopts. The mouse cardiac muscle separation is placed in the lysate (10mM Tris, PH 7.4,150mM NaCl, 5mM EDTA, 1%NP40,1%Txiton X-100) that contains protease inhibitors (Sigma), and mortar grinds. Adopt BCA protein determination kit (Thermo scientific) to detect protein concentration. Each group is got the 20 capable sds page of μ g albumen (Bio-rad) electrophoresis, transferring film, and the polyclone VEGF antibody (Clone VG1, DakoCytomation, Denmark) of (1: 400) is hatched after the dilution, 4 ℃, spends the night. Horseradish peroxidase-labeled sheep anti-mouse igg (Santa Cruz biotechnology, 1: 5000) is hatched 1h after washing film. Enhanced chemiluminescence method (ECL, Thermo scientific and Hyperfilm TM-MP, BioExpress) colour developing. The result adopts quantity one software analysis, scan light density (OD) value, and the albumen relative expression quantity compares value representation with destination protein with confidential reference items NADPH.
1.8 real-time quantitative RT-PCR detects
Adopt Trizol (Invitrogen) extracting respectively to organize the total RNA of murine myocardium and purifying (Qiagen, Gemany). Adopt SuperScript cDNA synthesis kit (Invitrogen) that the mRNAs reverse transcription is become cDNAs. ICycler iQ real-time quantitative PCR detection system (Bio-Rad Laboratories) is for detection of the expression of cDNA. Beacon Designer 2.0 Software for Designs detect the primer of gene, and mouse VEGF primer is as follows: upstream 5 '-AACCATGAACTTTCTGCTCTC-3 '; Downstream 5 '-GTG ATTTTCTGGCTTTGTTC-3 '; Confidential reference items GAPDH primer is as follows: upstream 5 '-CCCTTC ATTGACCTCAACTACAATGGT-3 '; Downstream 5 '-GAGGGGCCATCCACAGTCTTCTG-3 '. The quantitative reaction system comprises: iQ SYBR Green I (Bio-Rad) 25 μ l; Each 200nM of upstream and downstream primer; CDNA; Deionized water amounts to 50 μ l. Course of reaction is as follows: 95 ℃, and 3min; 95 ℃, 10s, 40 circulations; 56 ℃, 30s; 72 ℃, 30s.
For estimating the specificity of PCR, solubility curve is also detected. Estimate VEGF mrna expression level with the cycle threshold (Ct) of markization.
1.9 statistical analysis
Adopt SPSS 13.0 statistical softwares, a plurality of sample averages are relatively used one-way analysis of variance (One-Way ANOVA), relatively use in twos least significant difference (least significantdifference between a plurality of sample averages, LSD), if heterogeneity of variance then adopts the Games-howell check. All (x ± s) form represents all data, and there is statistical significance P＜0.05 for difference with mean ± standard deviation.
2 results
2.1 medicine of the present invention reduces serum levels of triglyceride and the horizontal experimental study of VLDL
The result shows: each organizes mice serum blood-sugar content there was no significant difference; And than the normal group mouse, model group mice serum HDL-C (HDL), T-CHOL, triglyceride and C-VLDL (VLDL) content all obviously raise (P＜0.01), the generation of pointing out its hyperlipidemia. Compare with model group, medicine group mice serum cholesterol levels of the present invention does not have remarkable change (P＞0.05), and triglyceride and VLDL level then obviously reduce (P＜0.05), point out it can alleviate the atherosclerotic process. Specifically see Fig. 1.
2.2 medicine of the present invention obviously improves endothelium-dependent vasodilatation function and blood vessel elasticity experimental study
2.2.1 obviously improve ApoE-/-the mouse endothelium-dependent vasodilatation function
The initiating agent that the atherosclerotic that is considered to blood vessel endothelium dysfunction takes place and the important symbol thing of the atherosclerotic order of severity. Research also show ApoE-/-mouse arterial wall Patch size and vasomotoricity be negative correlation. In this research, but acetylcholine dose dependent (0.1-10 μ M) is induced the stretching reaction (51% ± 9%) of normal group mouse aorta ring, model group mouse endothelium-dependent vasodilatation is obviously impaired (23% ± 2%, P＜0.01) then; Compare with model group, medicine group mouse blood vessel diastolic rate of the present invention is obviously improved (44% ± 3%, P＜0.05), and is almost suitable with normal mouse auterial diastole rate, specifically sees Fig. 2. Fully proved invention medicine can effectively protect ApoE-/-Mouse Endothelial, improve endothelium-dependent vasodilatation function.
2.2.2 significantly improve ApoE-/-the mouse aorta blood vessel elasticity
Sustainer peak systolic flow velocity (PSV) can reflect sustainer blood supply situation with TAV (MFV). In addition, PI (PI) is a good parameter of blood vessel elasticity, and it can reflect vascular resistence and compliance, is proportionate with atherosclerosis. Drag index (RI) is usually used to judge vascular resistence. In general, PI and RI increase show that blood vessel elasticity and compliance go down, and vascular resistence increases. In this research, compare with control group mice, model group mouse aorta PSV and MFV all decrease, and PI then increases to some extent; With model group relatively, medicine group mouse aorta PSV of the present invention and MFV all obviously improve (P＜0.01), PI then obviously reduction (1.60 ± 0.17vs 1.41 ± 0.17; P＜0.05), specifically sees Fig. 3. Show that medicine of the present invention can improve the atherosclerotic blood vessel elasticity, strengthen its Cardiomyocytes and organize the blood supply ability, thus improve ApoE-/-the mouse core function.
2.3 medicine of the present invention improves the experimental study of VEGF gene and protein expression
VEGF (VEGF) is a kind of multi-functional glycoprotein that can promote endothelial cell mitogen, has high affinity at trunk and capilary and endothelial cell. In addition, VEGF is the important regulatory factor of physiological or pathological, can cause vascular permeability to increase. This result of study shows: compare with control group, (0.83 ± 0.11vs 0.78 ± 0.06 for model group murine myocardium vegf protein, P＞0.05) and mrna expression there are no significant changes, compare with model group, medicine group mouse cardiac muscle vegf protein of the present invention is expressed obviously increases (1.42 ± 0.43, P＜0.05), sees Fig. 4; VEGFmRNA expresses simultaneously increases by 4.59 times (P＜0.01), sees Fig. 5.
2.4 medicine of the present invention suppresses the Angiogenesis in Atherosclerosis Plaque experimental study
Angiogenesis in Atherosclerosis Plaque can increase the unstability of patch, and is in close relations with various clinical vascular complications such as patch internal haemorrhage, plaque rupture and unstable angina pectoris. Angiogenesis relates to endothelial cell proliferation, migration and forms the microtubule chamber, and VSMC (VSMC) moves and jointly forms intrinsic capilary with the microtubule chamber. This result of study is found, compare with the normal group mouse, the model group mouse contains patch aortic tissue 1 all interior new vessels length obviously increases (639.62 ± 125.85 μ m vs975.27 ± 85.57 μ m, P＜0.01), show that its angiogenesis ability strengthens, medicine of the present invention can obviously suppress ApoE-/-mouse contains patch aortic tissue angiogenesis (664.09 ± 107.25 μ m, P＜0.01), sees Fig. 6.
2.5 medicine of the present invention improves the heart function experimental study
Obviously and widely atherosclerotic patch appears on the model group mouse arterial wall in this research, meanwhile, compare with the normal group mouse, the various parameters such as LVEF, SV, CO and LVFS of model group mouse reflection heart function all decrease, and point out its heart function to descend. With the model group mouse relatively, medicine group mouse These parameters level of the present invention all significantly raises (P＜0.05), specifically sees Table 1, show medicine of the present invention have the ApoE-of improvement/-the mouse core function.
Table 1 is respectively organized the mouse core functional parameter relatively
| Group | HR(bmp) | LVEF(％) | SV(μl) | CO(ml) | LVFS(％) |
| Control group | 378.37±51.07 | 60.51±10.63 | 37.55±12.21 | 14.13±4.63 | 32.21±7.47 |
| Model group | 413.87±46.20 | 38.89±14.49 * | 26.95±12.13 * | 11.12±5.30 * | 18.98±7.88 * |
| Medicine group of the present invention | 407.57±41.94 | 60.71±11.50 # | 41.60±10.93 # | 16.68±3.58 # | 32.49±7.80 # |
Compare with control group,*P＜0.05; Compare with model group,#P＜0.05。
3 conclusions
Above zoopery confirms, Chinese medicine composition of the present invention can reduce the blood lipid level of hypercholesterolemiapatients patients, can improve endothelium-dependent vasodilatation function and blood vessel elasticity, strengthen the artery Cardiomyocytes and organize the application of blood supply ability, can strengthen VEGF (VEGF) gene and protein expresses, can suppress Angiogenesis in Atherosclerosis Plaque, thereby effectively improve the cardiac dysfunction that hypercholesterolemia is brought out.
The specific embodiment
Embodiment 1: the preparation of capsule
A) the crude drug prescription is:
Radix Ginseng 39.6g Hirudo 72.6g Eupolyphaga Seu Steleophaga 46.2g Olibanum (system) 13.2g
Radix Paeoniae Rubra 33g Lignum Dalbergiae Odoriferae 13.2g Lignum Santali Albi 13.2g Scorpio 19.8g
Periostracum Cicadae 46.2g Scolopendra 6.6g Borneolum Syntheticum 33g Semen Ziziphi Spinosae (stir-fry) 33g;
B) pulverizing medicinal materials technology:
Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga and five kinds of worm medicines of Periostracum Cicadae are prepared burden by prescription through the Olibanum (processed) that cleans, washes after handling the back and cleaning the process of preparing Chinese medicine, pulverized by pulverizer, the medicated powder fineness reaches more than 80 orders; Medicated powder behind the coarse powder carries out micronizing through various superfine communication techniques, makes the medicated powder mean diameter less than 30-40 μ m; Medical material to be pulverized is prepared burden after the cleaning, drying sterilization;
C) extract concentrated and drying process:
Reuse water extraction behind Lignum Dalbergiae Odoriferae and the Lignum Santali Albi elder generation extracting in water volatile oil, Radix Paeoniae Rubra and Semen Ziziphi Spinosae add suitable quantity of water and decoct secondary, and each 3 hours, merge the water extract, after the filtration, extractum to be condensed into; Radix Ginseng is with an amount of 70% ethanol extraction secondary, each 3 hours, merge extractive liquid,, reclaim ethanol to there not being the alcohol flavor, the reuse water extraction, alcohol extract is condensed into 60 ℃, and to measure relative densities be 0.9～1.1 alcohol-extracted extract, the water extract filter with above-mentioned all water extract mixings after be concentrated into 60 ℃ to measure relative densities be 0.9～1.1 clear paste, standby;
D) preparation process:
In Fluidbedgranulatingdrier, add the superfine powder flour, again the step c) gained is extracted extractum and spray into granulation; The granule made through granulate, is added the Borneolum Syntheticum fine powder, spray into the volatile oil that extracts by Lignum Dalbergiae Odoriferae and Lignum Santali Albi, by the capsule filler filling, make 1000 capsules behind the mixing.
Amount of drug of the present invention for each 2-4 grain, is taken three times every day.
Embodiment 2: the preparation of tablet
A) the crude drug prescription is:
Radix Ginseng 66g Hirudo 52.8g Eupolyphaga Seu Steleophaga 46.2g Olibanum (system) 13.2g
Radix Paeoniae Rubra 33g Lignum Dalbergiae Odoriferae 13.2g Lignum Santali Albi 13.2g Scorpio 59.4g
Periostracum Cicadae 46.2g Scolopendra 6.6g Borneolum Syntheticum 33g Semen Ziziphi Spinosae (stir-fry) 33g
B) pulverizing medicinal materials technology:
Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga and five kinds of worm medicines of Periostracum Cicadae are prepared burden by prescription through the Olibanum (processed) that cleans, washes after handling the back and cleaning the process of preparing Chinese medicine, pulverized by pulverizer, the medicated powder fineness reaches more than 80 orders; Medicated powder behind the coarse powder carries out micronizing through various superfine communication techniques, makes the medicated powder mean diameter less than 70-90 μ m; Medical material to be pulverized is prepared burden after the cleaning, drying sterilization;
C) extract concentrated and drying process:
Reuse water extraction behind Lignum Dalbergiae Odoriferae and the Lignum Santali Albi elder generation extracting in water volatile oil, Radix Paeoniae Rubra and Semen Ziziphi Spinosae add suitable quantity of water and decoct secondary, and each 3 hours, merge the water extract, after the filtration, extractum to be condensed into; Radix Ginseng is with an amount of 70% ethanol extraction secondary, each 3 hours, merge extractive liquid,, reclaim ethanol to there not being the alcohol flavor, the reuse water extraction, alcohol extract is condensed into relative density and is determined as 1.0～1.05 alcohol-extracted extracts at 60 ℃, the water extract filter with above-mentioned all water extract mixings after be concentrated into 60 ℃ to measure relative densities be 1.0～1.1 clear paste, standby;
D) preparation process:
In Fluidbedgranulatingdrier, add the superfine powder flour, again the step c) gained is extracted extractum and spray into granulation; The granule made through granulate, is added the Borneolum Syntheticum fine powder, spray into the volatile oil that is extracted by Lignum Dalbergiae Odoriferae and Lignum Santali Albi, preparation process is pressed into 1000 routinely.
Amount of drug of the present invention for each 2-4 sheet, is taken three times every day.
Embodiment 3: the preparation of pill
A) the crude drug prescription is:
Radix Ginseng 39.6g Hirudo 66g Eupolyphaga Seu Steleophaga 46.2g Olibanum (system) 13.2g
Radix Paeoniae Rubra 33g Lignum Dalbergiae Odoriferae 13.2g Lignum Santali Albi 13.2g Scorpio 46.2g
Periostracum Cicadae 46.2g Scolopendra 6.6g Borneolum Syntheticum 33g Semen Ziziphi Spinosae (stir-fry) 33g
B) pulverizing medicinal materials technology:
Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga and five kinds of worm medicines of Periostracum Cicadae are prepared burden by prescription through the Olibanum (processed) that cleans, washes after handling the back and cleaning the process of preparing Chinese medicine, pulverized by pulverizer, the medicated powder fineness reaches more than 80 orders; Medicated powder behind the coarse powder carries out micronizing through various superfine communication techniques, makes medicated powder mean diameter 10-20 μ m; Medical material to be pulverized is prepared burden after the cleaning, drying sterilization;
C) extract concentrated and drying process:
Reuse water extraction behind Lignum Dalbergiae Odoriferae and the Lignum Santali Albi elder generation extracting in water volatile oil, Radix Paeoniae Rubra and Semen Ziziphi Spinosae add suitable quantity of water and decoct secondary, and each 3 hours, merge the water extract, after the filtration, extractum to be condensed into; Radix Ginseng is with an amount of 70% ethanol extraction secondary, each 3 hours, merge extractive liquid,, reclaim ethanol to there not being the alcohol flavor, the reuse water extraction, alcohol extract is condensed into 60 ℃, and to measure relative densities be 0.9～1.0 alcohol-extracted extract, the water extract filter with above-mentioned all water extract mixings after be concentrated into 60 ℃ to measure relative densities be 1.0～1.1 clear paste, standby;
D) preparation process:
Preparation process is made 1000 pills routinely.
Amount of drug of the present invention for each 2-4 grain, is taken three times every day.
Claims (10)
1. the application of Chinese medicine composition in the preparation medicine, this Chinese medicine composition is made by following bulk drugs:
Radix Ginseng 3-10 Hirudo 3-11 Eupolyphaga Seu Steleophaga 5-10 Olibanum (system) 1-5 Radix Paeoniae Rubra 3-9 Lignum Dalbergiae Odoriferae 1-5
Lignum Santali Albi 1-5 Scorpio 3-9 Periostracum Cicadae 3-12 Scolopendra 1-3 Borneolum Syntheticum 1-7 Semen Ziziphi Spinosae (stir-fry) 3-10.
It is characterized in that this Chinese medicine composition improves application in the cardiac dysfunction medicine that hypercholesterolemia brings out in preparation.
2. application as claimed in claim 1 is characterized in that, this Chinese medicine composition is made by following bulk drugs:
Radix Ginseng 6 Hirudo 10 Eupolyphaga Seu Steleophagas, 7 Olibanums (system) 2 Radix Paeoniae Rubra 5 Lignum Dalbergiae Odoriferaes 2
Lignum Santali Albi 2 Scorpios 7 Periostracum Cicadaes 7 Scolopendra 1 Borneolum Syntheticum, 5 Semen Ziziphi Spinosaes (stir-fry) 5.
3. as each described application among the claim 1-2, it is characterized in that the active component of described Chinese medicine composition is made up of following ingredients:
The a mean diameter is less than Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga, Periostracum Cicadae and Olibanum (system) medicated powder of 100 μ m;
B Borneolum Syntheticum medicated powder;
The volatile oil that c is extracted by Lignum Dalbergiae Odoriferae and Lignum Santali Albi;
The alcohol-extracted extract of the alcohol extract of d Radix Ginseng after after concentrating with ethanol extraction;
The water extracted immersing paste that is condensed into behind the water extract after the Lignum Dalbergiae Odoriferae behind the e extraction composition c and water extract, Radix Paeoniae Rubra and the Semen Ziziphi Spinosae (stir-fry) of Lignum Santali Albi medicinal residues decoct with water and the water extract filtration of the medicine residues of Radix Ginseng after the extraction ingredient d, the mixing.
4. as each described application among the claim 1-2, it is characterized in that this Chinese medicine composition is capsule, tablet, granule, powder, oral liquid or pill as the pharmaceutical preparation of active component.
5. according to the preparation method of the described medicine capsule of claim 4, it is characterized in that it is made by following steps:
A) take by weighing each crude drug according to the weight portion ratio;
B) pulverizing medicinal materials technology:
Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga and five kinds of worm medicines of Periostracum Cicadae are prepared burden by prescription through the Olibanum (processed) that cleans, washes after handling the back and cleaning the process of preparing Chinese medicine, pulverized by pulverizer, the medicated powder fineness reaches more than 80 orders; Medicated powder behind the coarse powder carries out micronizing through various superfine communication techniques, makes the medicated powder mean diameter less than 100 μ m; Medical material to be pulverized is prepared burden after the cleaning, drying sterilization;
C) extract concentrated and drying process:
Reuse water extraction behind Lignum Dalbergiae Odoriferae and the Lignum Santali Albi elder generation extracting in water volatile oil, Radix Paeoniae Rubra and Semen Ziziphi Spinosae decoct with water, after the water extract filters, extractum to be condensed into; Radix Ginseng with ethanol extraction after, reuse water extraction, alcohol extract are condensed into alcohol-extracted extract after reclaiming ethanol, the water extract filter with all water extract mixings after be condensed into the water extracted immersing paste;
D) preparation process:
In Fluidbedgranulatingdrier, add the superfine powder flour, again the step c) gained is extracted extractum and spray into granulation; The granule made through granulate, is added the Borneolum Syntheticum fine powder, spray into the volatile oil that extracts by Lignum Dalbergiae Odoriferae and Lignum Santali Albi, by the capsule filler filling, make capsule behind the mixing.
6. according to the preparation method of the described medicine capsule of claim 6, it is characterized in that it is made by following steps:
A) take by weighing each crude drug according to the weight portion ratio;
B) pulverizing medicinal materials technology:
Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga and five kinds of worm medicines of Periostracum Cicadae are prepared burden by prescription through the Olibanum (processed) that cleans, washes after handling the back and cleaning the process of preparing Chinese medicine, pulverized by pulverizer, the medicated powder fineness reaches more than 80 orders; Medicated powder behind the coarse powder carries out micronizing through various superfine communication techniques, makes the medicated powder mean diameter less than 100 μ m; Medical material to be pulverized is prepared burden after the cleaning, drying sterilization;
C) extract concentrated and drying process:
Reuse water extraction behind Lignum Dalbergiae Odoriferae and the Lignum Santali Albi elder generation extracting in water volatile oil, Radix Paeoniae Rubra and Semen Ziziphi Spinosae decoct with water, after the water extract filters, extractum to be condensed into; Radix Ginseng with ethanol extraction after, reuse water extraction, alcohol extract are condensed into alcohol-extracted extract after reclaiming ethanol, the water extract filter with all water extract mixings after be condensed into the water extracted immersing paste, extractum directly is spray dried to spray powder;
D) preparation process:
The superfine powder flour is added in the Fluidbedgranulatingdrier with step c) gained spray drying powder, sprays solvent again and make granule; The granule made through granulate, is added the Borneolum Syntheticum fine powder, spray into the volatile oil that extracts by Lignum Dalbergiae Odoriferae and Lignum Santali Albi, by the capsule filler filling, make capsule behind the mixing.
7. according to each described application of claim 1-2, it is characterized in that the application of described Chinese medicine composition in preparation reduction hypercholesterolemiapatients patients blood lipid level medicine.
8. according to each described application of claim 1-2, it is characterized in that described Chinese medicine composition improves application in hypercholesterolemiapatients patients endothelium-dependent relaxation vasodilation function and the blood vessel elasticity medicine in preparation.
9. according to each described application of claim 1-2, it is characterized in that the application of described Chinese medicine composition in preparation enhancing hypercholesterolemiapatients patients vascular endothelial growth factor gene and protein expression medicine.
10. according to each described application of claim 1-2, it is characterized in that described Chinese medicine composition is the application in the angiogenesis medicament in preparation suppresses the hypercholesterolemiapatients patients atheromatous plaque.
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| CN104127526A (en) * | 2013-05-02 | 2014-11-05 | 河北以岭医药研究院有限公司 | Application of two compositions in preparation of drug for combinedly treating diabetic nephropathy |
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| CN104127526A (en) * | 2013-05-02 | 2014-11-05 | 河北以岭医药研究院有限公司 | Application of two compositions in preparation of drug for combinedly treating diabetic nephropathy |
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| CN114438167A (en) * | 2021-12-15 | 2022-05-06 | 宁夏众方生物健康科技有限公司 | Method for detecting change degree of amino acid of Chinese wolfberry to cardiovascular function |
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Application publication date: 20110615 |