CN1068790C - Medicinal composition containing total saponin extracted from stem and leaves of American ginseng - Google Patents
Medicinal composition containing total saponin extracted from stem and leaves of American ginseng Download PDFInfo
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Abstract
The present invention relates to the composition of total saponin of the stem and leaf of American ginseng, and medicine composition thereof, particularly to medical composition by using the composition of the total saponin of the stem and leaf of the American ginseng as a basic active component, the preparation method, and the application for preventing and treating myocardium or brain tissue ischemia of people or animals, oxygen deficiency and corresponding pathology conditions.
Description
The present invention relates to panax quinquefolium saponin and pharmaceutical composition thereof, particularly relating to the panax quinquefolium saponin is the pharmaceutical composition of primary activity composition, its preparation method and the application in preventing and treat human or animal's cardiac muscle or cerebral tissue ischemia, anoxia related pathologies condition.
Radix Panacis Quinquefolii (Panax quinguefolium Linn.) and Radix Ginseng belong to the araliaceae ginseng plant on Plant Taxonomy.Though Radix Ginseng particularly Radix Ginseng, is introduced China with Radix Panacis Quinquefolii and is had only nearly 200 years time in China's clinical practice history of existing nearly one thousand years as a kind of pharmaceutically acceptable plant part.In history, the Radix Panacis Quinquefolii that uses within Chinese territory for a long time is almost entirely by the original producton location import of state, North America.Since the fifties, China begins to introduce seeds of American ginseng and plants the test of Radix Panacis Quinquefolii at the northeast Changbaishan area that is suitable for planting Radix Ginseng.To the seventies in this century, the establishing in large scale of Radix Panacis Quinquefolii has been realized in area, ground, Chinese Changbai Mountain, thereby provides necessary raw material sources for develop this natural medicinal plant in China.A large amount of results of laboratory show, within Chinese territory, particularly Jilin Province's Changbaishan area Radix Panacis Quinquefolii of introducing a fine variety with originate in U.S. part state and the geographic Radix Panacis Quinquefolii of Quebec, CAN and Montreal does not have significant difference in fact.
Over the last couple of decades, many laboratorys are all to Radix Panacis Quinquefolii, the particularly chemical constituent of American ginseng root and its isolation and purification method, and pharmaceutically acceptable part particularly the pharmacological activity of the effective ingredient in the root carried out lot of experiments.Studies show that, though Radix Panacis Quinquefolii as a kind of medicinal plants, it contains many chemical active ingredients such as Saponin, volatile oil, protein, polysaccharide and trace element, thinks always that so far Saponin is a topmost active component in the Radix Panacis Quinquefolii.
Early eighties, people such as Staba and Chen (Planta Medica, 42:406-411,1981), and people such as Tanaka has successively isolated ginsenoside Rd, Re and Rg and Rb from Folium Panacis Quinquefolii
3And F
11Deng the panaxoside monomer chemical compound.Since the nineties, inventor's quantity research funds that have high input, systematically studied stem and leaf of Radix Panacis Quinquefolii this is taken as effective active composition in the plant waste part in the past comprehensively, and the content of finding panoxadiol's group (b group) Saponin in the stem and leaf of Radix Panacis Quinquefolii first is significantly higher than the protopanoxadiol group Saponin in the Stem and leaf of Radix Ginseng.On the contrary, in the Stem and leaf of Radix Ginseng Protopanaxatriol group (g group) Saponin then the Protopanaxatriol in the stem and leaf of Radix Panacis Quinquefolii organize Saponin.
For abundant these important natural resources of development and utilization Radix Panacis Quinquefolii aerial parts, the inventor was based on living into the protracted experience of research with class pharmacology mutually from purification and component analysis to panoxadiol's component in the past, to the Radix Panacis Quinquefolii of area, Jian, Chinese Jilin Province introducing and planting particularly its stem and leaf partly in separation and Extraction, physicochemical property evaluation and the pharmacological activity of active component carried out laboratory research extensively and profoundly.We have further improved the extracting method of panax quinquefolium saponin, separate from said total Saponin and purification and identified at least eight kinds of panaxoside monomer chemical compounds.Particularly we use the kinds of experiments animal model, general pharmacology and pharmacodynamics to stem and leaf of Radix Ginseng total saponins have carried out extensive studies, thereby provide necessary laboratory work basis for panax quinquefolium saponin being developed to a kind of medicine that can use clinically.
Though once delivered the publication of some relevant stem and leaf of Radix Panacis Quinquefolii Saponin basic research in the past, so far still not about panax quinquefolium saponin being developed to the report of medicine.On the basis of a large amount of laboratory researches that we are former, for the first time successfully prepared and to have met the clinical practice requirement fully, it with the panax quinquefolium saponin primary activity composition, the cardiac muscle that is used for the treatment of and prevents to cause and the pharmaceutical composition of pathological conditions such as cerebral tissue ischemia, anoxia and lipid oxide rising because of the sclerosis of heart and cerebral artery vessel and/or thromboembolism, thus the present invention finished.
Therefore, an object of the present invention is to provide a kind of is the primary activity composition with the panax quinquefolium saponin, and contains the pharmaceutical composition of one or more pharmaceutically acceptable carriers or excipient.
This purpose preferred embodiment according to the present invention, the content of the primary activity composition panax quinquefolium saponin in the wherein said pharmaceutical composition is at least 50% (w/w).
This purpose preferred embodiment according to the present invention, the primary activity composition panax quinquefolium saponin in the wherein said pharmaceutical composition is at least by the Ginsenoside Rb
2, Rb
3, Rd, Re, Rg
1, F
2, RT
5And anthropomorphic ginseng Saponin F
11Eight kinds of monomers are formed.
This purpose preferred embodiment according to the present invention contains also in the wherein said pharmaceutical composition that one or more are natural or chemosynthesis, with primary activity composition panax quinquefolium saponin auxiliary or synergistic other active component are arranged.
It is the method for the pharmaceutical composition of primary activity composition with the panax quinquefolium saponin that another object of the present invention provides production, and this method comprises:
(1) provides panax quinquefolium saponin;
(2) step (1) being obtained total panaquilon mixes mutually with one or more pharmaceutically acceptable carriers and/or excipient.
This purpose preferred embodiment according to the present invention can add in addition also in the wherein said pharmaceutical composition that one or more are natural or chemosynthesis, with primary activity composition panax quinquefolium saponin auxiliary or synergistic other active component are arranged.
It is the application of pharmaceutical composition in preventing and treat human or animal's cardiac muscle or cerebral tissue ischemia, anoxia related pathologies condition of primary activity composition that a further object of the present invention provides with the panax quinquefolium saponin.
This purpose preferred embodiment according to the present invention, wherein said human or animal's cardiac muscle or cerebral tissue ischemia, anoxia related pathologies condition comprise heart or cerebrovascular blood supply insufficiency, cerebral embolism, atherosclerosis and myocardial infarction.
The present invention relates to the panax quinquefolium saponin is the pharmaceutical composition of primary activity composition, its preparation method and the application in preventing and treat cardiac muscle and cerebral tissue ischemia, anoxia relevant disease.
Early eighties, people such as Staba and Chen (S.E.Chen et al., planta Medica, 42:406-411,1981), and people such as Tanaka has successively isolated ginsenoside Rd, Re and Rg and Rb from Folium Panacis Quinquefolii
3, Rd and F
11Deng the panaxoside monomer chemical compound.For abundant development and utilization Radix Panacis Quinquefolii resource on the ground, the inventor has carried out deep research and analysis to the contained ginsenoside's of stem and leaf of Radix Panacis Quinquefolii of Chinese Jilin Province introducing and planting chemical constitution simultaneously, separates and has identified the Ginsenoside Rb
2, Rb
3, Rd, Re, Rg
1, F
2, anthropomorphic ginseng Saponin F
11And RT
5Deng eight kinds of panaxoside monomers.
On the basis of chemical research and structure evaluation, we have carried out deep laboratory and clinical experimental study to special pharmacological effect, effect magnitude relation, medicine attitude kinetics and the safety in utilization of panax quinquefolium saponin, thereby can provide necessary laboratory work basis at the pharmaceutical composition of clinical practice for panax quinquefolium saponin is developed to.In addition, we also further improve and have simplified the separation and purification means of panax quinquefolium saponin, and make it to be more suitable for the industrialized mass requirement.
The invention provides with the panax quinquefolium saponin is the pharmaceutical composition of primary activity composition.According to a preferred embodiment of the present invention, wherein said panax quinquefolium saponin accounts for more than 75% (w/w) of said pharmaceutical composition, and said panax quinquefolium saponin is by the Ginsenoside Rb basically
2, Rb
3, Rd, Re, Rg
1, F
2, and anthropomorphic ginseng Saponin F
11And RT
5Form.
Can be by the panax quinquefolium saponin of known method preparation as pharmaceutical composition primary activity composition of the present invention.Briefly, be raw material with exsiccant stem and leaf of Radix Panacis Quinquefolii, after decocting boils repeatedly, collect filtrate and filtrate is crossed macroporous adsorbent resin (for example D4042) post, with promptly obtaining panax quinquefolium saponin behind the ethanol elution.
After the total Saponin of gained is dissolved in the water, with organic solvent ethyl acetate extraction for example.With aqueous slkali 1%NaOH solution-treated ethyl acetate layer for example, obtain low polarity Saponin behind the decompression and solvent recovery then.Separate said low polarity Saponin with conventional thin layer chromatography, obtain 3 kinds of unisexuality Saponins after with different eluant eluting: Saponin VI, VII, VIII.In addition, with the water layer that forms behind the saturated n-butanol extraction ethyl acetate extraction, distilling under reduced pressure obtains high polarity Saponin after removing and desolvating.Separate said high polarity Saponin with thin layer chromatography equally, to obtain 5 kinds of saponin monomers behind the different exhibition layer solvent elutions: saponin I, II, III, IV and V.
Analyze through infrared spectrum (IR), and thin layer chromatography and NMR (Nuclear Magnetic Resonance) spectrum (NMR) analysis, above-mentioned 8 kinds of Saponin monomer I-VIII are accredited as the Ginsenoside Rb respectively
2, Rb
3, Rd, Re, Rg
1, F
2, anthropomorphic ginseng Saponin F
11With ginsenoside RT
5We find, Ginsenoside Rb in the stem and leaf of Radix Panacis Quinquefolii
3Content is higher relatively, and particularly we also separate in stem and leaf of Radix Panacis Quinquefolii first and have obtained ginsenoside RT
5
As previously mentioned, after pretreated stem and leaf of Radix Panacis Quinquefolii decocted with water three times and filter collecting filtrate, the gained water extract with macroporous resin (for example D 4020 resins) absorption, is washed with water to colourless back reuse 95-98% ethanol elution.Collect eluate then and under decompression, be condensed into the extractum shape.Again after dissolving with 95-98% ethanol, remove by filter precipitate and reclaim filtrate.Obtain required panax quinquefolium saponin behind the decompression recycling ethanol.Chemical analysis shows that panax quinquefolium saponin content is approximately 75% in the gained end-product.
This shows, be divided into raw material with this Radix Panacis Quinquefolii plant shoot that is regarded as garbage for a long time of stem and leaf of Radix Panacis Quinquefolii always, with relatively simple extraction process, can produce the pharmaceutical composition that contains 50% (w/w) panax quinquefolium saponin at least at an easy rate by known technology in the pharmaceuticals industry.
According to pharmaceutical composition of the present invention, wherein except that the total panaquilon that contains at least 75% (w/w), a small amount of protein, peptide, aminoacid, the polysaccharide that also can contain Radix Panacis Quinquefolii plant itself residual in stem and leaf of Radix Panacis Quinquefolii Saponin separation and purification process, and trace element and volatile oil.It will be appreciated by those skilled in the art that, these impurity components bring adverse effect can for basically the pharmacological activity of panax quinquefolium saponin in the pharmaceutical composition of the present invention, on the contrary, in some cases in addition can be with the performance of total Saponin collaborative or assosting effect, and wherein also may exist new, the related activity composition that it be not immediately clear.
In addition, what should particularly point out is, can add one or more natural or synthetic other as required and have with panax quinquefolium saponin and work in coordination with or the active component of assosting effect in pharmaceutical composition of the present invention.Natural or the synthetic auxiliary activity composition that these may be added into is well known by persons skilled in the art and can expects.These natural or synthetic auxiliary activity compositions comprise but are not limited to Ginsengdiol histsaponin and Pyridopyrimidine ketone compounds.
Pharmaceutically acceptable carrier of panax quinquefolium saponin and one or more or excipient can be mixed by proper proportion, make the pharmaceutical composition of the different dosage form that is suitable for using clinically.For example said compositions can be mixed with the injection that can supply intravenous, intramuscular, intraperitoneal, subcutaneous, marrowbrain intracavity and intraocular injection administration, perhaps make the tablet, powder agent, pill, capsule and the suspending agent that are suitable for oral administration, and the spray, cream, ointment, elixir and the suppository that are suitable for topical.
In order to prepare the solution that is suitable for the outer approach medicine of gastrointestinal tract, for example can use distilled water, water for injection, isotonic sodium chlorrde solution or glucose solution, perhaps low concentration (for example 1-100mM) phosphate buffered saline (PBS) (PBS) is as carrier or excipient.Can in the preparation of these gastrointestinal tract external administrations, add one or more other auxiliary elements or additives, for example can use ascorbic acid as antioxidant, use sodium benzoate or methyl hydroxybenzoate as antiseptic, use dimethyl sulfoxide as absorption enhancer.
In order to prepare tablet, powder agent, suspending agent or the capsule that is suitable for oral administration, can use sucrose, galactose, corn starch, gelatin, lipid, microcrystalline Cellulose, Pulvis Talci etc. as carrier or excipient.Be suitable for also can containing other proper additive in the preparation of oral administration, for example solubilizing agent, disintegrating agent, lubricant, absorption enhancer, dispersant, surfactant, flavouring agent or coloring agent etc. at these.
Preferably pharmaceutical composition of the present invention is made the various dosage forms that are suitable for oral administration, for example tablet, powder agent, capsule, or oral liquid or Emulsion.The unit dose of these oral formulations generally comprises the 50-200mg panax quinquefolium saponin.When for example being used for the treatment of the ischemic cardio-cerebral diseases, the adult dosage of common 60 kg body weight is 100-500mg every day, divides three administrations.Another preferred route of administering of pharmaceutical composition of the present invention is the injection that intravenous or intramuscular injection are suitable for these route of administration.For example for some acute myocardial infarction or the convalescent patient of cerebral embolism, or the patient of the frequent outbreak of angina pectoris, the injection formulation of pharmaceutical composition of the present invention can be added in etc. and ooze in glucose solution or the isotonic sodium chlorrde solution, constantly dropleting medicine-feeding.The dosage of intravenous administration is generally 50-300mg every day.
The present invention further provides the said application of pharmaceutical composition in treatment or prevention whole body or local organization, particularly cardiac muscular tissue's ischemia, anoxia and related pathologies condition that contains panax quinquefolium saponin.
A large amount of general pharmacologies is learned and pharmacodynamic experiment shows, pharmaceutical composition of the present invention is to activity and the not obviously influence of behavior of animal (mice, rat and dog).Behind the intravenous injection panax quinquefolium saponin (25mg/kg), the blood pressure of animal, heart rate and electrocardiogram are all normal substantially, find no significant variation on the statistics.The pharmacodynamic study result shows, pharmaceutical composition of the present invention has significant protective effect to the rat heart muscle ischemia that experimental myocardial infarction and isoproterenol bring out.For example, give injection pharmaceutical composition of the present invention (25mg/kg) in the experimental myocardial infarction rabbit vein, can alleviate the Electrocardiographic ischemic change of front multi-lead (p＜0.05) significantly.The p-isopropyl epinephrine brings out the rat of myocardial ischemia behind intragastric infusion pharmaceutical composition of the present invention (100mg/kg); as seen serum paraoxonase creatine phosphate kinase of animal and lactic acid dehydrogenase activity reduce, and thereby infer that pharmaceutical composition of the present invention may be relevant with free fatty and lipid peroxide in its reduction ischemic myocardial tissue to the protective effect of myocardial damage.Simultaneously, we also observe the time-to-live that pharmaceutical composition of the present invention can prolong anoxia mice under the normal pressure that isoproterenol causes significantly, show that said composition can increase the anoxybiotic ability of cardiac muscle tolerance.
In addition, we have also observed pharmaceutical composition of the present invention to the coronary artery circulation of laboratory animal (dog) and the influence of myocardium oxygen metabolism.The result shows that pharmaceutical composition of the present invention can increase the blood flow of animal cardiac muscle significantly and reduce coronary resistance.Though see said composition the coefficient of oxygen utilization of cardiac muscle is not had a significant effect, find that it can reduce myocardial oxygen consumption and myocardial oxygen consumption index significantly.
In general, coronary vasodilator also can prop up blood flow afferent veins blood vessel by a moving venous anastomosis except that providing the nutritional blood flow for cardiac muscle by blood capillary, and both constitute total blood flow of coronary vasodilator jointly.Therefore, mensuration myocardial nutrition blood flow is more more objective and meaningful than the total blood flow that detects coronary vasodilator.In addition, known radiosiotope
86Rb has very strong affinity to cardiac muscular tissue.So in general, it is right to organize
86The picked-up ability of Rb is enough to reflect the size (both relations in direct ratio) of tissue blood flow's amount.Using
86In the experimentation that Rb carries out, our result shows, the pharmaceutical composition of the present invention of various dose (50,100 and 200mg/kg) can increase animal significantly
86Rb uptake ratio (data not shown goes out) shows that said composition can increase the myocardial nutrition blood flow to some extent.
Moreover in cardiac function and the hemodynamic animal experiment study, we find that pharmaceutical composition of the present invention mainly shows as depression effect to anaesthetizing down cardiac function and the hemodynamics of opening the breast animal after detecting medication.Experimental data shows that pharmaceutical composition of the present invention also has and reduces the effect of opening breast dog left ventricular pressure and reducing the maximum rising speed of left ventricular pressure except the hypotensive effect with tangible persistence.Yet pharmaceutical composition of the present invention is to the cardiac output and the not obviously influence of SI of reflection heart pump function, and prompting is under employed dosage (25 and 50mg/kg), and compositions does not have the obvious suppression effect to myocardial contractility.In addition, according to similarity method cardiac function and the hemodynamic assessment that experimental myocardial infarction dog carries out shown, pharmaceutical composition of the present invention can delay the decline rate of circulatory function after the myocardial infarction effectively, and can keep the systolic and diastolic function of infraction back cardiac muscle effectively.
The following example is intended to further describe for example the present invention, rather than limits the present invention by any way.Under the prerequisite that does not deviate from the spirit and principles in the present invention, any change or change that those of ordinary skills that the present invention did are realized easily all will fall within the claim scope that awaits the reply of the present invention.Embodiment 1: the preparation of panax quinquefolium saponin
To clean also in the rustless steel capacity in advance, exsiccant Radix Panacis Quinquefolii (production of Chinese Jilin Province Ji'an City first ginseng) stem and leaf 1kg adds an amount of water heated and boiled (three times, each 40 minutes) repeatedly.Collect and merge the flooding extract of gained, and use G
3Funnel filters.Filtrate is added in advance on the large aperture adsorption resin D4020 that handles with bronsted lowry acids and bases bronsted lowry (Chinese Tianjin chemical reagent two factories of the Nankai University produce) post, with deionized water wash post after eluate does not have color with 95% ethanol (about 500ml) eluting.Collect effusive eluate and under decompression, reflux and concentrate it.The gained concentrate is placed MgSO in the empty true exsiccator
4Obtain the total Saponin 68g of pale yellow powder shape (yield 6.8%) after the drying of top.Embodiment 2: the proximate analysis of panax quinquefolium saponin
To be dissolved in the 1000ml distilled water by the panax quinquefolium saponin 50.0g that embodiment 1 described method is extracted.Extract (each 100ml) repeatedly 5 times with ethyl acetate.Collection also merges resulting acetic acid ethyl acetate extract, adds 1% (w/v) sodium hydrate aqueous solution then, mixes repeatedly 10 minutes.Decompression refluxes this mixture to remove organic solvent (ethyl acetate) down, obtains low polarity Radix Panacis Quinquefolii Saponin (component I).
Press known method (Shao Chunjie and Xu Jingda, Chinese herbal medicine 13 (2): 19,1982) use adsorbent silica gel G (Chinese Haiyang Chemical Plant, Qingdao produces) preparation silica gel thin-layer (thick 0.25mm) chromatoplate, and above-mentioned low polarity Saponin component I (10 μ l) point sample used ginsenoside Re, Rb simultaneously on this plate
3With personification ginseng Saponin F
11Standard substance (5mg/ml methanol solution) in contrast.Use solvent orange 2 A: obtain component I a, I b and I c behind chloroform/methanol/ethyl acetate/water (2: 2: 4: 1, v/v, lower floor) eluting.
With same silica gel plate chromatography component I a, and obtain Saponin IV and V (0.06%) with above-mentioned solvent orange 2 A eluting.With same silica gel plate chromatography components I b and I c, and use solvent B: toluene/carbon tetrachloride/dichloroethanes/methanol (2: 48: 25: 25, v/v) eluting obtains Saponin VI (0.5%), VII (0.05%), VIII (0.05%).
In addition, it is above-mentioned with the water layer that obtains behind the ethyl acetate extraction to add water saturation, and uses n-butanol extraction, and decompression obtains the about 30g of high polarity stem and leaf of Radix Panacis Quinquefolii Saponin after refluxing down and removing n-butyl alcohol.As stated above this high polarity Saponin is carried out silica gel thin-layer chromatography, and use solvent C successively: chloroform/methanol/water (65: 35: 10, lower floor), solvent D: n-butyl alcohol/ethyl acetate/water (4: 1: 2, the upper strata), with above-mentioned solvent orange 2 A exhibition layer eluting, obtain Radix Panacis Quinquefolii Saponin I (0.09%), II (0.4%), III (0.1%), IV (0.1%), V (0.08%) respectively.
Structure qualification result to the panax quinquefolium saponin each component is as follows:
Saponin I: it is Powdered to be white in color.[α]
D 20:+12.3°(C=0.92,MeoH)。IR(HBr)cm
-1:3400(OH)；1620(C=C)。This component is behind heating hydrolysis in the presence of the dilute hydrochloric acid (0.1N), and gained glycoside unit is accredited as Ginsengdiol histsaponin, and its sugared portion is accredited as glucose and arabinose.Thin layer chromatography,
1H-NRR and
13C-NMR spectrum analysis result confirms that the Radix Panacis Quinquefolii Saponin I is the Ginsenoside Rb
2
The Saponin II: it is Powdered to be white in color.[α]
D 20:+19.4°(C=100,MeOH)。IR(HBr):cm
-1:3400(OH),1620(C=O)。This component is after using dilute hydrochloric acid (0.1N) hydrolysis under the heating, and gained glycoside unit is accredited as panoxadiol's chemical compound, and sugar moieties is glucose and xylose.Silica gel thin-layer chromatography,
1H-NMR and
13C-NMR spectrum analysis proof component is the Ginsenoside Rb
3
Saponin III: white powder.[α]
D 20:+19.2°(C=0.4 MeOH)。IR(HBr)cm
-1:3400(OH),1630(C=C)。After adding thermal decomposition in the presence of the dilute sulfuric acid, glycoside unit is accredited as the panaxatriol, and sugar moieties is proved to be glucose.Thin layer chromatography,
1H-NMR and
13The C-NMR analysis result shows that this component and ginsenoside Rd are in full accord.
Saponin IV: be white powder.[α]
D 20:+1.5°(C=0.52,MeOH)。IR(HBr)cm
-1:3400(OH),1630(C=C)。Separated product proves that through dilute sulfuric acid (0.1N) heating hydrolysis glycoside unit is the Radix Ginseng diol component, and sugar moieties is glucose and rhamnose.The silica gel thin-layer chromatography of this component, and
1H-NMR and
13The C-NMR curve of spectrum and ginsenoside Re's standard reference material are identical.
Saponin V: be white powder.[α]
D 20:-1.5°(C=0.25,MeOH)。IR(HBr)cm
-1:3400(OH),1640(C=C)。After the dilute sulfuric acid hydrolysis, prove that glycoside unit part is the panaxatriol under the heating condition, sugar moieties is a glucose.Through thin layer chromatography,
1H-NMR and
13The C-NMR spectrum analysis proves that this component is a panaxoside Rg
1
Saponin VI: be white powder.[α]
D 20:+20.0°(C=0.5,MeOH)。After the dilute sulfuric acid hydrolysis, ruscogenin partly is accredited as the panoxadiol down in heating, and sugar moieties is accredited as glucose.Thin layer chromatography,
1H-NMR and
13Lucky and the ginsenoside F of C-NMR spectral analysis data
2Contrast, so prove that it is ginsenoside F
2
Saponin VII: white powder.[α]
D 20:-13.0°(C=1.0,MeOH)。Behind heating hydrolysis under the dilute sulfuric acid existence, certified glucose of gained sugar portion and rhamnose.Behind thin layer chromatography,
1H-NMR and
13The C-NMR spectrum analysis proves that this component is anthropomorphic ginseng Saponin F
11(Pseudoginsenoside F
11).
Saponin VIII: colourless acicular crystals (MeOH-H
2O), m.p.:247-249 ℃.[α]
D 20:+13.5°(C=0.5,MeOH)。Behind the heating hydrolysis, the gained sugar moieties is accredited as glucose under dilute sulfuric acid exists.Behind thin layer chromatography,
1H-NMR and
13The C-NMR spectral analysis data proves that this component is for there being ginsenoside RT
5Embodiment 3: panax quinquefolium saponin is to the protective effect of zoopery myocardial inyaretion
It is the influence of the pharmaceutical composition (hereinafter to be referred as the panax quinquefolium saponin compositions) of primary activity composition to experimental myocardial infarction rabbit electrocardiogram, serum and myocardium lipid peroxide (LPO) level and myocardial infarction area with the panax quinquefolium saponin that present embodiment illustrates as the present invention.
With body weight is that 2.0 to 2.5kg 32 of big ear rabbit of male and female white are divided into four groups at random: heavy dose of administration group (panax quinquefolium saponin compositions 75ml/kg), low dose of administration group (panax quinquefolium saponin compositions 25mg/kg), positive controls (beta-blocker Propranolol (propranolol) 1mg/kg) and negative control (normal saline 2mg/kg).Every group of each 8 animal.
After animal via intravenous injection sodium pentobarbital (30mg/kg) anesthesia, press people such as Fang Yunxiang (Hunan medical college journal 5 (3): 229,1980) the high-order dual ligation left anterior descending coronary artery (LAD) of described method causes acute myocardial infarction (AMI) animal model.After causing AMI, each treated animal is immediately through the heavy dose of or low dose of experiment medicine of ear vein injection (panax quinquefolium saponin compositions, Jian Pharmaceutical Factory produces), or Propranolol (BJ Pharmaceutical Co., Ltd. production) or normal saline.
Back of the body position is animal fixedly, before causing myocardial infarction, reaches 2,4,24 hours at once after causing myocardial infarction, detects and electrocardiogram (ECG) variation of record animal with the front multi-lead.Calculate in 24 hours ST section 〉=2mm lead number (NST), ST field offset total voltage (mV) number (∑ ST), pathologic Q waveguide connection number (NQ) and pathologic Q ripple total voltage (mV) number (∑ Q) according to testing result.
Four treated animals respectively at cause before the myocardial infarction and infraction back 2,4 and 24 hours through ear edge vein exploitating blood (1ml), collect animal serum with 3.000rpm after centrifugal 10 minutes, (Norman Bethune Medical University's journal, 11 (4): 358,1985) described method is measured serum LPO level to press people such as Zhou Xiang.Block and put to death animal in back 24 hours, isolating cardiac also cuts the about 100mg of cardiac muscular tissue from infarct and non-infarct respectively, in piece of tissue, add an amount of 0.85%NaCl solution and make 10% tissue homogenate, then according to people's (up-to-date medical science such as the sincere sons of Da Shi, 33 (4): method 660,1978) is measured the LPO of cardiac muscular tissue content.
In order to study the influence of panax quinquefolium saponin compositions to zoopery myocardial inyaretion area, thoracic cavity and isolating cardiac were opened in operation once more by the preceding method anesthetized animal in 24 hours after causing myocardial infarction model.Clean chambers of the heart inner blood with normal saline, laterally cut out the tissue slice of the about 4-5mm of thickness then along long axis of heart from top to bottom successively, and these thin slices are carried out N-BT dyeing (referring to Brody, C.et al., Arch.Pathol., 84:312,1967).After the dyeing, macroscopic necrotic myocardium tissue weighed and calculate downright bad cardiac muscle accounts for the percentage ratio of chamber tissue wet whole-heartedly.
The following tabulation 1 of above-mentioned result of experiment difference is to shown in the table 3.Experimental data shown in the table is represented with the mean+SD of every group of eight animals.
Table 1 panax quinquefolium saponin compositions is blocked the influence of back 24 hours front multi-lead ECG to the AMI rabbit
| Group (n=8) | ∑ST | NST | NQ | ∑Q |
| The heavy dose of group of negative control group positive controls small dose group | 36.7 7.7 * 23.2 7.8 * | 121 37 * 98 35 * | 99 50 * 74 43 * | 48.9 29.9 * 35.4 20.2 * |
*Statistical procedures result shows P＜0.05.
Table 1 has shown that animal cardiac muscle blocks the testing result of back 24 hours front multi-lead electrocardiogram coherent detection indexs.Take place and its order of severity as the monitoring myocardial infarction, and the rough quantitative target of estimating the infarct size size, NST among the multi-lead ECG of front is the reflecting myocardium infarct size roughly, ∑ ST is reflecting myocardium infraction degree roughly, ∑ Q is the reflecting myocardium degree of necrosis roughly, and NQ reflects roughly that then the left ventricle contractility reduces degree.From the data shown in the table 1 as can be seen, the heavy dose that comes into operation in the myocardial infarction posterior vein (75mg/ml) panax quinquefolium saponin compositions can reduce front multi-lead ECG ischemic change (P＜0.05) significantly.
The N-BT coloration result of cardiac muscular tissue's specimen shows that the panax quinquefolium saponin compositions that comes into operation can reduce myocardial infarction area (data not shown goes out) significantly substantially, and this result directly perceived conforms to fully with the ECG testing result.
Table 2 panax quinquefolium saponin compositions to rabbit AMI after the influence of 24 hours serum and the LPO of cardiac muscular tissue content
| Group (n=8) | Serum LPO (nM/ml) | The LPO of cardiac muscular tissue (nM/g) | ||
| Before the infraction | Blocked back 24 hours | Infarct | Non-infarct | |
| The heavy dose of medication group of the low dose of medication group of negative control group positive controls | 1.62±0.57 1.86±0.66 1.79±0.72 1.52±0.53 | 2.18±0.11 1.93±0.12 2.12±0.28 1.73±0.09 * | 1 98.0±36.0 142.3±10.4 173.1±21.5 102.7±14.0 * | 136.6±13.7 128.6±10.2 124.7±11.4 117.0±7.5 |
*Compare P＜0.05 with negative control group.
Known under the situation of histanoxia, produce a large amount of free radicals in the cell and cause the biomembrane peroxidating, and then a series of cell function disorders (for example referring to Kuller JE.et al., Circulation 57:1,1978) take place.Experimental data shown in the table 2 shows that 24 hours serum LPO level are before myocardial infarction after the blank treated animal myocardial infarction, and in addition, the LPO level in the infarct area cardiac muscular tissue is apparently higher than non-infarct area.Yet heavy dose of panax quinquefolium saponin compositions that comes into operation can make that the LPO level in the serum LPO level and myocardial infarction area cardiac muscular tissue all obviously reduces (P＜0.05) after the myocardial infarction.These results have further illustrated the anti-myocardial infarction action principle of panax quinquefolium saponin compositions from an aspect.Embodiment 4: the effect of the rat heart muscle ischemia that panax quinquefolium saponin compositions antagonism isoproterenol brings out
Present embodiment illustrates at the subcutaneous injection isoproterenol and causes under the situation of myocardial ischemia, in advance oral administration come into operation the panax quinquefolium saponin compositions of various dose to the animal cardiac muscle ischemia after the influence of serum phosphokinase (CPK) and lactic acid dehydrogenase (LDH) gross activity level.
The healthy male Wistar rat of 50 body weight 198 ± 14g is divided into 5 groups at random.Every group of 10 animals.Except that the blank group, other each treated animal per os gavage normal saline (0.2ml/mg) (pathological changes matched group), general bitter edible plant Luo Er (30mg/kg) (positive drug matched group), panax quinquefolium saponin compositions (50mg/kg or 100mg/kg) (total saponin I group and II group).Behind the successive administration seven days, subcutaneous injection isoproterenol (2mg/kg) causes the animal cardiac muscle ischemia.Animal blood and separation of serum are gathered in anesthesia down after 24 hours.Use COBAS FARA type automatic biochemistry analyzer to measure clear CPK of the heart and LDH activity level, and according to once extracting colorimetry (referring to Shanghai City medical science assay office, clinical biochemical check (first volume), the 168-170 page or leaf, Science and Technology of Shanghai publishing house, 1979) detection free serum fatty acid (FFA) content.Put to death animal then, the isolating cardiac tissue also prepares the homogenate of 10% cardiac muscular tissue, and uses TBA development process (Ohkama H, et al., Anal.Biochem.95:351,1979) to measure the LPO of cardiac muscular tissue level.
Tabulate shown in 3 under the result.Experimental data is represented with the mean+SD of every group of 10 animals.
Table 3 panax quinquefolium saponin compositions to the rat experiment myocardial ischemia after cardiac muscle stalk hinder the influence of related enzyme activity and metabolite content
| Group (n=10) | ||||
| CPK(U/L) | LDH(U/L) | LPO (nM/ restrains weight in wet base) | FFA(μEq/L) | |
| The total Saponin II of the blank group ischemic control group total saponin I group of positive drug group group | 74.9±16.2 91.2±11.0 * 75.3±10.8 * 85.5±14.3 77.0±10.7 * | 2390±444 2949±369 * 2495±342 * 2754±433 2440±262 * | 96±11.1 143.3±20.1 ** 121.9±15.1 * 132.7±21.6 111.6±16.3 ** | 227.2±49.6 33 1.4±87.0 * 242.9±63.8 * 278.5±71.4 252.3±53.7 * |
*The t assay shows with blank group diversity remarkable, P＜0.05;
*The t assay shows with ischemia pathological changes matched group diversity very remarkable, P＜0.01.
When the myocardial ischemia anoxia, the endochylema membrane permeability increases, and causes endocellular enzyme to be released into blood flow and thereby serum CPK and LDH gross activity is increased.From the result shown in the table 3 as can be seen, different third adrenal gland of subcutaneous injection causes the serum CPK and the LDH gross activity of the ischemic control treated animal of myocardial ischemic injury to be significantly higher than blank group (P＜0.05).Oral administration can make the increase of serum CPK and LDH gross activity be subjected to remarkable inhibition after with beta-blocker Propranolol or panax quinquefolium saponin compositions, shows that the panax quinquefolium saponin compositions has almost completely identical defencive function with the general bitter edible plant Luo Er of known anti-myocardial damage medicine.In addition, it can also be seen that the panax quinquefolium saponin compositions can suppress equally as the myocardium LPO level of myocardial ischemic injury indication and the increase of FFA level from the result shown in the table 3.Embodiment 5: the panax quinquefolium saponin compositions is to the influence of animal cardiac muscle blood flow and oxygen metabolism
Present embodiment illustrates with panax quinquefolium saponin as the pharmaceutical composition (hereinafter to be referred as the panax quinquefolium saponin compositions) of primary activity composition to anaesthetizing down myocardial flow, coronary resistance and myocardium coefficient of oxygen utilization and the exponential influence of myocardial oxygen consumption of opening the breast animal, so as to estimating the facilitation effect of said pharmaceutical composition to animal cardiac muscle blood flow level and oxygen metabolism.
The hybrid dog of 10 body weight 11.9 ± 1.6kg is divided into two groups at random.Behind intravenous injection pentobarbital sodium (30mg/kg) anesthetized animal, tracheal intubation practices artificial respiration.In the 4th intercostal incision animal thoracic cavity and separate LCA, a left side, then electromagnetic flowmeter (MF-2F type) probe is placed the LC root.Behind femoral arteriography, use the blood stream pressure sensor record femoral blood pressure that is connected to the wave amplitude amplifying device, write down the standard limbs II lead electrocardiogram of animal simultaneously by implanted electrodes.Perform the operation used eight road above-mentioned each parameter of physiology monitors record as administration in back 30 minutes before data.By per kilogram the weight of animals 25mg or the 50mg dosage transfemoral catheterization of femoral vein injection panax quinquefolium saponin composition solution (1ml/kg) that comes into operation, write down above-mentioned data after the administration in 20,30 and 60 minutes once more.Stopped up with femoral artery from Coronary vein in 30,60 minutes before administration and after the administration in addition and take a blood sample simultaneously, and monitor blood oxygen concentration with CORNING 178 type blood gas analyzers.Calculate each parameter by following formula:
Myocardial oxygen consumption (the ml/100g cardiac muscle/minute)=(femoral artery blood oxygen amount Coronary vein stops up blood oxygen amount coronary flow 0
Myocardial oxygen consumption index=heart rate * blood pressure * 10
-2
Shown in the following tabulation 4 of experimental result.All data are all represented with the mean+SD of every group of 5 animals.With the significance of difference (p value) between each corresponding parameter before and after the t method of inspection comparison administration.
Table 4 panax quinquefolium saponin compositions is to the influence of animal (dog) myocardial flow and myocardium oxygen metabolism ability
| Detect | Dosage (mg/kg) | Before the administration | After the administration (branch) | |||
| 5 | 10 | 30 | 60 | |||
| Myocardial flow (the ml/100g cardiac muscle/minute) | 25 50 | 72±33 98±17 | 69±48 104±22 * | 69±45 105±19 * | 79±33 106±13 * | 74±33 102±16 * |
| Coronary resistance (the Kpa/ml/100g cardiac muscle/minute) | 25 50 | 0.19±0.08 0.15±0.02 | 0.18±0.08 0.14±0.03 | 0.18±0.08 0.14±0.03 | 0.17±0.07 0.13±0.01 * | 0.17±0.0700.1 3±0.01 * |
| Myocardial oxygen consumption (the ml/100g cardiac muscle/minute) | 25 50 | 31±9 33±8 | —— —— | —— —— | 32±9 28±11 | 28±12 21±7 * |
| Cardiac muscle coefficient of oxygen utilization (%) | 25 50 | 56±7 63±11 | —— —— | —— —— | 52±15 58±12 | 56±4 59±9 |
| The myocardial oxygen consumption index | 25 50 | 23.2±2.4 26.4±2 3 | —— —— | —— —— | 20.9±2.8 23.0±3.0 * | 20.8±2.6 23.0±3.2 * |
*With the p that compares before the administration＜0.05:
*With the p that compares before the administration＜0.01.
From the experimental data shown in the table 4 as can be seen, intravenous injection panax quinquefolium saponin compositions 50mg/kg body weight, after the administration in 5-60 minute myocardial flow and hat vascular resistance obviously increase (p＜0.05 or 0.01) before than administration.Intravenous injection panax quinquefolium saponin compositions 50mg/kg body weight, 60 minutes visible myocardial oxygen consumption obviously reduce (p＜0.05) before than administration after the administration.Though see medicine after the administration myocardium coefficient of oxygen utilization is not had a significant effect, after the administration 30 and 60 minutes the time visible myocardial oxygen consumption index obviously reduce (p＜0.05) before than administration.When coming into operation the panax quinquefolium saponin compositions of relative smaller dose (25mg/kg body weight), myocardial flow and above-mentioned myocardium oxygen metabolism parameter are not seen that tangible influence is arranged.
Therefore, the conclusion of this research is, comes into operation with intravenous route that the panax quinquefolium saponin compositions of heavy dose of (50mg/kg body weight) can increase the myocardial flow of animal significantly, and reduces the coronary artery circulation resistance.Both act on the time-histories basically identical.In addition, although panax quinquefolium saponin compositions of the present invention does not have obvious influence to myocardium coefficient of oxygen utilization, it can reduce myocardium consumption rate and oxygen consumption index (table 4) significantly.
Embodiment 6: the panax quinquefolium saponin compositions is to experimental myocardial infarction animal hearts function and hemodynamic influence
Present embodiment illustrates with panax quinquefolium saponin as the influence to experimental myocardial infarction animal hearts index, SI and left ventricular work index etc. of the pharmaceutical composition (hereinafter to be referred as panax quinquefolium saponin) of primary activity composition, so as to estimating the enhanced activity of said pharmaceutical composition to the animal hearts function.
The hybrid dog of 18 body weight about 12 to 16kg is divided into three groups at random: saline control group, low-dose drugs group (panax quinquefolium saponin compositions 25mg/kg), high dose medicament group (panax quinquefolium saponin compositions 50mg/kg).Every group of 6 animals.Behind intravenous injection pentobarbital (30mg/kg) anesthetized animal, tracheal intubation is carried out malleation artificial respiration (12-16 time/minute).Operation is opened a blunt edge that a ligation heart coronary artery left side behind the breast circles round and is propped up and left anterior descending first and second branch, and props up and ramus anastomoticus with each side of pure edge Zhi Xianglian.In order to guarantee the concordance of myocardial infarct size between animal as much as possible, stipulate that pre-ischemic region should be equivalent to 1/2 area of left ventricle antetheca, and determine the position and the number of ligation coronary vasodilator according to this.Ligation blood vessel at twice: ligation for the first time (use mosquito forceps) was decontroled 5 minutes after 5 minutes, then to each treated animal come into operation panax quinquefolium saponin compositions of normal saline or various dose of intravenous respectively; Carried out the ligation second time after the administration in 5 minutes.Detected in 5,20,40 and 90 minutes before administration and after the administration and the record following parameters: with limbs II lead recording ecg (ECG) and heart rate (HR), measure arteriotony (mAP) (Kpa) through the common carotid artery intubate with pressure transducer, cardiac output (CO) (ml/ branch) with electromagnetic flowmeter determination, with the left ventricular pressure (LVP) of pressure transducer record (Kpa), according to LVP curved measurement left ventricular pressure peak value (LVSP) (Kpa) and the whole end of left ventricle contract and press (LVEDP) (Kpa).LVP signal of telecommunication input differentiator is traced the dp/dt curve, and record the maximum rate of change (± dp/dt max) (Kpa/ second) of left ventricular pressure from the dp/dt curve.Calculate each relevant parameter by following formula:
Shown in the following tabulation 5 of testing result.All data are all represented with the mean+SD of every group of 6 animals.With the normal saline processed group (matched group) in the t method of inspection comparative experiments myocardial inyaretion animal and the significance of difference between various dose (25mg/kg and 50mg/kg) panax quinquefolium saponin compositions-treated group (experimental group).
Table 5 panax quinquefolium saponin compositions is to cardiac function and the hemodynamic influence of experimental myocardial infarction animal (dog)
| Handle | Handle the back time (hour | mAP | LVSP | LVEDP | dp/dt max | CI | SI | LVWI |
| Normal saline | 5 20 40 90 | 9.5±0.9 8.5±1.2 8.3±0.9 7.9±0.9 | 16.3±0.9 15.5±0.6 15.1±0.9 14.1±0.4 | 2.30±0.86 2.28±0.86 2.20±0.75 2.35±0.63 | 119±51 145±80 173±100 144±69 | 1512±467 1453±558 1381±48 1137±352 | 18.7±5.7 18.1±7.1 16.8±6.7 14.6±4.5 | 13.7±4.6 11.8±4.5 10.5±4.2 8.2±2.8 |
| Panax quinquefolium saponin compositions (25mg/kg) | 5 20 40 90 | 12.0±0.1 12.0±1.4 11.7±10 11.3±11 | 19.3±0.9 18.8±1.1 18.5±1.6 17.6±1.6 | 1.80±0.42 1.81±0.60 1.79±0.42 1.89±0.54 | 253±82 263±66 255±79 233±62 | 1832±838 1762±726 1602±732 1430±658 | 18.8±10.0 18.2±9.7 16.3±8.7 14.9±6.2 | 19.7±9.6 18.9±10.1 16.5±8.6 13.8±5.4 |
| Panax quinquefolium saponin compositions (50mg/kg) | 5 20 40 90 | 11.9±1.5 11.1±1.9 10.9±2.0 11.1±1.9 | 18.0±1.1 18.1±1.2 17.7±1.3 1713±1.3 | 1.61±0.47 1.78±0.39 1.81±0.39 2.09±0.30 | 195±26 196±30 186±30 163±9 | 1637±442 1632±498 1628±574 1563±715 | 18.1±5.0 17.9±5.4 17.9±6.2 16.8±7.7 | 18.9±5.4 17.1±5.9 16.8±6.7 15.3±7.4 |
From the data shown in the last tabulation 5 as can be seen, in 40 hour observing time after causing zoopery myocardial inyaretion model through the ligation coronary artery, the control animals arteriotony (mAP) of only injecting physiologic dose brine descends and reaches more than 22%, and the experimental group animal of come into operation low or high dose panax quinquefolium saponin compositions then descends 3.8% and 14.2% respectively.On the other hand, in 90 fens clock times after causing myocardial infarction, compare animal LVAP, the LVEDP of the panax quinquefolium saponin compositions that comes into operation, dp/dt max and improvement is significantly all arranged by cardiac index (CI), SI (SI) and left ventricular work index cardiac function such as (LVWI) and cardiac hemodynamic parameter that these and other measured values are calculated with the matched group of the normal saline that only comes into operation.Therefore can think that the panax quinquefolium saponin compositions can alleviate or delay the circulatory function decay that myocardial infarction causes significantly, and can improve myocardium systolic and diastolic capacity and ventricular stroke work ability, thereby the protection heart delays the generation or the development of heart failure.Imitate the magnitude relation angle from medicine, as if do not have significant difference between high dose group and the low dose group.
Claims (6)
1. one kind is the primary activity composition with the panax quinquefolium saponin compositions, and contain the pharmaceutical composition of one or more medically acceptable carriers and/or excipient, wherein said panax quinquefolium saponin is under the condition of boiling, through three water extraction, filter and, obtain with the 95-98% ethanol elution with after the macroporous resin adsorption filtrate.
2. according to the pharmaceutical composition of claim 1, wherein said panax quinquefolium saponin composition levels as the primary activity composition is at least 50% (w/w).
3. according to the pharmaceutical composition of claim 1 or 2, wherein said panax quinquefolium saponin compositions as the primary activity composition is at least by the Ginsenoside Rb
2, Rb
3, Rd, Re, Rg
1, F
2, RT
5And anthropomorphic ginseng Saponin F
11Eight kinds of monomers are formed.
4. according to the pharmaceutical composition of claim 1, can contain also wherein that one or more are natural or chemosynthesis, with primary activity composition panax quinquefolium saponin compositions auxiliary or synergistic other active component are arranged.
5. producing with the panax quinquefolium saponin compositions is the method for the pharmaceutical composition of primary activity composition, and this method comprises:
1) provides the panax quinquefolium saponin that any one limited in the claim 1 to 3;
2) the panax quinquefolium saponin compositions that step 1) is obtained is mixed mutually with one or more pharmaceutically acceptable carriers and/or excipient.
6. according to the method for claim 5, wherein said pharmaceutical composition can be added with also that one or more are natural synthetic, with primary activity composition panax quinquefolium saponin compositions auxiliary or synergistic other active component is arranged.
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| CN102258600A (en) * | 2011-07-06 | 2011-11-30 | 孙晓波 | Medicine composition for treating cardiovascular disease |
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| CN102010456B (en) * | 2010-12-06 | 2012-07-25 | 吉林圣亚医药科技有限公司 | Method for extracting pseudoginsenoside RT5 and medical application |
| CN102228535B (en) * | 2011-07-06 | 2013-10-02 | 孙晓波 | Application of total saponins and total flavones in preparation of drugs for treating cardiovascular diseases |
| CN110393734A (en) * | 2019-08-26 | 2019-11-01 | 吉林农业大学 | Quinquefolium saponin delays the new application of chemotherapeutics cause cardiac muscle cross striation disorder drug and health care product in preparation |
| CN115006419A (en) * | 2022-06-06 | 2022-09-06 | 山东第一医科大学(山东省医学科学院) | Application of pseudoginsenoside F11 in preparation of medicine for treating heart failure, medicine for treating heart failure and preparation method |
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| CN1071583A (en) * | 1991-10-17 | 1993-05-05 | 新宾满族自治县建州人参加工总厂 | A kind of white ginseng processing |
| CN1168383A (en) * | 1997-06-27 | 1997-12-24 | 吉林大学 | Combined extraction technology of ginseng and American ginseng polysaccharide saponin |
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|---|---|---|---|---|
| CN1071583A (en) * | 1991-10-17 | 1993-05-05 | 新宾满族自治县建州人参加工总厂 | A kind of white ginseng processing |
| CN1168383A (en) * | 1997-06-27 | 1997-12-24 | 吉林大学 | Combined extraction technology of ginseng and American ginseng polysaccharide saponin |
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| CN102258600A (en) * | 2011-07-06 | 2011-11-30 | 孙晓波 | Medicine composition for treating cardiovascular disease |
| CN102258600B (en) * | 2011-07-06 | 2012-07-25 | 孙晓波 | Medicine composition for treating cardiovascular disease |
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