CN1911219A - Medicine composition, and its application for treating diseases of cardiovascular and cerebrovascular - Google Patents
Medicine composition, and its application for treating diseases of cardiovascular and cerebrovascular Download PDFInfo
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Abstract
A medical composition for treating the cardiovascular and cerebrovascular diseases including angina pectoris, coronary heart disease, ischemic cerebral apoplexy, cerebral ischemia/refilling injury, etc is prepared from hydroxy safflo yellow A and danshensu.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and its production and use, relate to pharmaceutical composition and the application in the medicine of preparation treatment or prevention cardiovascular and cerebrovascular disease thereof formed by danshensu and S-A Hydroxysafflor yellow A particularly.
Background technology
For a long time, along with the acceleration of aged tendency of population process and the change of life style, cardiovascular and cerebrovascular disease is the underlying cause of death of developed country always, wherein the death that causes of cardiac disorder is positioned at second, the mortality rate of cerebrovascular accident occupy the 3rd at world wide, China because of the dead ratio of arteriosclerosis up to 1/3, visible cardiovascular and cerebrovascular disease has become a global health problem, the health that endangers the people greatly.The exploitation of novel and effective control cerebrovascular medicine has been urgent clinical needs.
S-A Hydroxysafflor yellow A extracts acquisition from Flos Carthami, be the effective ingredient of Flos Carthami, and S-A Hydroxysafflor yellow A has anti-local cerebral ischemia damage, the cerebral blood flow increasing amount can suppress the platelet aggregation that platelet activating factor brings out, and removes free radical, suppresses lipid peroxidation, protection cell membrane [Zang Baoxia, gold ring, compass in ancient China, Deng, S-A Hydroxysafflor yellow A is to the antagonism of platelet activating factor, Acta Pharmaceutica Sinica, 2002,37 (9), 696-699; Jin Ming, Li Jinrong, Wu Wei, S-A Hydroxysafflor yellow A Antioxidation Effects, Chinese herbal medicine, 2004,35 (6): 665-666].
Danshensu (chemistry β-3 by name, 4-dihydroxyphenyl lactic acid) extracts from Radix Salviae Miltiorrhizae and obtains, and is the effective ingredient of Radix Salviae Miltiorrhizae.The bibliographical information danshensu has the certain protection effect aspect cardiovascular and cerebrovascular disease, see [Jiang Wende, Chen Yuhua, Wang Yingping, etc. the Shanghai first medical college journal, 1982,9 (1): 13-94.]; [Tang Lihui, Wang Xiaoming, Liang Dianquan, etc. Chinese Journal of Pathophysiology, 1989,6 (2): 65-9.]; [tension force, Wang Xiaoming, Liang Dianquan, etc. Chinese Journal of Pathophysiology, 1990,6 (6): 420-423.]; [Chang Yingzi, Liang Dianquan, Wang Xiaoming, etc. Chinese Journal of Pathophysiology, 1991,7 (5): 449-452.]; [Su Xiaohua, Liang Dianquan, Wang Xiaoming. Pathophysiology magazine, 1992,8 (2): 122-124.]; [Gu Yanghong, Zhang Caiying, Huang Guiqiu, etc. Shanghai Second Emdical University's journal, 1990,10 (3): 208-211.]; [Li Chengzhu, Yang Shichun, Zhao Fengdi, etc. combination of Chinese and Western medicine magazine, 1983,3 (5): 297-299.].
The inventor is by a large amount of experimentatioies, a kind of pharmaceutical composition and application of being made up of danshensu and S-A Hydroxysafflor yellow A in the medicine of preparation treatment or prevention cardiovascular and cerebrovascular disease thereof is provided, and this pharmaceutical composition has synergism when being used for cardiovascular and cerebrovascular disease.
Summary of the invention
The invention provides a kind of pharmaceutical composition of being made up of S-A Hydroxysafflor yellow A and danshensu, its weight ratio is 1: 9～9: 1, is preferably 1: 5～5: 1, and danshensu can also exist with the form of slaine, is preferably sodium salt.
The invention provides the preparation of drug combination method of forming by S-A Hydroxysafflor yellow A and danshensu.
The invention provides the application of above-mentioned composition in the medicine of preparation treatment or prevention cardiovascular and cerebrovascular disease.
The invention provides the application of above-mentioned composition in preparing treatment or prevention coronary heart disease, anginal medicine.
The invention provides the application of above-mentioned composition in the medicine of preparation treatment or prevention ischemia apoplexy.
The invention provides the application of above-mentioned composition in the medicine of preparation treatment or prevention of brain ischemia/reperfusion injury.
The invention provides the application of above-mentioned composition in the medicine of preparation treatment or prevention of brain wound.
Pharmaceutical composition provided by the invention can be by oral, Sublingual, percutaneous, through muscle or subcutaneous, mucocutaneous, intravenous route administration.Pharmaceutical composition can exist with the form of injectable powder, injection, tablet, capsule, soft capsule, drop pill or oral liquid, is preferably freeze-dried powder.Various pharmaceutical dosage form provided by the present invention all can be prepared from the pharmacy conventional method.
Pharmaceutical composition provided by the invention is when being used for such use, and its using dosage scope is 60mg-2000mg, preferred 60mg-1000mg.
Pharmaceutical composition provided by the invention, the content of its active component are 60-2000mg.
S-A Hydroxysafflor yellow A of the present invention extraction separation from Flos Carthami obtains, and adopts water extraction, and last low pole macroporous adsorbent resin is gone up polyamide column again, its content (weight) 〉=90%.
Danshensu of the present invention is that extraction separation obtains from Radix Salviae Miltiorrhizae, adopts water extraction, last macroporous adsorbent resin, content of Danshensu (weight) 〉=90%.
The inventor has carried out following pharmacological testing and has confirmed that the pharmaceutical composition of being made up of danshensu and S-A Hydroxysafflor yellow A has synergism when the purposes of preparation treatment or prevention cardiovascular and cerebrovascular disease.
The specific embodiment:
Preparation example 1: the preparation of S-A Hydroxysafflor yellow A, danshensu
Get dry flos carthami 10kg, water extraction 3 times, each 1 hour, merge extractive liquid; Filter, it is 1.05 (80 ℃) that filtrate decompression is concentrated into density, and adding ethanol to determining alcohol is 80%, precipitates 24 hours down in 4 ℃, filters; Filtrate to there not being the alcohol flavor, adds to the DM-130 macroporous adsorbent resin of handling well on 10 times of water dilution backs in 60 ℃ of decompression recycling ethanols, and applied sample amount (being equivalent to the crude drug amount) is 1: 1 (w/v) with the ratio of resin demand, with 3 column volumes of deionized water eluting, discards; Continue to collect eluent with 5 column volumes of deionized water eluting.Eluent is splined on the polyamide column of handling well, and the ratio that applied sample amount is equivalent to crude drug amount and resin demand is 3: 1 (w/v), with 3 column volumes of deionized water eluting, discards earlier; Continue with 8 column volumes of 95% alcoholic solution eluting, collect eluent in 60 ℃ of decompression recycling ethanols, drying under reduced pressure promptly gets S-A Hydroxysafflor yellow A 9.563g, and purity is 90.8%.
Getting Radix Salviae Miltiorrhizae 10kg crude drug pulverizes, the NaOH that adds 12 times of amounts 0.5% decocts twice, each 1.5 hours, filter, merging filtrate adsorbs (volume ratio of extracting solution and resin 3: 1) with the alkalescence macroporous adsorbent resin, with deionized water eluting 3-5 column volume, 2 column volumes of the NaOH eluting of reuse 0.4%, collect eluent, the adjusting pH value is 2-5, adsorbs (volume ratio of extracting solution and resin 3: 1) with low pole or nonpolar macroporous adsorption resin, with washing 5 column volumes again behind 1-2 column volume of deionized water eluting, collect eluent, concentrate crystallization, get danshensu sodium 9.626g, purity is 91.3%.
Preparation example 2: the preparation of S-A Hydroxysafflor yellow A, danshensu
Get dry flos carthami 10kg, water extraction 3 times, each 1 hour, merge extractive liquid; Filter, it is 1.15 (80 ℃) that filtrate decompression is concentrated into density, and adding ethanol to determining alcohol is 80%, precipitates 24 hours down in 4 ℃, filters; Filtrate to there not being the alcohol flavor, adds to the AB-8 macroporous adsorbent resin of handling well on 10 times of water dilution backs in 60 ℃ of decompression recycling ethanols, and applied sample amount (being equivalent to the crude drug amount) is 1: 1 (w/v) with the ratio of resin demand, with 3 column volumes of deionized water eluting, discards; Continue 5 column volumes of deionized water eluting, collect eluent.Eluent is splined on the polyamide column of handling well, and the ratio that applied sample amount is equivalent to crude drug amount and resin demand is 3: 1 (w/v), with 3 column volumes of deionized water eluting, discards earlier; Continue with 8 column volumes of 95% alcoholic solution eluting, collect eluent in 60 ℃ of decompression recycling ethanols, drying under reduced pressure promptly gets S-A Hydroxysafflor yellow A 9.321g, and purity is 92.1%.
Getting Radix Salviae Miltiorrhizae 10kg crude drug pulverizes, the NaOH that adds 12 times of amounts 0.5% decocts twice, each 1.5 hours, filter, merging filtrate adsorbs (volume ratio of extracting solution and resin 3: 1) with the alkalescence macroporous adsorbent resin, with deionized water eluting 3-5 column volume, 2 column volumes of the NaOH eluting of reuse 0.4% are collected eluent, and the adjusting pH value is 2-5, adsorb (volume ratio of extracting solution and resin 3: 1) with low pole or nonpolar macroporous adsorption resin, with washing 5 column volumes again behind 1-2 column volume of deionized water eluting, collect eluent, concentrate, adding an amount of HCl transfers pH to acid, crystallization gets danshensu sodium 9.356g, and purity is 91.5%.
Preparation example 3: the freeze-dried powder that preparation is made up of S-A Hydroxysafflor yellow A and danshensu
Under cleaning condition, get S-A Hydroxysafflor yellow A 54g, danshensu 6g, be dissolved in 1000mL water for injection, add 100g mannitol, stirring and dissolving, ultrafiltration, obtain apyrogenic clear liquor, pour in the 10mL cillin bottle, 1.0mL/ only, press the lyophilizing of freeze-dried powder technology, make the freeze-dried powder of hydroxyl carthamin yellow A-containing 54mg, danshensu 6mg.
Preparation example 4: the freeze-dried powder that preparation is made up of S-A Hydroxysafflor yellow A and danshensu
Under cleaning condition, get S-A Hydroxysafflor yellow A 6g, danshensu 54g, be dissolved in 1000mL water for injection, stirring and dissolving, ultrafiltration obtains apyrogenic clear liquor, pour in the 10mL cillin bottle, 1.0mL/ only, press the lyophilizing of freeze-dried powder technology, make the freeze-dried powder of hydroxyl carthamin yellow A-containing 6mg, danshensu 54mg.
Preparation example 5: the freeze-dried powder that preparation is made up of S-A Hydroxysafflor yellow A and danshensu
Under cleaning condition, get S-A Hydroxysafflor yellow A 10g, danshensu 50g, be dissolved in 1000mL water for injection, add the 100g low molecular dextran, stirring and dissolving, ultrafiltration, obtain apyrogenic clear liquor, pour in the 10mL cillin bottle, 1.0mL/ only, press the lyophilizing of freeze-dried powder technology, make the powder pin of hydroxyl carthamin yellow A-containing 10mg, danshensu 50mg.
Preparation example 6: the freeze-dried powder that preparation is made up of S-A Hydroxysafflor yellow A and danshensu
Under cleaning condition, get S-A Hydroxysafflor yellow A 40g, danshensu 20g, be dissolved in 1000mL water for injection, add the 100g low molecular dextran, stirring and dissolving, ultrafiltration, obtain apyrogenic clear liquor, pour in the 10mL cillin bottle, 1.0mL/ only, press the lyophilizing of freeze-dried powder technology, make the freeze-dried powder of hydroxyl carthamin yellow A-containing 40mg, danshensu 20mg.
Preparation example 7: the freeze-dried powder that preparation is made up of S-A Hydroxysafflor yellow A and danshensu
Under cleaning condition, get S-A Hydroxysafflor yellow A 20g, danshensu 40g, be dissolved in 1000mL water for injection, stirring and dissolving, ultrafiltration obtains apyrogenic clear liquor, pour in the 10mL cillin bottle, 1.0mL/ only, press the lyophilizing of freeze-dried powder technology, make the freeze-dried powder of hydroxyl carthamin yellow A-containing 20mg, danshensu 40mg.
Preparation example 8: the freeze-dried powder that preparation is made up of S-A Hydroxysafflor yellow A and danshensu
Under cleaning condition, get S-A Hydroxysafflor yellow A 50g, danshensu 10g, be dissolved in 1000mL water for injection, stirring and dissolving, ultrafiltration obtains apyrogenic clear liquor, pour in the 10mL cillin bottle, 1.0mL/ only, press the lyophilizing of freeze-dried powder technology, make the freeze-dried powder of hydroxyl carthamin yellow A-containing 50mg, danshensu 10mg.
Preparation example 9: the freeze-dried powder that preparation is made up of S-A Hydroxysafflor yellow A and danshensu
Under cleaning condition, get S-A Hydroxysafflor yellow A 75g, danshensu 75g, be dissolved in 1000mL water for injection, stirring and dissolving, ultrafiltration obtains apyrogenic clear liquor, pour in the 10mL cillin bottle, 1.0mL/ only, press the lyophilizing of freeze-dried powder technology, make the freeze-dried powder of hydroxyl carthamin yellow A-containing 75mg, danshensu 75mg.
Preparation example 10: the freeze-dried powder that preparation is made up of S-A Hydroxysafflor yellow A and danshensu
Under cleaning condition, get S-A Hydroxysafflor yellow A 100g, danshensu 20g, be dissolved in 1000mL water for injection, stirring and dissolving, ultrafiltration obtains apyrogenic clear liquor, pour in the 10mL cillin bottle, 1.0mL/ only, press the lyophilizing of freeze-dried powder technology, make the freeze-dried powder of hydroxyl carthamin yellow A-containing 100mg, danshensu 20mg.
Preparation example 11: the freeze-dried powder that preparation is made up of S-A Hydroxysafflor yellow A and danshensu
Under cleaning condition, get S-A Hydroxysafflor yellow A 20g, danshensu 100g, be dissolved in 1000mL water for injection, stirring and dissolving, ultrafiltration obtains apyrogenic clear liquor, pour in the 10mL cillin bottle, 1.0mL/ only, press the lyophilizing of freeze-dried powder technology, make the freeze-dried powder of hydroxyl carthamin yellow A-containing 20mg, danshensu 100mg.
Preparation example 12: the freeze-dried powder that preparation is made up of S-A Hydroxysafflor yellow A and danshensu
Under cleaning condition, get S-A Hydroxysafflor yellow A 90g, danshensu 10g, be dissolved in 1000mL water for injection, stirring and dissolving, ultrafiltration obtains apyrogenic clear liquor, pour in the 10mL cillin bottle, 1.0mL/ only, press the lyophilizing of freeze-dried powder technology, make the freeze-dried powder of hydroxyl carthamin yellow A-containing 90mg, danshensu 10mg.
Preparation example 13: the freeze-dried powder that preparation is made up of S-A Hydroxysafflor yellow A and danshensu
Under cleaning condition, get S-A Hydroxysafflor yellow A 10g, danshensu 90g, be dissolved in 1000mL water for injection, stirring and dissolving, ultrafiltration obtains apyrogenic clear liquor, pour in the 10mL cillin bottle, 1.0mL/ only, by freeze-dried powder technology freeze in, make the freeze-dried powder of hydroxyl carthamin yellow A-containing 10mg, danshensu 90mg.
Test example 1: different proportioning pharmaceutical compositions are to the influence of rat local cerebral ischemia damage
(1) material: S-A Hydroxysafflor yellow A, danshensu, by preparation example 1 preparation, compositions: preparation in proportion as required.Red tetrazolium: U.S. Sigma company product, face with preceding and be made into 4% solution with normal saline.
Nim: Shandong XinHua Pharmacy stock Co., Ltd, 040705,1.0mg/100ml.
Laboratory animal: the SD rat, Shandong greenery natural drug Societe Principia Research Development Experimental Animal Center provides, the quality certification number: SYXK (Shandong) 20030020.
(2) method and result:
Animal is divided into sham operated rats (normal saline) at random, model control group (normal saline), Nim (1.0mg/kg) group, S-A Hydroxysafflor yellow A low dose (2mg/kg) group, dosage in the S-A Hydroxysafflor yellow A (6mg/kg) group, danshensu low dose (2mg/kg) group, dosage in the danshensu (6mg/kg) group, compositions 1[S-A Hydroxysafflor yellow A (5.4mg/kg)+danshensu (0.6mg/kg)], compositions 2[S-A Hydroxysafflor yellow A (5mg/kg)+danshensu (1mg/kg)], compositions 3[S-A Hydroxysafflor yellow A (0.6mg/kg)+danshensu (5.4mg/kg)], compositions 4[S-A Hydroxysafflor yellow A (1mg/kg)+danshensu (5mg/kg)], compositions 5[S-A Hydroxysafflor yellow A (3mg/kg)+danshensu (3mg/kg)], compositions 6[S-A Hydroxysafflor yellow A (4mg/kg)+danshensu (2mg/kg)], compositions 7[S-A Hydroxysafflor yellow A (2mg/kg)+danshensu (4mg/kg)], compositions 8[S-A Hydroxysafflor yellow A (30mg/kg)+danshensu (30mg/kg)], compositions 9[S-A Hydroxysafflor yellow A (50mg/kg)+danshensu (50mg/kg)], compositions 10[S-A Hydroxysafflor yellow A (100mg/kg)+danshensu (100mg/kg)], composition oral group [S-A Hydroxysafflor yellow A (15mg/kg)+danshensu (15mg/kg)], 10 every group.After the fasting 12 hours, and chloral hydrate (350mg/kg, i.p.) anesthesia separates right carotid, and folder closes in the neck, common carotid artery, external carotid artery proximal part and distal end ligation, cut off the centre.The external carotid artery free-end is pulled to internal carotid artery in alignment, bolt line (selecting diameter 0.24mm nylon wire for use, length 5.0cm) is inserted into intracranial by external carotid artery, stop when meeting slight resistance, insertion depth is about 2cm.Ligation external carotid artery opening, and open the common carotid artery bulldog clamp, the disinfection and stitching wound causes right side middle cerebral artery ischemia model; The sham group is only carried out the separation (above experiment is all carried out at 23 ℃～25 ℃) of right carotid, internal carotid artery, external carotid artery.Composition oral dosage group successive administration 3 days, fasting is after 16 hours after administration in the 2nd day, and administration in the 3rd day was performed the operation after 30 minutes, and all the other respectively organize postoperative intravenous injection relative medicine.Press document [Liu Xiaoguang, Xu Lina, a kind of rat brain medium-sized artery model that can estimate thrombolytic and anti-thrombolytic after 24 hours, Acta Pharmaceutica Sinica, 1995,30:662] described method and standard is observed and the behavior disorder of record rat: (A) carry the Mus tail and observe forelimb flexing situation, stretch to ground as two forelimb symmetries, count 0 fen, the wrist flexing occurs as operation offside forelimb and count 1 fen, the elbow flexing is counted 2 fens, the shoulder inward turning is counted 3 fens, existing wrist flexing and/or elbow flexing have shoulder inward turning person again, count 4 fens.(B) animal is placed on the plane earth, push away both shoulders respectively, check resistance to side shifting.As bilateral resistance equity and strong, count 0 fen, as resistance descender when the operation offside promotes, according to decline degree difference be divided into gently, in, weigh three degree, count 1,2 and 3 fen respectively.(C) the two forelimbs of animal are put on the wire netting, observed the muscular tension of two forelimbs.Two muscle of anterior limb tension force equities and strong person count 0 fen.Count 1,2 and 3 fen according to operation offside muscular tension decline degree difference equally.(D) animal has ceaselessly to a side person of turn-taking, and counts 1 fen.According to the standard scoring, full marks are 11 minutes, and mark is high more, and expression animal behavior obstacle is serious more.
Put to death rat behind the behavior scoring, get brain, remove olfactory bulb, cerebellum and low brain stem, crownly be cut into 5, the brain sheet takes on a red color after normal structure is dyed with red tetrazolium (TTC) dyeing, and blocking tissue is white in color, taking a picture in dyeing back, asks the infarct size ratio with Chinese Aero-Space university pathological image analysis software.
Data represent that with x ± SD the cerebral ischemia area carries out statistical procedures with t check between group, and the behavior disorder mark carries out statistical procedures with rank test between group.
The result is as shown in table 1, and ischemia is after 24 hours, and the model group rat shows tangible behavior disorder, and tangible kitchen range shape ischemic region also appears in rat cerebral tissue, reaches about 24% of full brain.S-A Hydroxysafflor yellow A low dose (2mg/kg) group, danshensu low dose (2mg/kg) group are failed to improve the rat behavior obstacle, are reduced ischemic areas; Dosage in the S-A Hydroxysafflor yellow A (6mg/kg) group, dosage in the danshensu (6mg/kg) group, composition oral group [S-A Hydroxysafflor yellow A (15mg/kg)+danshensu (15mg/kg)] are improved the rat behavior obstacle, are reduced ischemic areas (P＜0.05; Compositions 1[S-A Hydroxysafflor yellow A (5.4mg/kg)+danshensu (0.6mg/kg)], compositions 2[S-A Hydroxysafflor yellow A (5mg/kg)+danshensu (1mg/kg)], compositions 3[S-A Hydroxysafflor yellow A (0.6mg/kg)+danshensu (5.4mg/kg)], compositions 4[S-A Hydroxysafflor yellow A (1mg/kg)+danshensu (5mg/kg)], compositions 5[S-A Hydroxysafflor yellow A (3mg/kg)+danshensu (3mg/kg)], compositions 6[S-A Hydroxysafflor yellow A (4mg/kg)+danshensu (2mg/kg)], compositions 7[S-A Hydroxysafflor yellow A (2mg/kg)+danshensu (4mg/kg)] significantly improve the rat behavior obstacle, reducing ischemic areas (compares with model group, p＜0.01), to improving the rat behavior obstacle, reduce ischemic areas and 6mg/kg danshensu group, 6mg/kg S-A Hydroxysafflor yellow A group relatively also has significant difference (p＜0.05); Compositions 8[S-A Hydroxysafflor yellow A (30mg/kg)+danshensu (30mg/kg)], compositions 9[S-A Hydroxysafflor yellow A (50mg/kg)+danshensu (50mg/kg)], compositions 10[S-A Hydroxysafflor yellow A (100mg/kg)+danshensu (100mg/kg)] improve the rat behavior obstacle extremely significantly, reduce ischemic areas (comparing p＜0.001) with model group, compositions 9[S-A Hydroxysafflor yellow A (50mg/kg)+danshensu (50mg/kg)] and compositions 10[S-A Hydroxysafflor yellow A (100mg/kg)+danshensu (100mg/kg)] relatively, to improving the rat behavior obstacle, reduce ischemic areas no significant difference (p＞0.05).The pharmaceutical composition treating cerebral ischemia of being made up of S-A Hydroxysafflor yellow A and danshensu obviously is better than singly using with dosage S-A Hydroxysafflor yellow A or danshensu (P＜0.05), and S-A Hydroxysafflor yellow A and danshensu have synergism in the prompting compositions.
The different proportioning pharmaceutical compositions of table 1 are to the influence of rat local cerebral ischemia damage
| Group | Dosage (mg/kg) | Behavior disorder | Ischemic areas (%) |
| Dosage group composition dosage group 1 composition dosage group 2 composition dosage groups 3 composition dosage groups 4 composition dosage groups 5 composition dosage groups 6 composition dosage groups 7 composition dosage groups 8 composition oral group composition dosage groups 9 composition dosage groups 10 in the dosage group hydroxyl radical carthamin yellow carthamus A small dose group hydroxyl radical carthamin yellow carthamus A in the sham group model control group Nim group danshensu small dose group danshensu | Physiological saline physiological saline 1.0 2626 5.4+0.6 5+1 0.6+5.4 1+5 3+3 4+2 2+4 30+30 15+15 50+50 100+100 | --- 9.80±0.92 6.60±2.21 ** 9.30±1.16 8.80±1.03 * 9.10±1.20 8.78±0.99 * 7.90±0.74 **#M 7.80±0.75 **#M 7.70±0.74 **#M 7.60±0.74 **#M 7.50±0.72 **#M 7.50±0.71 **#M 7.50±0.70 **#M 6.60±1.58 *** 8.71±0.95 * 5.95±1.60 *** 5.80±1.48 *** | --- 23.90±5.03 15.61±3.57 ** 22.32±5.21 19.65±3.61 * 21.83±3.16 19.60±3.57 * 16.36±2.90 **#M 16.20±2.80 **#M 16.16±2.90 **#M 16.26±2.90 **#M 16.10±2.90 **#M 16.05±2.90 **#M 16.09±2.90 **#M 15.1±2.80 *** 19.40±3.47 * 14.0±2.55 *** 13.9±2.39 *** |
Compare with model control group,
*P＜0.05,
*P＜0.01,
* *P＜0.001
Compare with dosage group in the danshensu,
#P＜0.05; Compare with dosage group in the S-A Hydroxysafflor yellow A,
MP＜0.05
Test example 2: different proportioning pharmaceutical compositions are to the influence of rat local cerebral ischemia/reperfusion injury
(1) material: S-A Hydroxysafflor yellow A, danshensu, by preparation example 1 preparation, compositions: preparation in proportion as required.
Laboratory animal: the SD rat, Shandong greenery natural drug Societe Principia Research Development Experimental Animal Center provides, the quality certification number: SYXK (Shandong) 20030020.
Nim: Shandong XinHua Pharmacy stock Co., Ltd, 040705,1.0mg/100ml.
(2) method and result:
Animal is divided into sham operated rats (normal saline) at random, model control group (normal saline), Nim (1.0mg/kg) group, S-A Hydroxysafflor yellow A low dose (2mg/kg) group, dosage in the S-A Hydroxysafflor yellow A (6mg/kg) group, danshensu low dose (2mg/kg) group, dosage in the danshensu (6mg/kg) group, compositions 1[S-A Hydroxysafflor yellow A (5.4mg/kg)+danshensu (0.6mg/kg)], compositions 2[S-A Hydroxysafflor yellow A (5mg/kg)+danshensu (1mg/kg)], compositions 3[S-A Hydroxysafflor yellow A (0.6mg/kg)+danshensu (5.4mg/kg)], compositions 4[S-A Hydroxysafflor yellow A (1mg/kg)+danshensu (5mg/kg)], compositions 5[S-A Hydroxysafflor yellow A (3mg/kg)+danshensu (3mg/kg)], compositions 6[S-A Hydroxysafflor yellow A (4mg/kg)+danshensu (2mg/kg)], compositions 7[S-A Hydroxysafflor yellow A (2mg/kg)+danshensu (4mg/kg)], compositions 8[S-A Hydroxysafflor yellow A (30mg/kg)+danshensu (30mg/kg)], compositions 9[S-A Hydroxysafflor yellow A (50mg/kg)+danshensu (50mg/kg)], compositions 10[S-A Hydroxysafflor yellow A (100mg/kg)+danshensu (100mg/kg)], composition oral group [S-A Hydroxysafflor yellow A (15mg/kg)+danshensu (15mg/kg)], 10 every group.After the fasting 12 hours, chloral hydrate (350mg/kg, i.p.) anesthesia, chloral hydrate (350mg/kg, i.p.) anesthesia separates bilateral carotid, after the bulldog clamp folder closes bilateral carotid 60min, unclamp the bulldog clamp of bilateral carotid, respectively organize the sublingual vein administration immediately, administration volume 0.4mL/200g, model control group gives the NS with volume, put to death rat after 24 hours, get brain, remove olfactory bulb, cerebellum and low brain stem.The sham component is from bilateral carotid but do not press from both sides and close bilateral carotid, and all the other are operated with above-mentioned.Gently inhale the moisture on brain surface with filter paper, weigh, 100 ℃ were dried by the fire 10 hours, took out, and cooling is weighed, and calculates brain water content.The brain percentage of moisture (%)=(cutaneous horn weight-brain stem is heavy)/heavy * 100% of cutaneous horn, data are represented with X ± s, carry out statistical procedures with t check between group.
The result is as shown in table 2, and after ischemia was irritated 24 hours again, model group rat brain water content reached 79.5%, and S-A Hydroxysafflor yellow A low dose (2mg/kg) group, danshensu low dose (2mg/kg) group fail to reduce brain water content; Dosage in the S-A Hydroxysafflor yellow A (6mg/kg) group, dosage in the danshensu (6mg/kg) group, composition oral group [S-A Hydroxysafflor yellow A (15mg/kg)+danshensu (15mg/kg)] reduce brain water content (P＜0.05); Compositions 1[S-A Hydroxysafflor yellow A (5.4mg/kg)+danshensu (0.6mg/kg)], compositions 2[S-A Hydroxysafflor yellow A (5mg/kg)+danshensu (1mg/kg)], compositions 3[S-A Hydroxysafflor yellow A (0.6mg/kg)+danshensu (5.4mg/kg)], compositions 4[S-A Hydroxysafflor yellow A (1mg/kg)+danshensu (5mg/kg)], compositions 5[S-A Hydroxysafflor yellow A (3mg/kg)+danshensu (3mg/kg)], compositions 6[S-A Hydroxysafflor yellow A (4mg/kg)+danshensu (2mg/kg)], compositions 7[S-A Hydroxysafflor yellow A (2mg/kg)+danshensu (4mg/kg)] significantly reduce brain water content (with the model group comparison, p＜0.01), reduce brain water content and 6mg/kg danshensu group, 6mg/kg S-A Hydroxysafflor yellow A group relatively also has significant difference (p＜0.05); Compositions 8[S-A Hydroxysafflor yellow A (30mg/kg)+danshensu (30mg/kg)], compositions 9[S-A Hydroxysafflor yellow A (50mg/kg)+danshensu (50mg/kg)], compositions 10[S-A Hydroxysafflor yellow A (100mg/kg)+danshensu (100mg/kg)] reduce brain water content extremely significantly (with the model group comparison, p＜0.001), compositions 9[S-A Hydroxysafflor yellow A (50mg/kg)+danshensu (50mg/kg)] and compositions 10[S-A Hydroxysafflor yellow A (100mg/kg)+danshensu (100mg/kg)] relatively, to reducing brain water content no significant difference (p＞0.05).The pharmaceutical composition anti-cerebral ischemia that S-A Hydroxysafflor yellow A and danshensu are formed filling effect more obviously is better than singly using with dosage S-A Hydroxysafflor yellow A or danshensu (P＜0.05), and S-A Hydroxysafflor yellow A and danshensu have synergism in the prompting compositions.
The different proportioning pharmaceutical compositions of table 2 are to the influence of rat local cerebral ischemia/reperfusion injury damage
| Group | Dosage (mg/kg) | Brain water content (%) |
| Dosage group composition dosage group 1 composition dosage group 2 composition dosage groups 3 composition dosage groups 4 composition dosage groups 5 composition dosage groups 6 composition dosage groups 7 composition dosage groups 8 composition oral group composition dosage groups 9 composition dosage groups 10 in the dosage group hydroxyl radical carthamin yellow carthamus A small dose group hydroxyl radical carthamin yellow carthamus A in the sham group model control group Nim group danshensu small dose group danshensu | Physiological saline physiological saline 1.0 2626 5.4+0.6 5+1 0.6+5.4 1+5 3+3 4+2 2+4 30+30 15+15 50+50 100+100 | 77.0±0.4 79.5±0.4 78.0±0.8 ** 79.3±0.6 79.1±0.5 * 79.2±0.7 79.1±0.4 * 78.0±0.8 **#M 78.4±0.9 **#M 78.5±0.7 **#M 78.4±0.7 **#M 78.5±0.6 **#M 78.4±0.8 **#M 78.3±0.8 **#M 78.0±0.6 *** 79.0±0.5 * 77.9±0.6 *** 77.8±0.5 *** |
Compare with model control group,
*P＜0.05,
*P＜0.01,
* *P＜0.001.
Compare with dosage group in the danshensu,
#P＜0.05; Compare with dosage group in the S-A Hydroxysafflor yellow A,
MP＜0.05
Test example 3: different proportioning pharmaceutical compositions are to the influence of rat heart muscle ischemic injuries
(1) material: S-A Hydroxysafflor yellow A, danshensu: by preparation example 1 preparation, compositions: preparation in proportion.Chlorination nitro blue tetrazolium (N-BT) is provided by Military Medical Science Institute medical supply station.
Nifedipine: Datong pharmaceutical factory, 100mg, 040515.
Laboratory animal: the SD rat, Shandong greenery natural drug Societe Principia Research Development Experimental Animal Center provides, the quality certification number: SYXK (Shandong) 20030020.
(2) method and result:
Animal is divided into sham operated rats (normal saline) at random, model control group (normal saline), nifedipine (6mg/kg) group, S-A Hydroxysafflor yellow A low dose (2mg/kg) group, dosage in the S-A Hydroxysafflor yellow A (6mg/kg) group, danshensu low dose (2mg/kg) group, dosage in the danshensu (6mg/kg) group, compositions 1[S-A Hydroxysafflor yellow A (5.4mg/kg)+danshensu (0.6mg/kg)], compositions 2[S-A Hydroxysafflor yellow A (5mg/kg)+danshensu (1mg/kg)], compositions 3[S-A Hydroxysafflor yellow A (0.6mg/kg)+danshensu (5.4mg/kg)], compositions 4[S-A Hydroxysafflor yellow A (1mg/kg)+danshensu (5mg/kg)], compositions 5[S-A Hydroxysafflor yellow A (3mg/kg)+danshensu (3mg/kg)], compositions 6[S-A Hydroxysafflor yellow A (4mg/kg)+danshensu (2mg/kg)], compositions 7[S-A Hydroxysafflor yellow A (2mg/kg)+danshensu (4mg/kg)], compositions 8[S-A Hydroxysafflor yellow A (30mg/kg)+danshensu (30mg/kg)], compositions 9[S-A Hydroxysafflor yellow A (50mg/kg)+danshensu (50mg/kg)], compositions 10[S-A Hydroxysafflor yellow A (100mg/kg)+danshensu (100mg/kg)], composition oral group [S-A Hydroxysafflor yellow A (15mg/kg)+danshensu (15mg/kg)], 10 every group.After the fasting 12 hours, limbs II lead electrocardiogram is surveyed in ip urethane (1.2g/kg) anesthesia.Cut off left front fur, iodine tincture and alcohol disinfecting are along left border of sternum 1cm place, cut off thoracic wall muscle and two ribs, open the thoracic cavity rapidly, expose heart, ligation left coronary artery between arterial cone and left auricle, immediately heart is put back to, squeeze the thoracic cavity air, use the mosquito forceps closed-chest, cause Model Rats with Acute Myocardial Ischemia, sham organizes not ligation left coronary artery, and all the other are operated with above-mentioned.Nifedipine group is gastric infusion before anesthesia, composition oral dosage group successive administration 3 days, and fasting is after 16 hours after administration in the 2nd day, and administration in the 3rd day was performed the operation after 30 minutes, and all the other respectively organize postoperative with both intravenous injection relative medicines.1.5h, 3h electrocardiogram before the record administration and after the administration take out heart behind the 6h, after cleaning with cold saline, and-20 ℃ of refrigerator freeze overnight.Next day, refrigerated heart is cut into 5 by ligation place to apex uniform thickness, immerse in the freshly prepared 0.5% NBT phosphate buffer (pH7.4).37 ℃ of water-bath jolting 10～15min.Blot the dyeing liquor of slice surface with filter paper, separate the coloured portions and the part of being unstained, weigh the compute infarct size.Infarct size (%)=infarction part weight/(non-infarction part weight+infarction part weight) * 100% data are represented with x ± SD, carry out statistical procedures with F check between group.
The result is as shown in table 3, and myocardial ischemia is after 6 hours, and tangible kitchen range shape ischemic region appears in the model group rat heart muscle, reaches about 26%.S-A Hydroxysafflor yellow A low dose (2mg/kg) group, danshensu low dose (2mg/kg) group fail to reduce rising, the minimizing ischemic areas of limb lead electrocardiogram J point; Dosage in the S-A Hydroxysafflor yellow A (6mg/kg) group, dosage in the danshensu (6mg/kg) group, composition oral group [S-A Hydroxysafflor yellow A (15mg/kg)+danshensu (15mg/kg)] all reduce rising, the minimizing ischemic areas (comparing p＜0.05 with model group) of limb lead electrocardiogram J point to a certain extent; Compositions 1[S-A Hydroxysafflor yellow A (5.4mg/kg)+danshensu (0.6mg/kg)], compositions 2[S-A Hydroxysafflor yellow A (5mg/kg)+danshensu (1mg/kg)], compositions 3[S-A Hydroxysafflor yellow A (0.6mg/kg)+danshensu (5.4mg/kg)], compositions 4[S-A Hydroxysafflor yellow A (1mg/kg)+danshensu (5mg/kg)], compositions 5[S-A Hydroxysafflor yellow A (3mg/kg)+danshensu (3mg/kg)], compositions 6[S-A Hydroxysafflor yellow A (4mg/kg)+danshensu (2mg/kg)], compositions 7[S-A Hydroxysafflor yellow A (2mg/kg)+danshensu (4mg/kg)] to the rising of limb lead electrocardiogram J point, reduce ischemic areas and 6mg/kg danshensu group, 6mg/kg S-A Hydroxysafflor yellow A group more also has significant difference (p＜0.05); Compositions 8[S-A Hydroxysafflor yellow A (30mg/kg)+danshensu (30mg/kg)], compositions 9[S-A Hydroxysafflor yellow A (50mg/kg)+danshensu (50mg/kg)], compositions 10[S-A Hydroxysafflor yellow A (100mg/kg)+danshensu (100mg/kg)] reduce extremely significantly limb lead electrocardiogram J point rising, reduce ischemic areas (with model group relatively, p＜0.001); Composition dosage group 9[S-A Hydroxysafflor yellow A (50mg/kg)+danshensu (50mg/kg)] and composition dosage group 10[S-A Hydroxysafflor yellow A (100mg/kg)+danshensu (100mg/kg)] relatively, to the rising and the ischemic areas no significant difference (p＞0.05) of limb lead electrocardiogram J point.S-A Hydroxysafflor yellow A and danshensu have synergism in the prompting compositions.
The different proportioning pharmaceutical compositions of table 3 are to the influence of rat heart muscle ischemic injuries
| Group | Dosage (mg/kg) | Infarct size (%) | The J point is raised (mv) | |
| 1.5h | 3h | |||
| Dosage group composition dosage group 1 composition dosage group 2 composition dosage groups 3 composition dosage groups 4 composition dosage groups 5 composition dosage groups 6 composition dosage groups 7 composition oral group composition dosage groups 8 composition dosage groups 9 composition dosage groups 10 among the dosage group hydroxyl A small dose group hydroxyl A in the sham group model control group Nifedipine group danshensu small dose group danshensu | Physiological saline physiological saline 62626 5.4+0.6 5+1 0.6+5.4 1+5 3+3 4+2 2+4 15+15 30+30 50+50 100+100 | --- 26.2±5.5 18.4±4.6 ** 24.7±4.9 21.8±3.5 * 24.3±4.5 21.9±3.3 * 18.9±2.8 **#M 18.9±2.7 **#M 18.6±2.7 **#M 18.0±2.5 **#M 17.8±2.5 **#M 18.0±2.4 **#M 18.1±2.8 **#M 21.5±3.3 * 14.8±3.7 *** 13.1±3.6 *** 12.8±3.5 *** | --- 0.446±0.180 0258±0.070 ** 0.398±0.080 0.278±0.100 * 0.408±0.083 0.275±0.100 * 0.202±0.056 **#M 0.201±0.055 **#M 0.199±0.055 **#M 0.201±0.056 **#M 0.195±0.056 **#M 0.193±0.054 **#M 0.199±0.056 **#M 0.265±0.100 * 0.175±0.049 *** 0.158±0.047 *** 0.155±0.045 ***S | --- 0.433±0.133 0.276±0.082 ** 0.411±0.108 0.291±0.123 * 0.401±0.118 0.293±0.113 * 0.235±0.086 **#M 0.233±0.084 **#M 0.235±0.085 **#M 0.234±0.086 **#M 0.230±0.086 **#M 0.225±0.084 **#M 0.215±0.086 **#M 0.290±0.113 * 0.210±0.046 *** 0.185±0.042 *** 0.183±0.043 *** |
Compare with model control group,
*P＜0.05,
*P＜0.01,
* *P＜0.001.
Compare with dosage group in the danshensu,
#P＜0.05; Compare with dosage group in the S-A Hydroxysafflor yellow A,
MP＜0.05
Claims (10)
1. a pharmaceutical composition is made up of S-A Hydroxysafflor yellow A and danshensu, and its weight ratio is 1: 9～9: 1.
2. compositions according to claim 1, its ratio be preferably 1: 5～and 5: 1.
3. compositions according to claim 1 and 2, danshensu can also exist with the form of slaine.
4. compositions according to claim 3, danshensu salt is preferably sodium salt.
5. compositions according to claim 1 and 2, the content of its active component are 60-2000mg.
6. the application of the arbitrary described compositions of claim 1-5 in the medicine of preparation treatment or prevention cardiovascular and cerebrovascular disease.
7. application according to claim 6, the application of said composition in preparing treatment or prevention coronary heart disease, anginal medicine.
8. application according to claim 6, the application of said composition in the medicine of preparation treatment or prevention ischemia apoplexy.
9. application according to claim 6, the application of said composition in the medicine of preparation treatment or prevention of brain ischemia/reperfusion injury.
10. application according to claim 6, the application of said composition in the medicine of preparation treatment or prevention of brain wound.
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| CN102614166A (en) * | 2011-12-07 | 2012-08-01 | 中国人民解放军第四军医大学 | Injection solution prepared from Safflomin A and Sodium danshensu and preparation method thereof |
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| CN1278703C (en) * | 2004-08-16 | 2006-10-11 | 张正生 | Freeze-dried powder and injection preparation of red sage root and safflower, and preparation method |
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| CN102614166A (en) * | 2011-12-07 | 2012-08-01 | 中国人民解放军第四军医大学 | Injection solution prepared from Safflomin A and Sodium danshensu and preparation method thereof |
| CN102614166B (en) * | 2011-12-07 | 2014-04-09 | 中国人民解放军第四军医大学 | Injection solution prepared from Safflomin A and Sodium danshensu and preparation method thereof |
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