CN100482218C - Application of Danshensu in preparation of medicine for treating cerebrovascular diseases - Google Patents
Application of Danshensu in preparation of medicine for treating cerebrovascular diseases Download PDFInfo
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Abstract
The present invention provides application of Danshensu in preparation of medicine for treating cerebrovascular diseases, concretely relates to application of Danshensu in preparation of medicine for treating ischemic stroke, application of Danshensu in preparation of medicine for treating NMDA receptor derivation neurons in the brain damage, application of Danshensu in preparation of medicine for treating brain trauma. The invention also provides medicine composition containing Danshensu for treating cerebrovascular diseases, whose unit dose is 50-200mg.
Description
Technical field
The present invention relates to the application of danshensu in the medicine of preparation treatment cerebrovascular disease.
Background technology
Along with the acceleration of aged tendency of population process and the change of life style, cerebrovascular disease has become a global health problem, and the mortality rate of cerebrovascular accident occupies the 2nd at world wide, the health that endangers the people greatly.The exploitation of novel and effective control cerebrovascular medicine has been clinical needing badly.
Danshensu is the water soluble ingredient of salviamiltiorrhizabung, has effects such as blood vessel dilating, coronary blood flow increasing, antithrombotic formation, is the effective ingredient of FUFANG DANSHEN DIWAN, Radix Salviae Miltiorrhizae Injection etc.
The danshensu structural formula
Salviamiltiorrhizabung is widely used in cardiovascular and cerebrovascular diseases, a large amount of documents and materials have been reported the protective effect [Han Chang of Radix Salviae Miltiorrhizae to myocardial ischemia, cerebral ischemia and reperfusion injury, Wang Xiaoming, Zhang Guoyi. Radix Salviae Miltiorrhizae is to the influence of ischemia and reperfusion injury Myocardial Lipid Peroxidation and regional blood flow. the journal .1990 of Harbin Medical University, 24 (4): 262～267; Xu Hongtao, Chen Shiliang, Li Lansun. Radix Salviae Miltiorrhizae during to coronary stricture left ventricular diastolic function influence combination of Chinese and Western medicine magazine, 1990,10 (12): 737～739; Zheng Ruoxuan, Fang Sanman, Han Baoming. the Radix Salviae Miltiorrhizae water extract causes the protective effect of rat myocardial ischemia to chemistry. combination of Chinese and Western medicine magazine .1990,10 (10): 609～611; Tao Yueyu, Guo Songduo, Lu Bufeng, etc. compound Salviae Miltiorrhizae is to the metabolic influence of ischemic myocardium phospholipid inositol. Chinese combination of Chinese and Western medicine magazine .1993,13 (6): 354～355]; Li Chengzhu etc. reported danshensu blood coagulation resisting function [Li Chengzhu, Yang Shichun, Zhao Fengdi. the research of danshensu blood coagulation resisting function. combination of Chinese and Western medicine magazine .1983,3 (5): 297-299]; Li Yuehua etc. have reported the protective effect [Li Yuehua of danshensu to experimental hepatic injury, Wu Cuizhen, fault tinkling of pieces of jade jasmine. growth of danshensu enhance hepatocyte and the protective effect in the medicine hepatocyte injury thereof. the journal .1996 of Nanjing Medical University, 16 (4): 346～348; Li Jing, Li Yuehua, danshensus such as Xue Longcui are to the protective action of experimental hepatocyte injury. combination of Chinese and Western medicine hepatopathy magazine .1996,6 (3): 29～30]; Thereby the Baconic that rectifies etc. discovers may have protective effect to focal ischemia's reperfusion injury by the expression that influences HSP70 by Radix Salviae Miltiorrhizae [Baconic rectifies; Wu Weiping; Liu Jun; Deng. Radix Salviae Miltiorrhizae was to the influence-immunocytochemistry and the pathological research of heat shock protein 70 when focal ischemia poured into again. apoplexy and sacred disease .1995,3 (2): 61～64].But the effect that has the treatment cerebrovascular disease about danshensu does not in vivo appear in the newspapers; Given this, the inventor finds that by a large amount of experimentatioies danshensu has the medical usage of treatment cerebrovascular disease.
Summary of the invention
The invention provides the application of danshensu in the medicine of preparation treatment apoplexy.
The invention provides danshensu and cerebral ischemia, nmda receptor are induced the protective effect of cranial nerve cell damage.
The invention provides the application of danshensu in the medicine of preparation treatment Cerebral Ischemia damage.
The invention provides the application of danshensu in the medicine of preparation treatment cerebral trauma.
The invention provides with the danshensu is the pharmaceutical composition that is used for the treatment of cerebrovascular disease of active component.
Danshensu of the present invention is when being used for above-mentioned arbitrary purposes, and its using dosage scope is 10mg～1000mg/ days, and the preferred dose scope is 100mg～500mg/ days.
The danshensu that uses among the present invention by document [Deng Xiling, Chen Xuemin. the synthetic and pharmacological action of danshensu. land-reclaimable medical science .2002,24 (5): 362～364] described method preparation.
The danshensu that uses among the present invention can use separately or use with pharmaceutical compositions.Pharmaceutical composition comprises that as the danshensu of active component and pharmaceutical carrier this pharmaceutical composition contains the danshensu and the pharmaceutical carrier of 50mg～200mg unit dose, is preferably the danshensu and the pharmaceutical carrier that contain 50mg～100mg unit dose.This pharmaceutical composition 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.Various pharmaceutical dosage form provided by the present invention all can be prepared from the pharmacy conventional method.
The inventor has confirmed that by following test danshensu has the effect of treatment cerebrovascular disease, and the following examples are used for more detailed description the present invention, but and do not mean that the present invention only limits to this.Test used danshensu and press document [Deng Xiling by natural drug Engineering Technical Research Centre modern Chinese medicine research department, Shandong Province, Chen Xuemin. the synthetic and pharmacological action of danshensu. land-reclaimable medical science .2002,24 (5): 362～364] described method preparation is through the HPLC detection level〉95%.
The specific embodiment
Preparation example 1: the preparation of danshensu freeze-dried powder
Precision takes by weighing danshensu raw material 20.0g and medicinal mannitol 40.0g, be dissolved in the 1000ml water for injection, fully stir and make dissolving, add water for injection to 2000ml, add pin activated carbon 2.0g, be heated to 60 ℃ and stirred 30 minutes, carbon-point filters, and filtrate is through 0.25 μ m filtering with microporous membrane degerming, be sub-packed in 1000 cillin bottles, loading amount 2.0ml/ props up, lyophilization, promptly.Every contains danshensu 20mg.
Preparation example 2: the preparation of danshensu injection
Precision takes by weighing danshensu raw material 20.0g, is dissolved in the 1000ml water for injection, fully stirs and makes dissolving, add water for injection to 2000ml, add pin activated carbon 2.0g, be heated to 60 ℃ and stirred 30 minutes, carbon-point filters, filtrate is through 0.25 μ m filtering with microporous membrane degerming, be sub-packed in 1000 cillin bottles, loading amount 2.0ml/ props up, and seals, sterilization, promptly.Every contains danshensu 20mg.
Test example 1: danshensu is to the protective effect of rat neural cell injury due to N-methyl D-Aspartic Acid
(1) material
Danshensu: press document [Deng Xiling, Chen Xuemin. the synthetic and pharmacological action of danshensu. land-reclaimable medical science .2002,24 (5): 362～364] described method preparation, the time spent is diluted to suitable concn with normal saline.Poly-D-lysine is a Sigma company product.The DMEM culture medium is a Gibco company product; All the other reagent are analytical pure.
Laboratory animal: 18 of regular grade Sprague Dawley rats, ♂, body weight 250g-280g, Shandong Province's natural drug Engineering Technical Research Centre Experimental Animal Center provides, the quality certification number: No. 200106005, Shandong kinoplaszm word.
(2) method
(2.1) neurocyte former be commissioned to train foster
Conceived 15d rat chloral hydrate anesthesia, 75% ethanol disinfection breast abdominal part, under aseptic condition, take out the tire Mus, strip out, separate both sides cortical tissue, be cut into rotten shape with scalpel, immigration contains and discards Digestive system after digesting 30min (37 ℃) in the 0.125% tryptic phosphate buffer, add and contain 10% hyclone, 10% horse serum, 100 μ/ml penicillin, the DMED culture fluid of 100 μ/ml streptomycin, blow and beat dispersion repeatedly with small-bore suction pipe, after 200 order cells sieve filters, adjust cell concentration to 10 with DMEM
6Individual/ml, be seeded in the 35mm culture dish that scribbles 0.01% poly-D-lysine in advance, every ware 2ml puts CO
2Hatch for 37 ℃ in the incubator, in culture fluid, added cell division inhibitor cylocide storing solution (6 μ l/ ware) on the 3rd day to suppress the hyper-proliferative of non-neuronal cell in cultivating, renew bright culture fluid behind the effect 48h, change liquid later on weekly 2 times, liquid is partly measured in each replacing.
(2.2) NMDA induces neural cell injury
Cell culture divides the normal control group at random to d14, NMDA 50 μ molL
-1Group, danshensu group (10,100 μ molL
-1); Each group is changed to contain low serum DMEM (5% hyclone, 5% horse serum, the 30mmolL of different pharmaceutical
-1HEPES) continue to cultivate 6h, add 50mmolL again
-1NMDA, hatch behind the 12h by document [Yan Chaohua, Feng Yipu. butylphthalide is to the protective effect of the rat layer neural cell injury of low sugar hypoxia inducible. Acta Pharmaceutica Sinica .1998,33 (7): 486-492.] described method observation of cell form, calculate cell mortality.
(2.3) statistical procedures
Data are represented with x ± SD, all carry out statistical procedures with reference differential technique (ANOVA) between administration front and back, group in the group.
(3) result
(3.1) to cultivating the influence of neurocyte metamorphosis
Normal neuronal cell cultures is during to d14, well-grown, and cell space is tapered, fusiformis or triangle, and synapse is thick and grow, and is the tree root shape to be woven into net; When cell is containing 50 μ molL
-1When hatching 12h in the culture medium of NMDA, swelling, soft edge appear in cell, synapse fracture, disappearance even cell disruption; As cell while and 10,100 μ molL
-1Danshensu is hatched, and then the cell injury degree obviously alleviates, and cellular morphology is kept perfectly substantially, but cell density decreases, still phenomenon such as visible synapse fracture; Show that danshensu has significant protective effect to the inductive rat neural cell injury of NMDA.
(3.2) to cultivating the influence of nerve cell death rate
Neurocyte is containing 50 μ molL
-1After hatching 12h in the culture medium of NMDA, trypan blue cytochrome showed increased (the NMDA 50 μ molL that dyeing
-1Group: 86%vs normal control group: 10%, P＜0.001), the prompting cell mortality increases; In culture medium, add 10,100 μ molL simultaneously
-1Danshensu (being respectively 38%, 24%) can obviously reduce cell mortality, with NMDA50 μ molL
-1Group compares that there were significant differences.
Test example 2: danshensu causes the influence of neural cell injury to the rat local cerebral ischemia
(1) material:
Danshensu injection: by the preparation of preparation example 1 method.Red tetrazolium: U.S. Sigma company product, face with preceding and be made into 4% solution with normal saline.Laboratory animal: regular grade Wistar rat, male, body weight 280g-350g, natural drug Engineering Technical Research Centre zoopery center, Shandong Province provides.The quality certification number: No. 200106005, Shandong kinoplaszm word.
(2) method and result:
Animal is divided into sham operated rats (waiting the capacity solvent) at random, model control group (waiting the capacity solvent), the nimodipine group (Nim, 1.5mg/kg), danshensu 1mg/kg group, danshensu 5mg/kg group, danshensu 10mg/kg group, danshensu 25mg/kg group, danshensu 50mg/kg group, danshensu 100mg/kg group, 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 left side middle cerebral artery ischemia model; Sham operated rats is only carried out the separation (above experiment is all carried out at 23 ℃～25 ℃) of right carotid, internal carotid artery, external carotid artery.Each treated animal intravenous injection relative medicine of postoperative (administration volume 1ml/200g).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 are represented with X ± s, carry out statistical procedures with t check between group.
The result is as shown in table 1, and ischemia is after 24 hours, and rat shows tangible behavior disorder, and tangible kitchen range shape ischemic region also appears in rat cerebral tissue, reaches about 25% of full brain; Give the danshensu of various dose, the animal behavior obstacle has alleviating in various degree, and the rat cerebral ischemia district also takes an evident turn for the better, and is dose dependent.
Danshensu 50mg/kg treating cerebral ischemia is better than 25mg/kg (P＜0.05), but does not relatively have significant difference (P〉0.05) with 100mg/kg.Prompting is when Ji Liang ≧ 50mg/kg, and drug effect does not continue increase.
The influence that table 1 danshensu damages the rat local cerebral ischemia (x ± SD, n=10)
Compare with model control group
*P＜0.05,
*P＜0.01; Compare with the 50mg/kg group
ΔP＜0.05,
#P〉0.05.
Test example 3: danshensu is to rat cerebral ischemia/perfusion causes the influence of neural cell injury again
(1) material:
Danshensu injection: by the preparation of preparation example 2 methods.Red tetrazolium: U.S. Sigma company product, face with preceding and be made into 4% solution with normal saline.Laboratory animal: regular grade Wistar rat, male, body weight 280g-350g, natural drug Engineering Technical Research Centre zoopery center, Shandong Province provides.The quality certification number: No. 200106005, Shandong kinoplaszm word.
(2) method and result:
Animal is divided into sham operated rats (waiting the capacity solvent) at random, model control group (waiting the capacity solvent), the nimodipine group (Nim, 1.5mg/kg), danshensu 1mg/kg group, danshensu 5mg/kg group, danshensu 10mg/kg group, danshensu 25mg/kg group, danshensu 50mg/kg group, danshensu 100mg/kg group, 10 every group.After the fasting 12 hours, cause left side middle cerebral artery ischemia by experimental example 1 described method; Each treated animal intravenous injection relative medicine of postoperative 10min (administration volume 1ml/200g).Behind the ischemia 2 hours, extract nylon wire out, cause rat cerebral ischemia/reperfusion injury; Put to death rat after irritating 24h again; get brain; remove olfactory bulb; cerebellum and low brain stem; crownly be cut into 5; the brain sheet is put in 10% formalin fixing; through dehydration; waxdip; embedding; after the steps such as section; make the thick tissue slice of 8um; Toluidine blue staining; select every rat optic chiasma and infundibular stalk line midpoint to press document [Liu Xiaoguang; Feng Yipu. butylphthalide is to the protective effect of local rats with cerebral ischemia behavior and pathological change. Acta Pharmaceutica Sinica .1995; 30 (12): 896-903] described method is carried out cell counting with cell counter; hypochromatosis; the index as neuronal necrosis is secretly dyed in cyton, calculates the percentage ratio that downright bad neuron number accounts for total neuron number.
Data are represented with x ± SD, all carry out statistical procedures with reference differential technique (ANOVA) between administration front and back, group in the group.
The result shows that model control group rat neuron peripheral clearance enlarges, and what occur being dispersed in secretly dyes neuron, and shrinkage in various degree appears in neurocyte.Give the danshensu treated animal alleviating in various degree arranged.We carry out cell counting with the brain sheet penumbra region of same profile.By table 2 as seen, various dose danshensu treatment group cortex, the downright bad percentage ratio of striatal neuron obviously reduce, with model control group comparing difference remarkable (P＜0.05 or P＜0.01).
Danshensu 50mg/kg anti-cerebral ischemia/reperfusion injury effect is better than 25mg/kg (P＜0.05), but does not relatively have significant difference (P〉0.05) with 100mg/kg.Prompting is when Ji Liang ≧ 50mg/kg, and drug effect does not continue increase.
Table 2 danshensu to the influence of local rats with cerebral ischemia neuronal necrosis percentage ratio (x ± SD, n=10)
Compare with model control group
*P＜0.05,
*P＜0.01; Compare with the 50mg/kg group
ΔP＜0.05,
#P〉0.05.
Test example 4: danshensu is to the protective effect of mice closure cerebral trauma
(1) material:
Danshensu injection: by the preparation of preparation example 2 methods.Cleaning level kunming mouse, 18～22g, male and female half and half are provided by natural drug Engineering Technical Research Centre zoopery center, Shandong Province.The quality certification number: No. 200106003, Shandong kinoplaszm word.
(2) method and result
Get 80 of mices, be divided into normal control group (waiting the capacity solvent) at random, model control group (waiting the capacity solvent), danshensu 2mg/kg group, danshensu 10mg/kg group, danshensu 20mg/kg group, danshensu 50mg/kg group, danshensu 100mg/kg group, danshensu 200mg/kg group, 10 every group.Press document [Wang Chaoyun, Jiang Wanglin, the red English of intelligence, etc. baicalin is to the protective effect of brain injury. Chinese herbal medicine, 2004,35 (2): 188～190] described method causes mice closure cerebral trauma model, and each organizes intravenously administrable, strips the Mus brain after 24 hours, the weighing weight in wet base, dried 24 hours for 70 ℃, claim dry weight, calculate brain water content; Brain water content is higher than normal value and represents the brain edema.
The result is as shown in table 3, and the closure cerebral trauma causes the serious edema of mouse brain, gives the danshensu of various dose, and the mouse brain edema has alleviating in various degree, and is dose dependent.
Danshensu 100mg/kg reduces the cerebral edema effect and is better than 50mg/kg (P＜0.05), but does not relatively have significant difference (P〉0.05) with 200mg/kg.Prompting is when Ji Liang ≧ 100mg/kg, and drug effect does not continue increase.
Table 3 danshensu to the influence of closure cerebral trauma (x ± SD, n=10)
Compare with model control group
*P＜0.05,
*P＜0.01; Compare with the 100mg/kg group
ΔP＜0.05,
#P〉0.05.
Test example 5: danshensu acute toxicity test
(1) material:
Danshensu injection: by preparation example 1 preparation.Cleaning level kunming mouse, 18～22g, male and female half and half are provided by natural drug Engineering Technical Research Centre zoopery center, Shandong Province.The quality certification number: No. 200106003, Shandong kinoplaszm word.Feedstuff identifies that by Chinese pharmaceutical biological product check is provided.
(2) method
According to trial test design dosage and the blank group of dividing into groups, 100mg/kg, 150mg/kg, 225mg/kg, 337.5mg/kg, 506.25mg/kg, 759.375mg/kg, 1139.0625mg/kg group, totally 8 groups, 10 every group.After weighing, press the volume intravenous injection of 0.2ml/10g, matched group gives the equal-volume solvent.Toxic reaction of close observation mice and death condition in 7 days after the administration, and measure LD by improving karber's method
50
(3) result
The LD of danshensu injection
50Be 688.7 ± 78.6mg/kg; LD
5095% fiducial limit: 589.2～729.5mg/kg.
Claims (6)
1, the application of danshensu in the medicine of preparation treatment cranial nerve cell damage.
2, application according to claim 1, the application of danshensu in the medicine of preparation treatment ischemia apoplexy.
3, application according to claim 1, danshensu is induced application in the medicine of cranial nerve cell damage at preparation treatment nmda receptor.
4, application according to claim 3, danshensu is induced application in the medicine of cranial nerve cell damage at the nmda receptor that preparation treatment is caused by cerebral ischemia or cerebral ischemia re-pouring.
5,, it is characterized in that described medicine contains danshensu and the pharmaceutical carrier of 50mg-200mg according to the arbitrary described application of claim 1-4.
6, application according to claim 5 is characterized in that described medicine contains danshensu and the pharmaceutical carrier of 50mg-100mg.
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| CN101597231B (en) * | 2009-07-10 | 2012-07-04 | 中国人民解放军第四军医大学 | NO donor medicine and synthesis method thereof |
| CN102342909A (en) * | 2010-07-30 | 2012-02-08 | 湖南康普医药研究院 | Preparation method of salvianic acid A sodium injection |
| CN103215222A (en) * | 2013-04-19 | 2013-07-24 | 陈云燕 | Induction medium for inducing human adipose tissue-derived stromal cells as nerve cells and method |
| CN108421033A (en) * | 2018-03-12 | 2018-08-21 | 杭州荣泽生物科技有限公司 | The reagent and its application method of promotion nerve stem cell proliferation based on ginsenoside Rg1 |
| CN109364055B (en) * | 2018-10-31 | 2020-10-02 | 滨州医学院 | Application of danshensu in preparation of medicine for treating and/or preventing lupus nephritis |
| CN111346083A (en) * | 2020-04-28 | 2020-06-30 | 鲁东大学 | Application of compound in preparation of medicine for treating cerebrovascular diseases |
| CN113952324A (en) * | 2021-09-02 | 2022-01-21 | 滨州医学院 | Application of salvianic acid A-ester in preparation of medicine for treating cerebral arterial thrombosis, pharmaceutical composition and preparation method of salvianic acid A-ester |
| CN113712952A (en) * | 2021-09-15 | 2021-11-30 | 滨州医学院 | Preparation of tanshinol ethyl ester, pharmaceutical composition containing tanshinol ethyl ester and application of pharmaceutical composition in preparation of medicines for treating cerebral arterial thrombosis |
| CN115887478B (en) * | 2022-11-17 | 2023-09-08 | 中国中医科学院中医基础理论研究所 | Application of composition in preparation of medicine for treating cerebral ischemia and medicine for treating cerebral ischemia |
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Non-Patent Citations (2)
| Title |
|---|
| 丹参对窒息脑损伤的神经元保护作用. 赵玲等著.中华围产医学杂志，第6卷第3期卷. 2003 |
| 丹参对窒息脑损伤的神经元保护作用. 赵玲等著.中华围产医学杂志，第6卷第3期卷. 2003 * |
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