CN1879614A - A pharmaceutical composition and application thereof in treatment of cardiovascular and cerebrovascular disease - Google Patents
A pharmaceutical composition and application thereof in treatment of cardiovascular and cerebrovascular disease Download PDFInfo
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- CN1879614A CN1879614A CN 200510043780 CN200510043780A CN1879614A CN 1879614 A CN1879614 A CN 1879614A CN 200510043780 CN200510043780 CN 200510043780 CN 200510043780 A CN200510043780 A CN 200510043780A CN 1879614 A CN1879614 A CN 1879614A
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Abstract
The invention provides a pharmaceutical composition comprising salvianolic acid and carthamus tinctorius yellow color, and the use of the medicinal compositions in the preparation of medicaments for treating or preventing cardiovascular and cerebrovascular diseases, especially brain injury and myocardial ischemia.
Description
Technical field
The present invention relates to the pharmaceutical composition formed by danshensu and Flos Carthami flavochrome, also relate to the application of this pharmaceutical composition in the medicine of preparation treatment or prevention cardiovascular and cerebrovascular disease.
Background technology
Along with the acceleration of aged tendency of population process and the change of life style, cardiovascular and cerebrovascular disease has become a global health problem, and the mortality rate of coronary heart disease, apoplexy occupies the 1st, 3 respectively at world wide.The exploitation that novel and effective is prevented and treated the cardiovascular and cerebrovascular vessel medicine is very urgent.
Shen Cui cuckoo report Carthamus yellow can suppress the inductive platelet aggregation of ADP, suppress thrombosis and promote thrombosed dissolving [Shen Cuijuan. the research of Flos Carthami. Shanxi medical magazine, 1979; (1): 46-50].Its protection mechanism and Ca are thought in researchs such as Hu Shuqun
2+/ CaM dependent protein kinase ii (Ca
2+/ CaM PK II) relevant [Hu Shuqun, Zhang Guangyi. Carthamus yellow is to cerebral ischemia Ca
2+The active inhibitory action of/CaM PK II. Xuzhou Medical College's journal, 1999; 19 (5): 348-51].Report Carthamus yellows such as Piao Yongzhe can be alleviated the rat heart muscle ischemia, improve the rat heart muscle energy metabolism [Piao Yongzhe, gold ring, Zang Baoxia, etc. Carthamus yellow is alleviated the research of rat heart muscle ischemia effect. cardiopulmonary angiopathy magazine, 2002,21 (4): 225～8].
Wang Nan, Cai Haijiang report danshensu has the effect that lipoprotein is modified in cellular oxidation that suppresses, its oxidation resistance becomes positive correlation [Wang Nan with the amount of Radix Salviae Miltiorrhizae, Cai Haijiang. danshensu is to the inhibitory action (J) of bovine aortic smooth muscle cells oxidative modification LDL. Nanjing Medical University's journal, 1994,14 (4): 529.]; In addition; Gu Yanghong; it is synthetic that Zhang Caiying etc. think that danshensu can also suppress endogenous cholesterol; protection blood vessel barrier; prevent atherosclerosis form [Gu Yanghong, Zhang Caiying, Huang Guiqiu. Radix Salviae Miltiorrhizae and danshensu are to the influence (J) of anticoagulant of cattle endotheliocyte and fibrinolytic function. Shanghai Second Emdical University's journal; 1990,10 (3): 208.].
The inventor is by a large amount of experimentatioies, pharmaceutical composition and the application in the medicine of preparation treatment or prevention cardiovascular and cerebrovascular disease thereof be made up of danshensu and Flos Carthami flavochrome are provided, and this pharmaceutical composition has synergism when being used for cardiovascular and cerebrovascular disease.
Summary of the invention
The invention provides the pharmaceutical composition of being made up of Carthamus yellow and danshensu, its weight ratio is 1: 9～9: 1.Its preferred weight ratio is 1: 4～4: 1, and danshensu can also exist with the form of slaine, is preferably sodium salt.
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 the medicine for preparing the damage of treatment or prevention of brain, apoplexy.
The invention provides the application of above-mentioned composition in medicine preparation treatment or prevention myocardial ischemia, coronary heart disease, angina pectoris or myocardial infarction.
Pharmaceutical composition provided by the invention can be according to the preparation needs, add corresponding adjuvant, exist with tablet, pill, granule, capsule, suspension, solution, syrup, injection, cream, ointment, spray, chewing agent or patch form, be preferably freeze-dried powder.Various dosage form provided by the invention all can adopt the pharmacy conventional method to be prepared from.
Pharmaceutical composition provided by the invention, the content of its active component are 50-200mg.
Pharmaceutical composition provided by the invention is when being used for cardiovascular and cerebrovascular disease, and its using dosage scope is 50mg-200mg.
Carthamus yellow of the present invention can adopt the literature method preparation and get, as adopt document [Yu Hong, the Xu Li Son. the Coulometric Titration of general flavone content (J) in the Flos Carthami. analytical chemistry, 1997,25 (3): 371.] method preparation, the preferred water percolation extraction method that adopts with reuse polyamide column or polydextran gel behind the low pole macroporous adsorbent resin column chromatography, obtains Carthamus yellow.Danshensu of the present invention is that extraction separation obtains from Radix Salviae Miltiorrhizae, preferably adopts water extracting method, with macroporous adsorbent resin column chromatography method exquisiteness, obtains danshensu.
The inventor has carried out following test and has confirmed the effect in the medicine of preparation treatment or prevention cardiovascular and cerebrovascular disease of the pharmaceutical composition be made up of danshensu and Flos Carthami flavochrome, has synergism.
The specific embodiment:
Preparation example 1: the preparation of Carthamus yellow, danshensu
Get flos carthami 10kg, 25 times of water gaging percolation filter, after concentrating, with low pole absorption with macroporous adsorbent resin (volume ratio of extracting solution and resin 1: 1), behind 3 column volumes removals of deionized water eluting impurity, use 3 column volumes of 30% ethanol elution then, collect eluent, concentrate the back, wash with water earlier to colourless with polyamide absorption, use 95% ethanol elution of meta-alkalescence then, collect eluent, concentrate, drying obtains Carthamus yellow.
Getting the Radix Salviae Miltiorrhizae crude drug pulverizes, the NaOH that adds 12 times of amounts 0.5% decocts twice, each 1.5 hours, filter, merging filtrate, adsorb (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, getting danshensu sodium purity is 91.3%.
Preparation example 2: the preparation of Carthamus yellow, danshensu
Get flos carthami 10kg, and the employing document [Yu Hong, Xu Li Son. the Coulometric Titration of general flavone content (J) in the Flos Carthami. analytical chemistry, 1997,25 (3): 371.] extract purification, concentrated, drying obtains Carthamus yellow.
Getting the Radix Salviae Miltiorrhizae 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, add an amount of HCl and transfer pH to acid, crystallization, getting danshensu purity is 91.5%.
Preparation example 3: the freeze-dried powder that preparation is made up of Carthamus yellow and danshensu
Under cleaning condition, get Carthamus yellow 90g, danshensu 10g, be dissolved in 1000ml water for injection, add 100g mannitol, stirring and dissolving, ultrafiltration, obtain apyrogenic clear liquor, press the lyophilizing of freeze-dried powder technology, make the freeze-dried powder that contains Carthamus yellow 90mg, danshensu 10mg.
Preparation example 4: the freeze-dried powder that preparation is made up of Carthamus yellow and danshensu
Under cleaning condition, get Carthamus yellow 10g, danshensu 90g, be dissolved in 1000ml water for injection, stirring and dissolving, ultrafiltration obtains apyrogenic clear liquor, presses the lyophilizing of freeze-dried powder technology, makes the freeze-dried powder that contains Carthamus yellow 10mg, danshensu 90mg.
Preparation example 5: the freeze-dried powder that preparation is made up of Carthamus yellow and danshensu
Under cleaning condition, get Carthamus yellow 20g, danshensu 80g, be dissolved in 1000ml water for injection, add the 100g low molecular dextran, stirring and dissolving, ultrafiltration, obtain apyrogenic clear liquor, press the lyophilizing of freeze-dried powder technology, make the freeze-dried powder that contains Carthamus yellow 20mg, danshensu 80mg.
Preparation example 6: the freeze-dried powder that preparation is made up of Carthamus yellow and danshensu
Under cleaning condition, get Carthamus yellow 80g, danshensu 20g, be dissolved in 1000ml water for injection, add the 100g low molecular dextran, stirring and dissolving, ultrafiltration, obtain apyrogenic clear liquor, press the lyophilizing of freeze-dried powder technology, make the freeze-dried powder that contains Carthamus yellow 80mg, danshensu 20mg.
Preparation example 7: the freeze-dried powder that preparation is made up of Carthamus yellow and danshensu
Under cleaning condition, get Carthamus yellow 25g, danshensu 75g, be dissolved in 1000ml water for injection, stirring and dissolving, ultrafiltration obtains apyrogenic clear liquor, presses the lyophilizing of freeze-dried powder technology, makes the freeze-dried powder that contains Carthamus yellow 25mg, danshensu 75mg.
Test example 1: different proportioning pharmaceutical compositions are to the influence of rat local cerebral ischemia damage
Carthamus yellow, danshensu, by preparation example 2 preparations, 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.
Laboratory animal: regular grade SD 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 (normal saline) at random, model control group (normal saline), compositions A[Carthamus yellow (10mg/kg)+danshensu (0mg/kg)], compositions B[Carthamus yellow (9mg/kg)+danshensu (1mg/kg)], compositions C[Carthamus yellow (8mg/kg)+danshensu (2mg/kg)], compositions D[Carthamus yellow (5mg/kg)+danshensu (5mg/kg)], compositions E[Carthamus yellow (2mg/kg)+danshensu (8mg/kg)], composition F [Carthamus yellow (1mg/kg)+danshensu (9mg/kg)], compositions G[Carthamus yellow (0mg/kg)+danshensu (10mg/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; 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.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 ± SD, carry out statistical procedures with F check 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 25% of full brain.The pharmaceutical composition (10mg/kg) of different proportionings all has significant protective effect (P＜0.05 or P＜0.01) to rat cerebral ischemia.Under the condition that dosage equates (10mg/kg), with Carthamus yellow and danshensu is that the pharmaceutical composition treating cerebral ischemia of main active obviously is better than singly using with dosage Carthamus yellow or danshensu (P＜0.05), and Carthamus yellow 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 | Behavior disorder | Ischemic areas (%) |
| Sham operated rats | 0 | 0 |
| Model control group | 10.6±1.1 | 25.6±4.5 |
| Compositions A | 9.1±1.2 * | 22.9±2.1 * |
| Compositions B | 8.4+1.1 ** | 22.5±2.1 * |
| Compositions C | 7.0±0.8 **# △ | 18.2±1.8 **# △ |
| Compositions D | 7.2±0.7 **# △ | 20.1±1.4 **# △ |
| Compositions E | 7.1±0.9 **# △ | 21.2±1.3 **# △ |
| Composition F | 8.5±0.8 * | 22.3±1.6 * |
| Compositions G | 8.9±0.7 * | 22.6±1.1 * |
Compare with model control group
*P＜0.05,
*P＜0.01.
Compare #P＜0.05 with compositions A group
Compare with compositions G group
△P＜0.05
Test example 2: the various dose pharmaceutical composition is to the influence of rat local cerebral ischemia damage
(1) material:
Carthamus yellow, danshensu: by preparation example 1 preparation, compositions: preparation in proportion.
Red tetrazolium: U.S. Sigma company product, face with preceding and be made into 4% solution with normal saline.
Laboratory animal: regular grade SD 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 (normal saline) at random, model control group (normal saline), nimodipine group (Nim, 1.0mg/kg), compositions A organizes [Carthamus yellow (2.5mg/kg)+danshensu (2.5mg/kg)], compositions B organizes [Carthamus yellow (5mg/kg)+danshensu (5mg/kg)], and compositions C organizes [Carthamus yellow (10mg/kg)+danshensu (10mg/kg)], 10 every group.After the fasting 12 hours, make rat local cerebral ischemia model and carry out neural behavior scoring, the dyeing of brain sheet by method shown in the experimental example 1.
Data are represented with x ± SD, carry out statistical procedures with F check between group.
The result is as shown in table 2, and the pharmaceutical composition of various dose has all improved the rat behavior obstacle to a certain extent, reduced ischemic areas.
Table 2 various dose pharmaceutical composition is to the influence of rat local cerebral ischemia damage
| Group | Behavior disorder | Ischemic areas (%) |
| Sham operated rats | 0 | 0 |
| Model control group | 11.50±1.31 | 25.41±4.22 |
| The Nim group | 7.15±2.66 ** | 17.33±5.68 ** |
| Compositions A group | 6.58±1.96 ** | 12.37±4.48 ** |
| Compositions B group | 6.37±2.35 ** | 11.34±7.56 ** |
| Compositions C group | 5.03±1.55 *** | 10.22±2.56 *** |
Compare with model control group
*P＜0.05,
*P＜0.01,
* *P＜0.001.
Test example 3: different proportioning pharmaceutical compositions are to the influence of rat heart muscle ischemic injuries
(1) material:
Carthamus yellow, danshensu: by preparation example 2 preparations, compositions: preparation in proportion.
Chlorination nitro blue tetrazolium (N-BT) is provided by Military Medical Science Institute medical supply station.
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 (normal saline) at random, model control group (normal saline), compositions A[Carthamus yellow (10mg/kg)+danshensu (0mg/kg)], compositions B[Carthamus yellow (9mg/kg)+danshensu (1mg/kg)], compositions C[Carthamus yellow (8mg/kg)+danshensu (2mg/kg)], compositions D[Carthamus yellow (5mg/kg)+danshensu (5mg/kg)], compositions E[Carthamus yellow (2mg/kg)+danshensu (8mg/kg)], composition F [Carthamus yellow (1mg/kg)+danshensu (9mg/kg)], compositions G[Carthamus yellow (0mg/kg)+danshensu (10mg/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, along left border of sternum 1cm place, cut off thoracic wall muscle and two ribs, open the thoracic cavity rapidly, expose heart, the ligation left coronary artery is put back to heart immediately between arterial cone and left auricle, squeezes the thoracic cavity air, use the mosquito forceps closed-chest, cause Model Rats with Acute Myocardial Ischemia.Each treated animal intravenous injection relative medicine of postoperative.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 (pH 7.4).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 ischemia is after 6 hours, and tangible kitchen range shape ischemic region appears in rat heart muscle, reaches about 25%.The pharmaceutical composition (10mg/kg) of different proportionings all has significant protective effect (P＜0.05 or P＜0.01) to the rat heart muscle ischemia.Compositions C, D, E and compositions A or G more all have significant difference (P＜0.05), and Carthamus yellow 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 | Ischemic areas (%) |
| Sham operated rats | 0 |
| Model control group | 24.9±4.4 |
| Compositions A | 22.8±2.0 * |
| Compositions B | 22.6±2.2 * |
| Compositions C | 18.1+1.7 **# △ |
| Compositions D | 20.0±1.3 **# △ |
| Compositions E | 21.1+1.2 **# △ |
| Composition F | 22.2±1.5 * |
| Compositions G | 22.6±1.3 * |
Compare with model control group
*P＜0.05,
*P＜0.01.
Compare #P＜0.05 with compositions A group.
Compare with compositions G group
△P＜0.05.
Test example 4: the various dose pharmaceutical composition is to the influence of rat heart muscle ischemic injuries
(1) material:
Carthamus yellow, danshensu: by preparation example 2 preparations, compositions: preparation in proportion.
Painstaking effort pellet (compound Salviae Miltiorrhizae) injection: Guizhou Shenqi Pharmaceutical Co., Ltd.
Chlorination nitro blue tetrazolium (N-BT) is provided by Military Medical Science Institute medical supply station.
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 (normal saline) at random, model control group (normal saline), FUFANG DANSHEN ZHUSHEYE group (DS, 10mg/kg), compositions A organizes [Carthamus yellow (2.5mg/kg)+danshensu (2.5mg/kg)], compositions B organizes [Carthamus yellow (5mg/kg)+danshensu (5mg/kg)], and compositions C organizes [Carthamus yellow (10mg/kg)+danshensu (10mg/kg)], 10 every group.The method shown in the experimental example 3 of pressing is made rat heart muscle ischemia model and calculating myocardium ischemia percentage ratio.
The result is as shown in table 4, and rising, minimizing ischemic areas and model group that the pharmaceutical composition of various dose all reduces the limb lead electrocardiogram J point that is caused by myocardial ischemia to a certain extent relatively have significant difference.
Table 4 Carthamus yellow, danshensu, compositions are to the influence of rat heart muscle ischemic injuries
| Grouping | Infarct size (%) | The J point raises (10 * mv) | ||
| Normally | 1.5h | 3h | ||
| Sham operated rats | 0 | —— | —— | —— |
| Model control group | 25.6±4.3 | 0.8±0.6 | 6.7+2.3 | 6.1±1.4 |
| The FUFANG DANSHEN ZHUSHEYE group | 17.8±6.2 * | 0.8+0.6 | 6.0±1.5 * | 5.1±1.3 * |
| Compositions A group | 13.6±4.5 ** | 0.8±0.6 | 4.9±2.1 ** | 4.1±1.8 ** |
| Compositions B group | 12.6±7.8 ** | 0.8±0.5 | 4.7+1.6 ** | 4.0±1.6 ** |
| Compositions C group | 10.5±2.7 *** | 0.7±0.6 | 4.3±1.7 *** | 3.7+1.9 *** |
Compare with model control group
*P＜0.05,
*P＜0.01,
* *P＜0.001.
Claims (10)
1. pharmaceutical composition is made up of Carthamus yellow and danshensu, and its weight ratio is 1: 9～9: 1.
2. compositions according to claim 1, its ratio be preferably 1: 4～and 4: 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, Carthamus yellow preferably adopt the water percolation to extract, and go up macroporous adsorbent resin, polyamide column or polydextran gel then, eluting and getting.
6. after compositions according to claim 1 and 2, danshensu preferably adopt water to carry, last macroporous resin chromatography and getting.
7. compositions according to claim 1 and 2, the content of its active component are 50-200mg.
8. the application of the arbitrary described compositions of claim 1-7 in the medicine of preparation treatment or prevention cardiovascular and cerebrovascular disease.
9. application according to claim 8, the application of said composition in the medicine for preparing the damage of treatment or prevention of brain, apoplexy.
10. application according to claim 8, the application of said composition in the medicine of preparation treatment or prevention coronary heart disease, angina pectoris, myocardial ischemia or myocardial infarction.
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Open date: 20061220 |