CN101450106A - Traditional Chinese medicine composition with ischemic myocardium angiogenesis promoting function - Google Patents
Traditional Chinese medicine composition with ischemic myocardium angiogenesis promoting function Download PDFInfo
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Abstract
The invention provides a composition for promoting the angiogenesis in ischemia cardiac muscle made up of extracts of astragalus root, red sage root, pseudo-ginseng and dalbergia wood. The weight proportion of the raw materials is: astragalus root 30-50%, red sage root 20-30%, pseudo-ginseng 2-10% and dalbergia wood 20-30%. The Chinese traditional medicine composition has protection function to myocardial ischemia; and the invention deeply expounds the action mechanism of the Chinese traditional medicine composition at molecular level started from the angiogenesis. The Chinese traditional medicine composition in the invention can be used in preparing medicine for promoting the angiogenesis in ischemia cardiac muscle.
Description
Technical field
The present invention relates to a kind of Chinese medicine composition for the treatment of cardiovascular disease; said composition has by promoting vascularization of ischemic cardiac muscle performance cardioprotection, and specifically said composition relates to the combination of the active component that extracts from the Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng and Lignum Dalbergiae Odoriferae pharmaceutical decocting piece.
Background technology
Cardiovascular disease is a commonly encountered diseases, also is one of disease kind of serious harm person in middle and old age colony.In recent years, since the development of society, the variation of work, life, dietary structure and environment etc., and cardiovascular patient is rising.According to interrelated data statistics, the sickness rate of cardiovascular patient above middle age reaches 2.47% one 3.18%.At present the Western medicine of treatment cardiovascular disease mainly is nitrate compound, beta-blocker and calcium antagonist etc., and these medicines can only relief of symptoms, is difficult to effect a permanent cure, and certain toxic and side effects is arranged.Though the action intensity of the single target spot of Chinese medicine is lower than Western medicine, its multipath, many target spots, dynamically wholistic therapy, characteristic that toxic and side effects is little then are far from Western medicine and can reach, and the Comprehensive Treatment effect of the Chinese patent medicine of determined curative effect will surpass Western medicine.
At present the clinical prescription and the Chinese patent medicine of treatment cardiovascular disease are a lot, for example, and the benefiting QI for activating blood circulation side that forms by the Radix Astragali, Radix Codonopsis, Radix Angelicae Sinensis, Radix Salviae Miltiorrhizae, Flos Carthami; Square substantially by the coronary heart disease that the Radix Astragali, Radix Codonopsis, Radix Ophiopogonis, Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong, Lignum Dalbergiae Odoriferae are formed; Pay square Radix Notoginseng oral liquid by what Radix Notoginseng, the Radix Astragali, Radix Puerariae were formed; By Radix Salviae Miltiorrhizae, Rhizoma Corydalis, the Radix Astragali, Radix Paeoniae Rubra, Rhizoma Chuanxiong, when Shuxintongmai sheet that is grouped into or the like.Above clinical prescription and Chinese patent medicine all have certain weak point, or are partial to QI invigorating, or relatively activate yang, or relatively invigorate blood circulation, or dosage form is not ideal enough, do not obtain clinically popularizing in an all-round way.And the Chinese medicinal formulae of a kind of just new effective treatment coronary heart disease with qi deficiency and blood stasis of the QISHENYIQI FANG of forming by the Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng, Lignum Dalbergiae Odoriferae, it all has to a certain degree mitigation to the symptom of various cardiovascular disease clinically.
QISHENYIQI FANG is made up of the Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng and Lignum Dalbergiae Odoriferae, supplementing qi and invigorating vasculum, promoting blood circulation and stopping pain.Be used for blood stasis-type thoracic obstruction caused by qi deficiency, disease is seen feeling of oppression and pain in the chest, and shortness of breath and fatigue, cardiopalmus, lustreless complexion, spontaneous perspiration, corpulent tongue have indentation, dark tongue quality or purple dark or ecchymosis, deep pulse or heavy string arranged.Reuse the Radix Astragali in the side, get its strongly invigorating primordial QI, make gas prosperous capable, blood stasis dispelling and just not hindering with short blood; Gas is prosperous in short Tianjin row, row Tianjin diuresis, and then edema is from disappearing, and the power of the handsome all medicines of the Radix Astragali is monarch drug.Radix Salviae Miltiorrhizae: blood circulation promoting and blood stasis dispelling, inducing menstruation to relieve menalgia.Radix Notoginseng: blood circulation promoting and blood stasis dispelling, removing obstruction in the collateral to relieve pain, with Radix Salviae Miltiorrhizae be ministerial drug altogether.Lignum Dalbergiae Odoriferae: fragrant hot the loosing of gas, temperature is current to stagnate.All medicines share benefiting QI for activating blood circulation, inducing diuresis to remove edema, and removing obstruction in the collateral to relieve pain, it is normal to be able to QI-blood circulation, all card spontaneous recovery.
From modern pharmacology level analysis QISHENYIQI FANG: the Radix Astragali is a multiplicity to the mechanism of ischemic myocardium protective effect, can increase the content of CAMP, thereby performance positive inotropic action, by stablizing myocardial cell membrane, reduce generation, protective wire plastochondria and lysosomal function, the reduction myocardial oxygen consumption of lactic acid dehydrogenase, increase myocardium anti-anoxia ability; Radix Salviae Miltiorrhizae is by removing oxygen-derived free radicals, protective wire plastochondria, improving energy metabolism and to calcium ion regulatory, reach and improve the myocardial ischemia reperfusion injury effect; Radix Notoginseng main pharmacodynamics composition Radix Notoginseng total arasaponins has the reduction myocardial oxygen consumption, improves myocardial ischemia, decreased heart rate, expansion blood vessel blood pressure lowering, blood sugar regulation effect; Lignum Dalbergiae Odoriferae has the promoting the circulation of QI to relieve pain effect, can suppress thrombosis.Basic Experiment Study also shows obviously coronary blood flow increasing of QISHENYIQI FANG, and dilating coronary blood vessel, increase coronary sinus vein oxygen content improve the blood supply oxygen supply of cardiac muscle; Improve the acting of left chamber, increase cardiac output, adjust cardiovascular compliance, cardiovascular system is played regulate and the improvement effect; The myocardial infarction degree is obviously alleviated, and the serum CK value reduces, and SOD is active to be increased, and myocardial ischemia reperfusion injury is had significant protective effect.
This experiment is from angiogenesis, Chinese medicine composition carried out deep mechanism inquire into, and for the Chinese medicine Mechanism Study provides new method, also provides more definite experimental basis for clinical simultaneously.
Summary of the invention
The object of the present invention is to provide a kind of compositions with ischemic myocardium angiogenesis promoting function, extract by the Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng and Lignum Dalbergiae Odoriferae is formed, and the weight percentage that its raw material is formed is: the Radix Astragali 30～50%, Radix Salviae Miltiorrhizae 20～30%, Radix Notoginseng 2～10%, Lignum Dalbergiae Odoriferae 20～30%.
The weight percentage that the preferred compositions raw material is formed is: the Radix Astragali 45%, Radix Salviae Miltiorrhizae 25%, Radix Notoginseng 5%, Lignum Dalbergiae Odoriferae 25%.
With four kinds of water-soluble in proportion compositionss that are made into of extract, its ratio is that Radix Astragali extract is 10.56mg in every ml water solution, and Radix Salviae Miltiorrhizae extract is 8.48mg, and Radix Notoginseng extract is 0.932mg, and Lignum Dalbergiae Odoriferae extract is 0.468 μ l.
The raw material preparation method of extract realizes by following steps in the compositions of the present invention:
(1) preparation method of Radix Astragali extract is, gets Milkvetch Root decoction pieces 500g, is crushed to the degree that is easy to extract.In the 500g Radix Astragali, add 3L water, extract twice, refluxed respectively 2 hours and 1 hour, the extracting solution that merges extracted twice, filtrate is filtered on gauze, be concentrated into 500ml with Rotary Evaporators, add 95% ethanol, make determining alcohol reach about 70% (adding 1200ml approximately), the process that ethanol is added should slow down as much as possible, it is abundant as far as possible to make water extract-alcohol precipitation get, solution was put cold 2 hours, in 4 ℃ refrigerator, left standstill 12～24 hours then, filtrate is filtered on gauze, with the ethanol in the Rotary Evaporators recovery filtrate, at last with concentrated solution lyophilizing on freeze dryer.Obtain about 81g Radix Astragali extract.
(2) preparation method of Radix Salviae Miltiorrhizae extract is, gets red rooted salvia decoction pieces 500g, is crushed to the degree that is easy to extract.In the 500g Radix Salviae Miltiorrhizae, add 3.5L water, extract twice, each refluxed 2 hours, the extracting solution that merges extracted twice, filtrate is filtered on gauze, be concentrated into 500ml with Rotary Evaporators, add 95% ethanol, make determining alcohol reach about 70% (adding 1200ml approximately), the process that ethanol is added should slow down as much as possible, it is abundant as far as possible to make water extract-alcohol precipitation get, solution was put cold 2 hours, in 4 ℃ refrigerator, left standstill 12～24 hours then, filtrate is filtered on gauze, with the ethanol in the Rotary Evaporators recovery filtrate, at last with concentrated solution lyophilizing on freeze dryer.Obtain about 118g Radix Salviae Miltiorrhizae extract.
(3) preparation method of Radix Notoginseng extract is, gets pseudo-ginseng decoction pieces 500g, is crushed to the degree that is easy to extract.In the 500g Radix Notoginseng, add 3.5L water, extract twice, each refluxed 2 hours, the extracting solution that merges extracted twice, filtrate is filtered on gauze, be concentrated into 500ml with Rotary Evaporators, add 95% ethanol, make determining alcohol reach about 70% (adding 1200ml approximately), the process that ethanol is added should slow down as much as possible, it is abundant as far as possible to make water extract-alcohol precipitation get, solution was put cold 2 hours, in 4 ℃ refrigerator, left standstill 12～24 hours then, filtrate is filtered on gauze, with the ethanol in the Rotary Evaporators recovery filtrate, at last with concentrated solution lyophilizing on freeze dryer.Obtain about 67g Radix Notoginseng extract.
(4) preparation method of Lignum Dalbergiae Odoriferae extract is, gets Lignum Dalbergiae Odoriferae pharmaceutical decocting piece 500g, is crushed to the degree that is easy to extract.In the 500g Lignum Dalbergiae Odoriferae, add 3L water, extract the about 7ml of volatile oil with volatile oil extractor.
Another object of the present invention is to provide the application of described compositions in the medicine of preparation ischemic myocardium angiogenesis promoting function.
Thereby especially reach application in the medicine of treatment and angiocardiopathy preventing at the short vascularization of ischemic cardiac muscle of preparation.
Described medicine also contains preparation allowable pharmaceutical excipients or carrier.
Compositions provided by the invention can be made any dosage form on the pharmaceutics, comprises injection and oral formulations.Wherein injection comprises injection, drip liquid, injectable powder; Oral formulations comprises granule, tablet, electuary, powder, oral liquid, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, sucks agent, granule, pill, unguentum, sublimed preparation, spray, drop pill, disintegrating agent, oral cavity disintegration tablet, micropill etc.
Usefulness of the present invention is: Chinese medicine composition provided by the invention, myocardial ischemia is had protective effect, and from angiogenesis, the mechanism of action to Chinese medicine composition on molecular level has carried out deep elaboration.
Description of drawings
Fig. 1 is that angiogenesis is observed in HE and vWF dyeing.
Fig. 2 is the expression with respect to the mRNA of sham operated rats VEGF-A.
Fig. 3 is with respect to the expression of the mRNA of sham operated rats bFGF.
Fig. 4 is with respect to the expression of the mRNA of sham operated rats PDGF-B.
Fig. 5 is with respect to the expression of the mRNA of sham operated rats HIF-1a.
The change of each growth factor protein level of Fig. 6.
Fig. 7 is with respect to the expression of sham operated rats vegf protein.
Fig. 8 is with respect to the proteic expression of sham operated rats bFGF.
Fig. 9 is with respect to the proteic expression of sham operated rats PDGF-B.
The specific embodiment
Further describe flesh and blood of the present invention below in conjunction with embodiments of the invention, this embodiment only is used to the present invention is described and the present invention is not limited.
Embodiment one
Get Milkvetch Root decoction pieces 500g, be crushed to the degree that is easy to extract.In the 500g Radix Astragali, add 3L water, extract twice, refluxed respectively 2 hours and 1 hour, the extracting solution that merges extracted twice, filtrate is filtered on gauze, be concentrated into 500ml with Rotary Evaporators, add 95% ethanol, make determining alcohol reach about 70% (adding 1200ml approximately), the process that ethanol is added should slow down as much as possible, it is abundant as far as possible to make water extract-alcohol precipitation get, solution was put cold 2 hours, in 4 ℃ refrigerator, left standstill 12～24 hours then, filtrate is filtered on gauze, with the ethanol in the Rotary Evaporators recovery filtrate, at last with concentrated solution lyophilizing on freeze dryer.Obtain about 81g Radix Astragali extract.
Get red rooted salvia decoction pieces 500g, be crushed to the degree that is easy to extract.In the 500g Radix Salviae Miltiorrhizae, add 3.5L water, extract twice, each refluxed 2 hours, the extracting solution that merges extracted twice, filtrate is filtered on gauze, be concentrated into 500ml with Rotary Evaporators, add 95% ethanol, make determining alcohol reach about 70% (adding 1200ml approximately), the process that ethanol is added should slow down as much as possible, it is abundant as far as possible to make water extract-alcohol precipitation get, solution was put cold 2 hours, in 4 ℃ refrigerator, left standstill 12～24 hours then, filtrate is filtered on gauze, with the ethanol in the Rotary Evaporators recovery filtrate, at last with concentrated solution lyophilizing on freeze dryer.Obtain about 118g Radix Salviae Miltiorrhizae extract.
Get pseudo-ginseng decoction pieces 500g, be crushed to the degree that is easy to extract.In the 500g Radix Notoginseng, add 3.5L water, extract twice, each refluxed 2 hours, the extracting solution that merges extracted twice, filtrate is filtered on gauze, be concentrated into 500ml with Rotary Evaporators, add 95% ethanol, make determining alcohol reach about 70% (adding 1200ml approximately), the process that ethanol is added should slow down as much as possible, it is abundant as far as possible to make water extract-alcohol precipitation get, solution was put cold 2 hours, in 4 ℃ refrigerator, left standstill 12～24 hours then, filtrate is filtered on gauze, with the ethanol in the Rotary Evaporators recovery filtrate, at last with concentrated solution lyophilizing on freeze dryer.Obtain about 67g Radix Notoginseng extract.
Get Lignum Dalbergiae Odoriferae pharmaceutical decocting piece 500g, be crushed to the degree that is easy to extract.In the 500g Lignum Dalbergiae Odoriferae, add 3L water, extract the about 7ml of volatile oil with volatile oil extractor.
Embodiment two
Extract by the method for embodiment one and to obtain Radix Astragali extract, Radix Salviae Miltiorrhizae extract, Radix Notoginseng extract and Lignum Dalbergiae Odoriferae extract, by following formula combination: contain Radix Astragali 10.56mg in the 1mL aqueous solution, Radix Salviae Miltiorrhizae 8.48mg, Radix Notoginseng 0.932mg, Lignum Dalbergiae Odoriferae 0.468 μ l.
Embodiment three
Pharmacological evaluation: the compositions of the Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng, Lignum Dalbergiae Odoriferae extract promotes that coronary ligation causes rats with myocardial ischemia angiogenesis Study on Mechanism.
Modelling
Animal pattern: pentobarbital anesthesia (50mg/kg i.p.), open breast in the 4th intercostal, expose heart, ligation arteria coronaria left anterior descending branch closes breast and sews up.
The sham-operation animal: pentobarbital anesthesia (50mg/kg i.p.), open breast in the 4th intercostal, threading but not ligation arteria coronaria left anterior descending branch close breast and sew up.
Dosage regimen
Postoperative is divided into three groups with rat: sham operated rats, model group, administration group.After treating that animal revives fully, carry out gastric infusion by the compositions that the method for embodiment two obtains, dosage is the 1mL/100g rat; Other groups are given the distilled water with same dose, and successive administration is one day, three days and seven days respectively.
Respectively at carrying out following index determining in first day, the 3rd day and the 7th day.
Index determining
(1) in first day, the 3rd day and the 7th day, get blood and carry out the serum zymetology: isoenzymes of creatine kinase and lactic acid dehydrogenase (CK-MB, LDH) and hemorheology are learned and are measured.
(2) respectively at the 3rd day and the 7th day, take out heart, 10% neutral formalin is fixed, and carries out HE dyeing and carries out von Wilebrand factor (vWF) mensuration by SABC, observes angiogenesis;
(3) in first day, the 3rd day and the 7th day, below ligature, about 100mg cardiac muscular tissue is got in the left ventricle district, extracts total mRNA, and reverse transcription is cDNA, with realtime PCR VEGF, PDGF-B, bFGF and HIF-1 α is measured;
(4) the residue rat below ligature, the left ventricle district obtained cardiac muscular tissue's sample, carries out protein quantification, and with Westem Blot VEGF, PDGF-B, bFGF protein content is measured respectively at first day, the 3rd day and the 7th day.
Data analysis:Data are represented with the mean value variance, and n is number of animals, adopt variance analysis to carry out statistical test.
The result
(1) serum zymetology result
Experimental result sees Table 1, and when model group rat the first, three and seven days, CK-MB significantly raises, and the compositions of the Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng, Lignum Dalbergiae Odoriferae extract can significantly reduce CK-MB; When first day and the 3rd day; model group LDH also significantly raises; with the model group ratio, the compositions of the Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng, Lignum Dalbergiae Odoriferae extract significantly reduces raising of LDH, illustrates that the compositions of the Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng, Lignum Dalbergiae Odoriferae extract has protective effect to rats with myocardial ischemia.
Table 1 QISHENYIQI FANG is to the influence (n=10) of rats with myocardial ischemia serum zymetology
##P＜0.01 is compared with sham operated rats has highly significant difference;
#P＜0.05 is compared with sham operated rats has significant difference;
*P＜0.05 is compared with model group has significant difference.
(2) hemorheology is learned the result
The compositions of the Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng, Lignum Dalbergiae Odoriferae extract can be improved hemorheology.
Table 2 QISHENYIQI FANG is to the influence (n=10) of rats with myocardial ischemia hemorheology
#P＜0.05 is compared with sham operated rats has significant difference;
*P＜0.01 is compared with model group has significant differences;
*P＜0.05 is compared with model group has significant difference.
(3) HE dyeing and SABC result
This partial results is seen Fig. 1.Compare with model group, administration is after three days and seven days, and the compositions of the Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng, Lignum Dalbergiae Odoriferae extract can significantly promote the formation of new vessels.(A) is HE dyeing among Fig. 1; (B) vWF dyeing, arrow points is a blood vessel among the figure; (C) vascular counts is counted by the blood capillary counting method, allly presents brown single endotheliocyte or endotheliocyte bunch person all as 1 vascular counts unit, but the flesh layer is thicker and the tube chamber area is not counted greater than the blood vessel of 8 red blood cell diameters.5 visuals field are counted in every section under 400 times of visuals field.N=4,
*P＜0.05 has significant difference with the model group ratio;
*P＜0.01 has significant differences with the model group ratio.
(4) RT-PCR result
This partial results is seen Fig. 2-5.The result shows that the compositions of the Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng, Lignum Dalbergiae Odoriferae extract can increase the expression that promotes the angiogenesis relative growth factor and hypoxia inducible factor HIF-1 α mRNA.
(5) Western Blot result
This partial results is seen Fig. 6-9.The result shows, the compositions of the Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng, Lignum Dalbergiae Odoriferae extract promotes the expression of vegf protein when one day and seven days, also promoted the proteic expression of bFGF simultaneously in the time of seven days, and PDGF-B protein expression no change.
The present invention selects for use coronary ligation to cause SD rat heart muscle ischemia model, by to serum zymetology, hemorheology, SABC, RT-PCR and Western Blot result after the administration of SD rat heart muscle ischemia model, verify the short angiogenesis function of Chinese medicine composition of the present invention.We think that implementing the present invention will be the mechanism of Chinese medicine of setting forth from molecular level, thereby allow Chinese medicine go to the world, allow the Chinese medicine modern product can obtain the approval of international medical community, and this also is the needs that China implements modernization of Chinese medicine strategy at present simultaneously.
Claims (3)
1. Chinese medicine composition, it is characterized in that: said composition is made up of the extract of the Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng and Lignum Dalbergiae Odoriferae, and the weight percentage that its raw material is formed is: the Radix Astragali 30～50%, Radix Salviae Miltiorrhizae 20～30%, Radix Notoginseng 2～10%, Lignum Dalbergiae Odoriferae 20～30%.
2. the application of a kind of Chinese medicine composition according to claim 1 in the medicine of preparation ischemic myocardium angiogenesis promoting function.
3. the application of a kind of Chinese medicine composition according to claim 2 is characterized in that: described medicine also contains preparation allowable pharmaceutical excipients or carrier.
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| CN102119957A (en) * | 2011-03-11 | 2011-07-13 | 浙江大学 | Preparation method and application of effective ingredient of rosewood heart wood |
| CN102133260A (en) * | 2011-03-11 | 2011-07-27 | 浙江大学 | Preparation method and application of dalbergia wood active constituent with myocardial protection function |
| WO2012000425A1 (en) * | 2010-06-28 | 2012-01-05 | 天津天士力制药股份有限公司 | Use of a chinese medicine composition in preparing medicaments for treating secondary prevention of myocardial infarction |
| WO2019192339A1 (en) * | 2018-04-04 | 2019-10-10 | 天士力医药集团股份有限公司 | Traditional chinese medicine composition for preventing and/or treating ischemic reperfusion injury |
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| CN102119957A (en) * | 2011-03-11 | 2011-07-13 | 浙江大学 | Preparation method and application of effective ingredient of rosewood heart wood |
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| CN102119957B (en) * | 2011-03-11 | 2012-05-02 | 浙江大学 | Preparation method and application of effective component of dalbergia wood |
| CN102133260B (en) * | 2011-03-11 | 2013-03-13 | 浙江大学 | Preparation method and application of dalbergia wood active constituent with myocardial protection function |
| WO2019192339A1 (en) * | 2018-04-04 | 2019-10-10 | 天士力医药集团股份有限公司 | Traditional chinese medicine composition for preventing and/or treating ischemic reperfusion injury |
| JP2021520358A (en) * | 2018-04-04 | 2021-08-19 | タスリー・ファーマシューティカル・グループ・カンパニー・リミテッドＴａｓｌｙ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｇｒｏｕｐ Ｃｏ．， Ｌｔｄ． | Chinese herbal composition to prevent and / or treat ischemia-reperfusion injury |
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