CN1742808A - Medicine composition with synergetic function - Google Patents

Abstract

The present invention relates to a medicine composition, preparation method and its application. The described medicine composition contains salvia root and peony root for preventing and curing diabetes and complicating diseases, senile dementia, angiocardiopathy, cerebrovascular diseases, hyperlipemia, fatty liver and thrombosis of central vein of retina.

Description

A kind of have a synergistic pharmaceutical composition

Technical field

The present invention relates to drug regimen, specifically, be a kind of contain natural plant extracts or monomeric medicinal combination, be used for the treatment of and/or prevent cardiovascular and cerebrovascular disease, diabetes and complication thereof, senile dementia, central retinal vein occlusion, hyperlipemia, fatty liver, and the recurrence that is used to prevent cardiovascular and cerebrovascular disease.

Background technology

Diabetes are one of world's high incidence diseases.According to WHO research report, global diabetics surpasses 1.5 hundred million.Diabetes not only cause life danger because of acute complications, for example the more important thing is its various severe chronic complication: diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic neuropathy, diabetic fatty liver and Diabetes with Hypertension, hyperlipidemia etc. have higher morbidity, disable/dead rate, thereby are subjected to showing great attention to of medical worker.

Blood sugar lowering chemical synthetic drug newly developed continues to bring out, and has obtained application clinically.Yet regrettably, a large amount of untoward reaction reports are recognized people, and chemicals has inevitable side effect in the efficient therapeutical effect of performance.

In recent years, numerous scholars have done many work aspect the medicinal plants study of diabetes preventing and treating, analysis and research have been strengthened to active substance of plant, in the hope of further clear and definite its effect (for example: Chen Qiu, the research of single medicinal material treatment diabetic nephropathy is stated slightly, Chinese medicine academic periodical 2004,1:103-105; Guan Qingbao, single medicinal material and extract for treating diabetic nephropathy experimentation summary thereof, traditional Chinese medical science forum 2003,1:54-56; Chen Zhizhong, the research and development progress of natural drug anti-diabetic activity composition, Chinese national folk medical magazine 2004,1:1-3; Gao Meimei, blood sugar lowering effective monomer component and Pharmacological action study thereof progress in the medicinal natural goods, Chinese crude drug 1999,10:542-545; Guo Cheng, the progress of external plant amedica treatment diabetes, foreign medical science-Chinese medicine fascicle 1997,3:51-52).Yet the effect that obtains is limited, and this mainly is the pathogenesis complexity owing to diabetes, and normal with one or more different classes of complication, existing single active skull cap components is difficult to multi-faceted proving effective.

People attempt to adopt the mode of multiple natural drug coupling, in the hope of reducing dosage by adduction between them even synergism, thereby further reduce untoward reaction when guaranteeing (even raising) curative effect.Regrettably, the composition of natural drug is very complicated, and the pharmacokinetic parameter of most of natural drugs, drug metabolism mechanism, action target spot, the mechanism of action are all unclear.Therefore, compare, more be difficult to predict the interaction between natural drug with the interaction between the chemical drugs.

Therefore, there is urgent demand this area to natural drug (combination) safely and effectively.

The inventor attempts to provide a kind of product that can overcome above-mentioned defective.By a large amount of guiding tests, we tentatively determine to have such potential quality based on the medicine of Radix Salviae Miltiorrhizae and Radix Paeoniae.When attempt from prior art, to seek this bonded according to the time, we find: at Radix Salviae Miltiorrhizae can with the Radix Paeoniae use in conjunction, the mechanism of action of the two is underlying issues such as adduction, collaborative or antagonism, prior art does not up to now provide scientific basis.Whether can unite as for the two and to be used for other disease (for example cardiovascular disease, senile dementia etc.), prior art even similar hint not.

Summary of the invention

The inventor has carried out a large amount of explorations in this respect, and has obtained many gratifying results.

One object of the present invention is to provide Radix Salviae Miltiorrhizae and the application of Radix Paeoniae in treating and/or preventing diabetes and complication thereof, cardiovascular and cerebrovascular disease, senile dementia, central retinal vein occlusion, hyperlipemia, fatty liver diseases.

Below the present invention is further elaborated.

Diabetes and complication thereof

The beneficial effect of drug regimen of the present invention at first is to find in the process of research treatment diabetes.

Studies confirm that drug regimen of the present invention has the excellent treatment effect to diabetes and related complication thereof.

Known, Radix Salviae Miltiorrhizae (compound Salviae Miltiorrhizae) can be used for treating diabetes and complication thereof (for example, Beijing University of Chinese Medicine's journal-tcm clinical practice version 2002,1:14-17; The Jiangsu traditional Chinese medical science 1997,12:25-26) and peoniflorin have hypoglycemic activity (for example, Planta Med.,, 63 (4): 323) in 1997.Yet, in view of the mechanism of diabetes and complication thereof very complicated, academia and clinical dispute (J Am Coll Cardiol 2003,41 (1): 1-7 that this is also existed; Intern Med 2003,42 (7): 554-9; Exp Clin Endocrinol Diabetes 2002,110 (5): 212-8; BiolPharm Bull 2003,26 (12): 1668-73; Shandong medicine 2003,43 (1): 14-15), still do not have practicable therapeutic scheme (especially adopting the therapy of natural drug), the known technology deficiency thinks that coupling scheme of the present invention provides enough theoretical foundations.

On the basis of a large amount of experiments, we infer that courageously effect of the present invention is because Radix Salviae Miltiorrhizae acts on different target spots with Radix Paeoniae, especially at different pathological stages performance therapeutical effect, have brought into play the wholistic therapy advantage of drug combination.Especially it should be noted that with the Radix Salviae Miltiorrhizae or the Radix Paeoniae of independent use and compare that the present invention makes up the remarkable animal subject insulin resistant that reduced, and the stronger anti-inflammatory reaction of organizing.

Present academic theory is thought, diseases such as the nephropathy that diabetes cause, retinopathy, neuropathy, its basic pathology basis is that long-term hyperglycemia causes various cytokines to change, and then cause injuries of tissues and organs, wherein, multiple diabetic complication pathogeny is relevant with injury of vascular endothelial cells.We infer that on experiment basis described later the present composition makes it to protect vascular endothelial cell at the synergism of aspects such as antioxidation, anti-inflammatory response, and this may to be the present invention make up the key point that can effectively treat diabetic complication disease.

Described diabetes and complication thereof for example comprise: non-insulin-depending type (II type) diabetes, diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic neuropathy, Diabetes with Hypertension, fatty liver, hyperlipidemia etc.

Cardiovascular and cerebrovascular disease, senile dementia

The beneficial effect of the two coupling also not only is confined in diabetes and the complication thereof.In further research, we are surprised to find, and pharmaceutical composition of the present invention also shows the excellent treatment effect in the treating and/or preventing of cardiovascular and cerebrovascular disease (especially ischemic diseases), senile dementia.

Described cardiovascular and cerebrovascular disease for example comprises that coronary heart disease, apoplexy (also claiming apoplexy), myocardial infarction and described senile dementia comprise Alzheimer (being called for short AD) or vascular dementia (being called for short VD).

Hyperlipemia, fatty liver

In research, find that also the present invention makes up the effect with blood lipid regulation at above-mentioned disease.Because hyperlipemia is important (characteristic) presentation of non-alcoholic fatty liver disease patient, so we have further carried out the research of relevant hyperlipemia, fatty liver aspect, the result, we have excellent curative equally at pleasantly surprised discovery the present invention combination.

The cardiovascular and cerebrovascular disease recurrence

Another important discovery of the present invention is the beneficial effect of drug regimen of the present invention aspect the recurrence of prevention cardiovascular and cerebrovascular disease.

Cardiovascular and cerebrovascular disease is the commonly encountered diseases and the frequently-occurring disease of harm modern health, and its sickness rate, case fatality rate and disability rate are all very high.For example, particularly disadvantageously, the case fatality rate of recurrent cerebral infarction, disability rate all be significantly higher than first morbidity (Liang Yuhong, foreign medical science cerebrovascular disease fascicle 1993,1:155).

Current, the treatment result of study after the cardiovascular and cerebrovascular disease morbidity still can't be satisfactory, but generally acknowledged that this class disease is the disease (Sacco RL, Cerebrovasc Dis 1999, supplementary issue 3:37-44) that can prevent.According to the time of intervening measure intervention, prevention can be divided into two stages usually: " primary prevention ", promptly to healthy population or have the cardiovascular and cerebrovascular disease risk factor but crowd that cardiovascular and cerebrovascular disease do not take place as yet carries out prevention, usually (behavior) mode of mainly emphasizing to live is intervened, and does not advocate the use pharmaceutical intervention; " secondary prevention " promptly to occurring the cardiovascular and cerebrovascular disease symptom, carries out prevention as the patient of dementia onset history after transient ischemic attack (TIA) or the existing Ischemic Stroke, prevents that it from disease of the same race taking place once more and the measure taked.At this, the term that uses among the present invention " prevention) recurrence " is meant " secondary prevention ".

Though conventional chemical medicine for example aspirin etc. can be realized effective prevention to a certain extent, but suitable limitation is arranged, even Failure cases is also a lot (referring to Wang Shaohua, railway medical science 1999,27 (2): 136), be commonly called as clinically and be " aspirin resistance ".Simultaneously, aspirin increases the danger of body hemorrhage (especially upper gastrointestinal hemorrhage), and quite a few patient uses limited.And, report is arranged recently, the comprehensive existing data of U.S. food Drug Administration (FDA) is thought, there is the probability that increases the cardiovascular adverse events in NSAID (non-steroidal anti-inflammatory drug), it is worried that this just makes the clinicist produce when using this class medicine, that is might increase by the sickness rate of treatment disease when, treating disease.At present, in clinical practice, also can have following pharmacological action (particularly synergism) simultaneously without any a kind of medicine, the clinician is forced to select multiple medicine to use simultaneously.And use miscellaneous medicine simultaneously, bring the stack (although report is seldom, be difficult to decision-making during clinician's practical application medicine, take drug side effect often into account) of drug side effect probably.Particularly disadvantageously, in numerous risk factors of recurrence, any actually risk factor plays main effect to recurrence, does not also have clear and definite conclusion, does not therefore still have a kind of medicine at present and goes on the market as main activity/indication with " primary prevention " or " secondary prevention ".

The inventor has done good try and exploration in this regard, and has obtained tempting achievement.Zoopery shows, being combined in of Radix Salviae Miltiorrhizae and Radix Paeoniae controlled a plurality of main risk factors of recurrence aspects simultaneously and shown beat all synergism.In view of time and medical science logic factor, we have only carried out cerebral infarction " secondary prevention " the clinical observation test of limited quantity, but can therefrom dope the present invention is combined in cardiovascular and cerebrovascular disease " primary prevention ", especially " secondary prevention " potential application foreground clinically.

According to result of the test, and in conjunction with present internationally recognized cardiovascular and cerebrovascular disease " primary prevention ", " secondary prevention " evidence-based medicine EBM evidence, we infer, why pharmaceutical composition of the present invention can prevent the recurrence of cardiovascular and cerebrovascular disease effectively, very likely is the synergism that shows on following:

1. antiplatelet aggregative activity: anticoagulant and secretion, change the prostaglandin metabolism approach of platelet and endothelial cell, make that environment trends towards preventing platelet aggregation, prevents thrombosis and blood vessel endothelium breakage in the blood vessel;

2. blood lipid regulation effect: triglyceride and T-CHOL are reduced, and high density lipoprotein increases slightly, and the synthetic very low density lipoprotein (VLDL) of liver reduces, and these three kinds of variations can both actively prevent arteriosclerotic generation;

3. regulate carbohydrate metabolism: the blood sugar level of diabetics is controlled in the ideal range, improves lipodystrophy, control the synthetic of cholesterol;

4. antioxidation: the SOD in the human activin, suppress the effect of free radical, suppress the destruction of lipid peroxide to biomembrane normal function in the body, reduce tremulous pulse, especially arteriolar hardener meeting.

5. blood pressure regulation effect: reduce the passive expansion of blood vessel, reduce the suffered tension force of blood vessel wall, permeability increase, prevent that plasma fraction from exosmosing; Reduce the blood vessel wall thickness, its robustness is increased, prevent smooth muscle hyaline degeneration and necrosis.

6. vascular endothelial cell protective effect reduces the thrombosis chance.

Simultaneously, in view of the complexity of cardiovascular and cerebrovascular disease secondary prevention, inventor's expectation is not subjected to the restriction of any theory, and obtained beneficial effect all be experimental results show that by pharmacological effect.Advantageously, zoopery shows, drug regimen of the present invention also shows significant anti-inflammatory response effect: after using medicine of the present invention, the atheromatous plaque of animal subject forms is subjected to the inhibition degree, parallel with the reduction level of Inflammatory Mediators CRP in its body (perhaps MCP-1), this obviously points out drug regimen of the present invention by suppressing blood vessel generation inflammatory reaction, cause arteriosclerotic chance thereby suppressed the lipid calmness, reduced apoplexy recurrence or dead important risk factor.Above-mentioned discovery has verified further that in conjunction with clinical test results the present invention is combined in the application potential of cerebral infarction " secondary prevention " aspect.

Therefore, another object of the present invention is to be provided in Radix Salviae Miltiorrhizae and Radix Paeoniae are used for preventing the medicine of cardiovascular and cerebrovascular disease recurrence in preparation application.When clinical practice, the doctor can formulate individual dosage regimen according to factors such as patient's age, system, the orders of severity, for example gives 1/5-1 and doubly treat/prevent the pharmaceutical composition of the present invention of effective dose.As everyone knows, with regard to the treatment compliance, long-term oral administration relatively is suitable for the prevention of recurrence treatment.

Combination of the present invention and corresponding preparations

The present invention's combination is meant: supply administering drug combinations with the independent dosage form that contains Radix Salviae Miltiorrhizae, Radix Paeoniae separately, perhaps provide with the compositions/products form that contains the two simultaneously.

Therefore, another object of the present invention is to be provided for containing the Pharmaceutical composition of Radix Salviae Miltiorrhizae and Radix Paeoniae, wherein the part by weight of Radix Salviae Miltiorrhizae and Radix Paeoniae is 0.01-20: 1, and preferred 0.05-10: 1,0.1-5: 1 and more preferably 0.2: 1,0.5: 1,1: 1 and 2: 1.

In the present invention's combination, can select flavour of a drug (for example Radix Paeoniae) directly to be ground into powder and be used as medicine, extract or other form that also can be equivalent to above-mentioned natural drug material crude drug amount are used as medicine.Therefore, the active component of drug regimen of the present invention comprises the former powder of medical material, fat or water solubility extract, effective site or effective ingredient, perhaps adopts existing goods form in the prior art.For example, described active component comprises:

A. Radix Salviae Miltiorrhizae: Radix Salviae Miltiorrhizae extract, mainly contain salvianolic acid, TANSHINONES; Or water-soluble extract of red sage root, mainly contain with salvianolic acid A, salvianolic acid B, protocatechualdehyde, danshensu is the liposoluble ingredient (total phenolic content 40%, preferred more than 60%) of representative, or salvianolic acid monomer or its pharmaceutical salts (for example magnesium salt), or the monomeric mixture of salvianolic acid; Or the Radix Salviae Miltiorrhizae liposoluble extract, mainly contain TANSHINONES (TANSHINONES content 50%, preferred more than 80%, for example Tanshinone I, Tanshinone I I _A, Tanshinone I I _B, cryptotanshinone, dihydrotanshinone I etc.), or TANSHINONES monomer or its pharmaceutical salts (for example sulfonate sodium), or the monomeric mixture of TANSHINONES; With

B. Radix Paeoniae: the dry root powder of Radix Paeoniae (Radix Paeoniae Alba, Radix Paeoniae Rubra, river Radix Paeoniae Rubra), contain the extract of glycosides compound (being preferably peoniflorin and lactone glucoside of Radix Paeoniae) or peoniflorin monomer.In addition, studies show that the effective site that contains peoniflorin, lactone glucoside of Radix Paeoniae, Hydroxy peoniflorin, oxypaeoniflorin, benzoylpaeoniflorin, lacdtlorin, paeonol, the former glycosides of paeonol, Cortex Moutan phenolic glycoside, Radix Paeoniae aglycon etc. simultaneously also is useful.The source that it will be appreciated by persons skilled in the art that Radix Paeoniae glycoside of the present invention is not limited to Radix Paeoniae, contains belonging to other plant together and also can realizing the present invention of Radix Paeoniae glycoside, and it extracts and preparation method is a known technology, does not give unnecessary details at this.

In context, " drug regimen of the present invention " related term " Radix Salviae Miltiorrhizae ", " Radix Paeoniae " has above-mentioned definition.

Following test will confirm: the combination with above-mentioned definition it " Radix Salviae Miltiorrhizae " and " Radix Paeoniae " according to the present invention describes has beneficial effect of the present invention.In view of the technology that had existed suitable maturation and the effective above-mentioned definition component of preparation/purification in the prior art already, do not make emphasis at this and describe.For example, can adopt modern the extraction and isolation technics, with the purity that improves active substance, remove unwanted impurity, for example: Chinese patent application ZL011103787, ZL02156681X, ZL011301309, ZL2004100413049, ZL00120986, ZL2003101134541, ZL021179239, ZL02149694 etc. as far as possible.

Can be at Radix Salviae Miltiorrhizae, absorption characteristics in the dissolution characteristics of peoniflorin and the body, adopt the standard preparation technology, add pharmaceutic adjuvant and make suitable for oral administration or parenterai administration dosage form, similar techniques is also quite effectively ripe, for example: oral cavity quick disintegrating slice (ZL2003101133322), slow controlling agent (ZL011333332, ZL011387106), cyclodextrin clathrate (ZL01141436, ZL02108778), solid dispersion (ZL001194313), injection (ZL001215329, ZL031399428, ZL031573150, ZL2003101241702, ZL021337241), injectable powder (ZL200410037717, ZL031323820, ZL021446008, ZL200410002103), little or nanometer formulation (ZL021378630, ZL00119579), phosphatide complexes (ZL001278126, ZL031320627) etc.

Be understandable that, according to prior art at (for example: Chinese TCM basis medical journal 2004 to the instruction of the pharmacologically active of Radix Salviae Miltiorrhizae, Radix Paeoniae active component, 4:35-38, ZL011300868, ZL2003101210263, ZL021378630, ZL011333332, ZL02133915, ZL01819759 or ZL200310121058), those of ordinary skills can select various combination form (following experiment will further confirm the beneficial effect of these combining forms) for use according to different disease conditions.For example, described combination includes but not limited to: in the treatment based on study of anti-atherogenic effect, or acting as with anti-senile dementia in the main treatment, can adopt the combination of 0.01-20:1 " TANSHINONES+Radix Paeoniae (glycosides) "; And in based on the treatment of emphasizing the cardiovascular and cerebrovascular vessel activity, can adopt the combination of " salvianolic acid (danshensu)+Radix Paeoniae (glycosides) "; Certainly, also can adopt the combination of " TANSHINONES+salvianolic acid (danshensu)+Radix Paeoniae (glycosides) ".In the clinical use of the present composition, exemplary every day, oral recommended dose was: Radix Salviae Miltiorrhizae is (with danshensu or Tanshinone I I _A(C ₁₉H ₁₈O ₃) meter) 1-20mg (preferred 2-8mg, more preferably 2-4mg), Radix Salviae Miltiorrhizae be (with salvianolic acid B (C ₃₆H ₃₀O ₁₆) meter) 10-200mg (preferred 20-120mg, more preferably 40-80mg), peoniflorin 10-100mg (preferred 20-40mg, more preferably 20-40mg).

That carries out subsequently studies show that, (for example make up with the big prescription of existing " Radix Salviae Miltiorrhizae+Radix Paeoniae+other component ", ZL981107567, ZL001039695, ZL02149694, ZL98100232.3, ZL001327631, ZL011139919 etc.) compare, under the situation that has reduced one or more active component, it is identical that drug regimen of the present invention has still kept, even more favourable pharmacological action with regard to some aspect (for example having avoided some to become the unwanted pharmacological action or the untoward reaction of branch), many index significantly is better than the Radix Salviae Miltiorrhizae or the Radix Paeoniae of using separately, and this is that those skilled in the art can't infer according to prior art.

On behalf of natural drug, shortcomings such as the effect that said medicine combination of the present invention has overcome existing medicine existence is single, dosage is big treat and prevent the new trend of above-mentioned disease.

The pharmacology pharmacodynamic experimental study

One. the pharmacological action of diabetes aspect

1. to the expression and the regulating action of type ii diabetes rat kidney VEGF

VEGF (VEGF) may become the special target spot of control diabetic nephropathy (DN), and blocking VEGF is synthetic or biological action is significant.

1.1 materials and methods

48 of female rats, body weight 155-170g.With random blood sugar 〉=16.7mmol/L as type ii diabetes (T ₂DM) modelling standard.Rat is divided into 6 groups, 8 every group, sets up behind the DM model by following scheme administration:

1. diabetic nephropathy group (DN group): normal saline is irritated stomach; 2. high dose composition treatment group (A ⁺Group): Radix Paeoniae Alba extract (in peoniflorin)+Radix Salviae Miltiorrhizae extract (in salvianolic acid) 1: 5,60mg/kg irritates stomach; 3. low dosage combination treatment group (A-group): Radix Paeoniae Alba extract (in peoniflorin)+Radix Salviae Miltiorrhizae extract (in salvianolic acid) 1: 5,20mg/kg irritates stomach; 4. B organizes: Radix Salviae Miltiorrhizae extract (contains salvianolic acid, 40mg/kg) irritates stomach; 5. C organizes: Radix Paeoniae Alba extract (contains peoniflorin, 20mg/kg) irritates stomach; 6. sham operated rats: right kidney is separated from right back inlet in the anesthesia back, does not do any processing, closes otch, conventional feed, normal saline filling stomach.

1.2 observation index and method

Tail vein blood survey fasting glucose and serum creatinine (Scr), blood triglyceride (TG), cholesterolemia (TC); Insulin detects and adopts radioimmunology; Survey microdose urine protein with immunoturbidimetry; With VEGF, TGF-β ₁Adopt the S-P method.

1.3 result

Modeling group (40) is measured blood insulin, blood sugar concentration all is significantly higher than sham operated rats (P＜0.05, P＜0.01), and the model success is described.After treating for 6 weeks, compare with DN, the slight decline of blood glucose, blood insulin of high and low dose compositions group all has significant difference (being P＜0.05), and Radix Salviae Miltiorrhizae and Radix Paeoniae group then change not obvious, the results are shown in following table 1.

Blood fat, 24h urine protein, creatinine clearance rate (Ccr) change: in 9th, 12 weeks, DN group TC, TG, 24h urinaryalbumin obviously raise than sham operated rats, and Ccr descends.Compare with the DN group, every index of high and low dose compositions group is significantly improved, and Radix Salviae Miltiorrhizae and Radix Paeoniae group then change not obvious, the results are shown in following table 2.

The variation of kidney pathomorphism: during the 12nd week, DN group kidney weight/body weight, glomerule area and glomerular volume all obviously raise than sham operated rats, and high and low dose compositions group all reduces than the DN group, and Radix Salviae Miltiorrhizae and Radix Paeoniae group then change not obvious, the results are shown in following table 3.

Nephridial tissue VEGF and TGF-β 1 SABC change: sham operated rats all has a small amount of vegf expression at glomerule and renal tubules, and TGF-β 1 has trace expression; Visible VEGF and TGF-β 1 express and strengthen in the DN group glomerule, and VEGF matter between glomerule, renal tubules all has expression; The expression of TGF-β 1 is found in matter between glomerule and renal tubules and kidney.The SABC semi-quantitative analysis is the result show, the kidney VEGF of high and low dose compositions group and TGF-β ₁Expression obviously be less than DN group, Radix Salviae Miltiorrhizae and Radix Paeoniae organize then change not obvious.

1.4 conclusion

At this test preparation T ₂In the rat model of DM, possess the insulin resistant feature, the kidney hypertrophy occurred, albuminuria, kidney VEGF and TGF-β ₁High expressed.Above-mentioned experiment shows that the present composition can reduce T ₂DM rat model urine protein reduces renal hypertrophy, alleviates the kidney vegf expression, and the mechanism of its renal function protecting may be relevant with inhibition VEGF, and its effect obviously is better than using separately Radix Salviae Miltiorrhizae or Radix Paeoniae, and two groups of curative effects of high and low dose do not have significant difference.

The comparison of table 1 blood glucose, insulin (X ± s, n=8)

Group	Blood glucose mmol/L				Blood insulin IU/L
									5 weeks	6 weeks	9 weeks	12 weeks	5 weekends	6 weekends	9 weekends	12 weekends
	Sham-operation modeling DN C B A +A -	3.5±0.5 4.7±0.13 * - - -	3.6±0.3 18.9±2.7 ** - - -	4.0±0.3 - 19.1±4.0 ** 17.6±3.8 ** 18.9±4.8 ** 12.4±1.5 **# 12.8±1.7 **#	4.1±0.4 - 18.9±3.4 ** 17.8±3.5 ** 19.8±4.2 ** 13.9±2.1 **# 14.2±2.6 **#	34.23±6.27 49.94±9.48 * - - - - -	34.36±4.98 - - - - -	35.03±6.11 - 43.33±9.99 42.73±11.13 44.33±12.11 36.91±5.67 # 37.11±6.01 #									34.63±3.91 - 42.18±9.77 39.98±9.57 44.88±10.47 37.04±6.36 # 37.34±6.18 #

Annotate: compare with sham operated rats ^*P＜0.05 ^*P＜0.01; Compare #P＜0.05 with diabetic nephropathy (DN) group

The variation of table 2 TG, TC, 24 urinaryalbumin, Ccr (X ± s, n=8)

Group	TG mmol/L		TC mmol/L		24h urinaryalbumin mg		Ccr mL/min/100g
								9 weeks	12 weeks	9 weeks	12 weeks	9 weeks	12 weeks	12 weeks
	Sham-operation DN C	0.69±0.02 1.18±0.29 * 1.19±0.30 *	0.72±0.03 1.29±0.13 * 1.30±0.14 *	1.44±0.09 4.52±0.32 * 4.57±0.34 *	1.47±0.12 4.49±0.18 * 4.52±0.19 *	0.13±0.02 3.70±2.13 ** 3.72±2.11 **	0.16±0.13 6.22±1.21 ** 6.21±1.24 **								0.67±0.02 1.79±0.03 ** 1.82±0.03 **

B A + A -

1.20±0.28 * 1.15±0.23 *# 1.12±0.21 *#

1.31±0.15 * 1.07±0.22 *# 1.13±0.29 *#

4.54±0.36 * 2.44±0.21 **# 2.64±0.18 **#

4.57±0.21 * 1.88±0.13 *# 1.99±0.08 *#

3.78±1.94 ** 2.24±0.22 **# 2.22±0.26 **#

6.53±1.04 ** 3.87±0.09 **# 3.78±0.08 **#

1.78±0.04 ** 1.36±0.03 **# 1.46±0.06 **#

Compare with sham operated rats ^*P＜0.05 ^*P＜0.01; Organize than #P＜0.05 with diabetic nephropathy (DN)

Respectively organize when table 3 fed for the 12nd week rat variation (X ± s, n=8)

Group	VEGF	TGF-β1	Kidney weight/body weight * 10 2	Glomerule area * 10 2μm 2	Glomerular volume * 10 2μm 3
						Sham-operation DN C B A + A -	0.19±0.02 0.43±0.01 ** 0.40±0.03 ** 0.44±0.01 ** 0.25±0.03# 0.29±0.05 *#	0.32±0.01 0.59±0.01 ** 0.61±0.03 ** 0.63±0.03 ** 0.41±0.01 *# 0.39±0.02 *#	0.37±0.02 0.92±0.03 ** 0.89±0.06 ** 0.96±0.03 ** 0.54±0.02 *# 0.58±0.02 *#	6.4±0.36 11.33±1.13 ** 11.13±1.03 ** 10.93±1.12 ** 8.11±0.39 **# 8.38±0.29 **#	44.04±6.23 96.24±11.12 ** 93.44±10.22 ** 98.24±10.72 ** 60.34±9.87 **# 61.24±10.87 **#

Compare with sham operated rats, ^*P＜0.05, ^*P＜0.01; With diabetic nephropathy (DN) group ratio, #P＜0.05

2. to the diabetic retinal tissue in rat protective effect

2.1 materials and methods

Laboratory animal is selected 50 of male SD rats for use, and adaptability was raised 7 days, surveys fasting glucose and all is lower than 7mmol/L, is divided into 10 of normal control groups (E group) at random, 40 of experimental grouies.(STZ) brings out diabetes with streptozotocin.All blood glucose 〉=16.7mmol/L are divided into 3 groups more at random as diabetic groups, and each 10, the DM group is not treatment group of diabetes, and every day, normal saline 100mg/kg irritated stomach; The A group is Radix Salviae Miltiorrhizae extract group (containing TANSHINONES), and 50mg/kg irritates stomach; The B group is Radix Paeoniae Rubra extract group (containing peoniflorin), and 30mg/kg irritates stomach; C group is present composition group: Radix Paeoniae Alba extract (in peoniflorin)+Radix Salviae Miltiorrhizae extract (in TANSHINONES) 1: 5,40mg/kg irritates stomach.Each component 2 cage is fed, ad lib and drinking-water.

2.2 result

Test shows that the present composition has the effect that promotes weight increase, blood sugar lowering for the DM rat, sees Table 4.

Compare with normal group, each activity, the active of AR (aldose reductase) of organizing retinal tissue of rats with diabetic mellitus NOS significantly strengthens, and NO content significantly increases.Compare with the DM group, C group rat retina organizes the activity of NOS, the activity of AR obviously to be suppressed, and the content of NO also significantly reduces, and the inhibitory action of A, B group is not obvious, sees Table 5.

2.3 discuss

1. rising of hyperglycemia level and glycolated hemoglobin ratio and retinopathy have confidential relation between taking place, developing.Above-mentioned experiment shows, the effect of present composition blood sugar lowering can obviously suppress the activity of AR and NOS, reduces the synthetic of NO, and diabetic renal papillary necrosis is had obvious preventive and therapeutic effect.

Find that simultaneously the present composition can significantly reduce NO content, this may to improve the activity of retinal tissue of rats with diabetic mellitus SOD relevant with the present composition, and the SOD increased activity is in time removed the NO of excessive generation, and radical damage is played certain protective role.

2. in another test, investigated the influence of the present composition, studies show that the effect that the present composition has obvious functions of blood sugar and alleviates insulin resistant diabetes type piglets retinal vessel endothelial growth factor expression.

3. in addition, Chinese scholars is thought and can be stoped and postpone the formation of proliferative diabetic retinopathy (PDR) by the expression that suppresses VEGF.What the applicant had carried out studies show that, compare with matched group (high fat high-sucrose feedstuff+Radix Salviae Miltiorrhizae extract or Radix Paeoniae Alba extract), the vegf protein in the animal retinal tissue of treatment group (high fat high-sucrose feedstuff+present composition) is expressed has significant difference (P＜0.01).

The inventor wishes to borrow above-mentioned statement indefiniteness ground to explain that present composition effect obviously is better than using separately the mechanism of Radix Salviae Miltiorrhizae or Radix Paeoniae.

Rat body weight respectively organized by table 4 and blood glucose compares (n=10)

Group	Body weight (g)			Blood glucose (mmol/L)
							4 weeks	8 weeks	12 weeks	4 weeks	8 weeks	12 weeks
	E DM A B C	281±15 181±8 * 193±14 * 178±15 * 255±14 *#	301±12 169±11 * 167±9 *# 180±13 * 268±13 *#	316±11 158±16 * 165±9 * 170±7 * 219±9 *#	3.9±1.1 21.4±2.3 * 20.8±1.8 * 21.7±1.1 * 12.3±1.7 *#	4.2±0.5 22.9±1.3 * 21.3±1.5 * 21.4±1.5 * 10.4±1.2 *#							4.3±0.8 22.8±1.9 * 22.6±1.7 * 21.2±1.9 * 9.1±2.8 *#

Compare with the E group, ^*P＜0.01; Compare with the DM group, ^#P＜0.01

Table 5 is respectively organized rat retina and is organized the activity of the content of NO, NOS, the activity of AR (n=10)

Group	NO content (μ mol/gprot)	NOS activity (U/mg prot)	AR activity (mU/mg prot)
				E DM A B C	35.97±2.13 67.84±5.45 64.23±3.47 59.65±3.97 43.75±4.33	2.14±0.10 6.89±1.89 5.31±1.12 4.03±0.42 3.58±0.44	0.379±0.095 1.112±0.216 0.679±0.061 0.729±0.031 0.540±0.130

Two. the pharmacological action for the treatment of cardiac and cerebral vascular diseases

1. to the influence of different derivant induced platelet aggregations

1.1 material

Pharmaceutical composition of the present invention (peoniflorin+TANSHINONES 1: 1 is called for short compositions A, the 8mg/kg injection), and Radix Paeoniae Alba extract (containing peoniflorin)+Radix Salviae Miltiorrhizae extract (containing TANSHINONES) (1: 1, be called for short compositions B, 20,40,80mg/kg irritates stomach);

Blank group: normal saline;

Positive control drug: the Radix Paeoniae Alba extract that is equivalent to the one pack system of same dosage (contains peoniflorin, 20mg/kg); The Radix Salviae Miltiorrhizae extract that is equivalent to the one pack system of same dosage (contains TANSHINONES, 80mg/kg); Aspirin tablet; And the disclosed compositions of ZL00103969.5 (be reference composition, contain 12 flavor Chinese medicines such as Hirudo, Radix Salviae Miltiorrhizae, Radix Paeoniae Rubra).

1.2 experimental technique

The Cavia porcellus grouping was irritated stomach 5 days, the blank normal saline.Last administration rear neck artery blood sampling in 1 hour, with the sodium citrate anticoagulant, mixing, centrifugal, merge supernatant as PRP (platelet rich plasma), platelet count; Remaining blood plasma is centrifugal, gets supernatant as PPP (platelet poor plasma); With the PPP zeroing, to get PRP300 μ l and add opacity tube, 37 ℃ of incubations add derivant PAF (platelet activating factor), assemble different time, record data.The results are shown in Table 6.

The accumulative influence of the inductive guinea pig blood platelet of table 6. pair platelet activating factor (X ± s)

	Different time points platelet aggregation rate %					The platelet maximum agglutination rate
							1min	2min	3min	4min 5min
	Blank peony extract Salvia root P.E aspirin reference composition Zu compound A Zu compound B (low) Zu compound B (Zhong) Zu compound B (height)	28.81±8.74 18.65±6479 * 18.67±9.70 * 12.11±6.93 ** 18.70±9.14 * 12.04±7.31 ** 22.31±9.17 19.02±8.74 * 12.16±8.12 **	60.08±18.24 43.17±16.03 * 48.32±16.17 * 34.67±16.75 ** 47.78±17.46 * 33.19±15.64 ** 47.17±17.46 * 41.05±17.78 * 34.15±16.53 **	70.08±18.24 52.01±22.67 * 56.35±19.95 47.21±21.69 ** 55.35±19.05 47.07±22.77 ** 55.73±17.02 49.91±23.89 * 47.33±24.67 **	73.15±17.70 53.10±20.18 * 62.45±18.78 * 47.08±20.87 ** 60.45±17.71 * 45.18±20.91 ** 58.40±18.27 * 48.84±23.87 ** 47.27±19.07 **							74.15±18.85 52.17±17.85 * 67.92±±19.22 50.08±19.34 ** 67.09±18.31 47.03±17.84 ** 59.18±20.02 53.93±17.85 * 50.09±19.34 **	75.07±19.01 53.72±19.13 * 67.73±17.95 50.08±20.01 ** 66.72±19.75 47.07±18.72 ** 59.29±18.35 54.92±20.26 * 50.07±20.01 **

Compare with the blank group ^*P＜0.05 ^*P＜0.01

With adenosine diphosphate (ADP) is that the experimental result of derivant is similar.

By The above results as can be known, aspirin tablet, reference composition, Radix Paeoniae Alba extract, Radix Salviae Miltiorrhizae extract and height/middle dosage present composition, all can suppress different derivants to some extent and induce (platelet activating factor, adenosine diphosphate) platelet aggregation (coagulation), reduce maximum agglutination rate, wherein with aspirin tablet, present composition high dose effect is best, middle dosage group also shows the anticoagulant effect, Radix Paeoniae Alba extract that is better than using separately and Radix Salviae Miltiorrhizae extract (P＜0.05), also be better than reference composition, significant difference (P＜0.05) is relatively arranged between present composition high dose group and reference composition group.

The present composition then can improve cAMP content and suppress different derivant induced platelet aggregations, clinically verify that also compositions of the present invention is equal to or is better than aspirin in effect aspect the effect of anticoagulant, more be better than simple peoniflorin and TANSHINONES, and there is not the side effect (having the aspirin group patient of nearly half to drop by the wayside treatment) of aspirin because of strong side effect, processing is learned in two groups of side effect by statistics, has significant difference (P＜0.05).

2. to the thrombotic influence of rats in vitro

Take off according to pharmacology's known method and to measure wet weight of thrombus and thrombosis dry weight respectively.

The result shows, in rat artery-thrombotic experiment of venous blood flow coronary artery bypass grafting, with model control group relatively, the wet weight of thrombus that compositions of the present invention (TANSHINONES-peoniflorin 10: 1) and matched group form all has and alleviates present composition P＜0.01; In rats in vitro thrombosis process, the present composition makes wet weight of thrombus than matched group significant difference (P＜0.01) be arranged relatively, and the wet weight of thrombus that the TANSHINONES of one pack system and peoniflorin group and matched group form is compared also to have and is alleviated, but do not have significant difference (P＜0.05), its effect is similar to positive control drug.The inventor also finds to have significant difference (P＜0.05) between TANSHINONES that present composition group is used more separately and peoniflorin group.

3 pairs of influences that the mice thrombus in vivo forms

The above dosage continuous oral of present composition 0.035g/kg administration 5 days obviously suppresses the mice thrombus in vivo, and the hemiplegia that improves in the mice 15 minutes is recovered number, shows that this medicine forms thrombus in vivo and has obvious antagonism.

4 prevent postangioplasty restenosis

Postangioplasty restenosis (RS), its sickness rate is up to 30-50%.Because the abnormality proliferation of vascular smooth muscle cell (VSMCs) is the pathological characters of RS, therefore suppress the important means that the VSMCs abnormality proliferation becomes worldwide cardiovascular research prevention RS.

4.1 material

Pharmaceutical composition of the present invention (peoniflorin+danshensu+TANSHINONES 4: 1: 1, with 2,4,8mg/kg injection);

Blank group: normal saline;

Positive control drug: be equivalent to the peoniflorin injection of the one pack system of same dosage, 8mg/kg; The danshensu injection, 8mg/kg; The TANSHINONES injection, 8mg/kg; The arasaponin injection;

4.2 method

Vascular smooth muscle cell is separated, cultivates, is identified, reference literature (Piper HM edits, Cell CultureTechinques in Heart and Vessel Research.Springer-Verlag:Germany.1990:280) operation.

After treating that 90%VSMCs converges, through planting behind the trypsinization in culture dish, add the 10%FBS+SMWM incubated overnight, make cell attachment, cell converges about 80%, change serum-free DMEM again into and (contain penicillin 100U/ml, streptomycin 100 μ g/ml) continue to cultivate 24h, make the cell growth synchronously, change 10%FBS+DMEM at last into, and adding medicine at random, each concentration is diluted to 10 μ l/ holes with DMEM.

³H-TdR mixes experiment: replace the DMEM of every hole 1ml, add luCi's ³H-TdR measures the CPM value in each hole with liquid scintillation counter (1900CA).

Cell survival rate=attached cell/total cell number (attached cell+not attached cell)

4.3 result

The results are shown in down two tables.

To smooth muscle cell ³The influence of H-TdR incorporation (X ± s)

	Cultivated 24 hours		Cultivated 48 hours
					3H-TdR mixes	Suppression ratio %	3H-TdR mixes	Suppression ratio %
	The control group Paeoniflorin danshensu tanshinone notoginsenoside present composition (greatly) present composition (Zhong) present composition (little)	9027±451 8477±508 * 8607±513 7658±534 **△ 5349±479 **△△ 3029±127 **△△ 4370±581 **△△ 7685±554 **△	- 6.21 4.13 14.41 40.81 66.51 51.65 16.21	18790±1816 14214±1257 * 17431±1574 10271±1178 **△ 11588±2437 **△ 3327±249 **△△ 4113±303 **△△ 11617±2373 **△					- 24.59 6.73 43.51 38.54 82.35 78.20 39.49

Compare with blank, ^*P＜0.05 ^*P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with Radix Paeoniae/danshensu

To the influence of smooth muscle cell counting (X ± s)

	Cultivate 24 hour cell quantity 1 * 10 4	Cultivate 48 hour cell quantity 1 * 10 4
			Attached cell	Attached cell
	The control group Paeoniflorin danshensu tanshinone notoginsenoside present composition (greatly) present composition (Zhong) present composition (little)	40.27±2.11 39.41±2.23 39.85±2.08 36.10±2.38 **△ 37.81±2.32 **△ 25.78±1.45 **△△ 31.17±1.41 **△△ 36.21±2.01 **△			76.11±3.03 60.11±3.32 69.96±2.79 48.06±3.78 **△ 58.51±3.12 ** 32.74±3.23 **△△ 44.67±3.16 **△△ 50.15±2.98 **△

Compare with blank, ^*P＜0.05 ^*P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with Radix Paeoniae/danshensu

This experiment cell counting analysis, each organize the influence of medicine on cell proliferation with to smooth muscle cell ³H-TdR mixes basically identical, and records not obviously influence of cell survival rate, all more than 90%.

4.4 conclusion

Pharmaceutical composition of the present invention, TANSHINONES, arasaponin injection and peoniflorin are inhibited to the abnormality proliferation of vascular smooth muscle cell (VSMCs), pharmaceutical composition wherein of the present invention is the strongest, TANSHINONES, arasaponin and peoniflorin take second place, danshensu is the most weak, pharmaceutical composition of the present invention and peoniflorin and danshensu relatively have significant difference (P＜0.05) between group.

5. to the protective effect of cerebral ischemia

5.1 influence to the experimental rat ischemia

The male and female rat is divided into 7 groups at random, describes operation according to " pharmacological experimental methodology second edition " (Xu Shuyun chief editor), forms polarity imperfection cerebral ischemic model, according to following scheme administration three days:

5,10, the 20mg/kg present composition the 1st group: 0.9%NaCl matched group (cerebral ischemic model group): 2-4 group:; The 5th group: Radix Salviae Miltiorrhizae Flos Carthami injection 7mg/kg, ip; The 6th group: TANSHINONES 15mg/kg, ip, the 7th group: peoniflorin 15mg/kg, ip.

Surveying rat brain index, brain water content, cerebral ischemia hindbrain capillary permeability and rats with cerebral ischemia cerebral morphology respectively observes.The result shows that the cerebral tissue edema that combination of the present invention, Radix Salviae Miltiorrhizae Flos Carthami cause cerebral ischemia has especially significantly improvement effect, and TANSHINONES and peoniflorin group also obviously are better than matched group.Compare with matched group, the present invention's combination has significantly or the difference of highly significant, and compares between TANSHINONES of using separately and peoniflorin group, also has significant difference.

Experiment shows, when lacking peoniflorin or TANSHINONES in the prescription of the present invention, its drug effect does not all reach the drug effect that compositions of the present invention can reach, therefore, we are surprised to find, the combination of Radix Paeoniae and Radix Salviae Miltiorrhizae all is being significantly improved aspect the raising cardiovascular and cerebrovascular disease and is benefiting effect for the Radix Paeoniae of using separately.

Three. the pharmacological action of senile dementia aspect

1. the influence that alzheimer disease animal memory dysfunction is improved

This experiment keeps away camera bellows experiment for rat, with reference to chief editors such as Xu Shuyun " the pharmacological experimental methodology third edition " (People's Health Publisher, 2002:827).

Adopt Ibotenic acid (IBO) to cause rat alzheimer disease model, the results are shown in following table:

	Dosage (g/kg)	Incubation period (second)	Enter number of times in 5 minutes	Advance camera bellows Mus number
					Operative control group model group huperzine A Radix Paeoniae Alba extract Radix Salviae Miltiorrhizae extract FUFANG DANSHEN DIWAN	---- ---- 2.3×10 -5 0.05 0.05 0.05	220.1±125.6 ** 58.9±90.7 180.9±15.01 223.2±124.9 ** 228.6±70.3 ** 249.7±68.3 **	0.50±0.71 * 3.40±2.87 0.77±1.09 * 0.88±1.26 * 0.47±0.66 * 0.57±0.32 *	3 8 3 3 2 3

The present composition (low) present composition (height)

0.03 0.05

250.6±65.8 ** 267.5±69.9 **△

0.51±0.43 * 0.41±0.28 *△

2 2

Compare with model group ^*P＜0.05, ^*P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with Radix Paeoniae/Radix Salviae Miltiorrhizae

2. to the influence of alzheimer disease animal brain hippocampal tissue homogenate beta amyloid peptide

Above-mentioned experiment is got the ultrasonic homogenate of rat brain Hippocampus after finishing, and exempts from method survey β-AP content with putting, the results are shown in following table (x ± s, n=10):

Group	Dosage (g/kg)	β-AP(pg/ml)
			The operative control group model group huperzine peony extract Salvia root P.E compound danshen dripping pills present composition (low) present composition (height)	-- -- 2.3×10 -5 0.05 0.05 0.05 0.03 0.05	40.97±14.56 ** 65.56±12.81 55.89±13.53 50.78±11.02 * 51.07±10.12 * 51.53±11.23 * 48.25±10.87 * 44.07±9.10 **△

Compare with model group ^*P＜0.05, ^*P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with Radix Paeoniae/Radix Salviae Miltiorrhizae

The above-mentioned present composition that experiment showed, improves significantly to the memory dysfunction that senile dementia and cerebral ischemia cause, reduces the generation that the alzheimer disease rat hippocampus is organized β-AP.Experiment shows that Radix Paeoniae, Radix Salviae Miltiorrhizae and FUFANG DANSHEN JIAONANG all have the improvement effect to alzheimer disease.The drug combination of Radix Paeoniae and Radix Salviae Miltiorrhizae (part by weight is 6: 1) is intervened with the different approach and the mechanism of action from different aspects, has played synergism.

The present invention has also carried out giving the clinical observation of the present composition more than 1 year to AD patient's (20 example), the symptom on every side of hanging down inferior dementia is roamed, moves more, realized to result's demonstration to the patient certain effect, whole cases of the present composition all obtain improvement or are in steady statue in the test of intelligence score, and clinical display effect is better than matched group.

Four. the pharmacological action of antioxidation aspect

1. to the antioxidation of hyperlipidemia rat

1.1 material

Pharmaceutical composition of the present invention: peoniflorin+TANSHINONES 1: 5,50mg/kg irritates stomach;

Normal control group: normal saline;

Hyperlipidemia group: normal saline;

Positive control drug: Radix Salviae Miltiorrhizae extract (50mg/kg); Radix Paeoniae Alba extract (50mg/kg); VE (50mg/kg); FUFANG DANSHEN PIAN (50mg/kg); DANSHAO KELI (50mg/kg contains 9 flavor medicines such as Cornu Bubali, the Radix Rehmanniae, Radix Salviae Miltiorrhizae, Radix Paeoniae Rubra);

1.2 experimental technique

The foundation of high blood lipid model: the Wistar rat gives high lipid food; Normal control group feeding normal diet.Compare with normal group, the LPO of hyperlipidemia model serum and liver obviously raises, and obviously reduces and SOD is active.

Medicine is irritated stomach, handles animal, surveys LPO and SOD, according to the operation of test kit description, gets 1/2 liver LPO to be measured and SOD, the results are shown in following table:

The influence (nmol/L) of table 7. pair hyperlipemia rat serum and liver LPO and SOD

Group	Serum LPO	SOD in serum	Liver L PO	Liver SOD
					The high fat of blood Zu VE Zu Salvia root P.E peony extract Fufang Danshen Pian DANSHAO KELI present composition	8.99±2.00 6.54±1.23 * 8.02±1.19 7.89±1.17 8.16±1.33 6.96±1.07 *△ 6.38±1.15 **△△	400.9±56.7 440.1±28.9 * 429.8±27.7 451.6±40.1 * 448.8±30.6 * 451.8±35.6 *△ 458.7±27.9 *△	6.91±1.18 5.61±1.13 * 6.03±1.45 * 5.89±1.37 * 6.07±1.43 * 5.87±1.59 * 5.30±1.35 **△	7.59±1.19 8.87±1.27 * 8.90±1.36 * 8.73±1.18 * 8.69±1.41 * 9.01±1.28 * 9.21±1.20 *

Compare with the hyperlipidemia group ^*P＜0.05 ^*P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with Radix Paeoniae/Radix Salviae Miltiorrhizae

1.3 conclusion

Above-mentioned experiment shows that Radix Salviae Miltiorrhizae of using separately and Radix Paeoniae Alba extract (50mg/kg) show certain antioxidant activity, and low dosage is then not obvious.The present composition has obvious antioxidation activity, obviously is better than Radix Paeoniae, Radix Salviae Miltiorrhizae and other contrast medicine (P＜0.01) used separately.Other has experiment to show that use the fat soluble ingredient of red sage root or the TANSHINONES of clinical effective separately, its antioxidation and anti-platelet aggregation effect are better than VE and aspirin.

5 usefulness of the present composition are not then found toxic and side effects; therefore in order to ensure invigorate blood circulation, effects such as antioxidation, antiinflammatory; adopt Radix Paeoniae (glycosides) and Radix Salviae Miltiorrhizae (ketone) 5 usefulness, both having played synergism has increased curative effect, has overcome the adverse side effect that Radix Salviae Miltiorrhizae or Radix Paeoniae may bring again.

In addition; also from aspects such as neuroprotective cell, minimizing cerebral tissue malonaldehyde (MDA) and NO generations; investigated the antioxidation of the present composition; the result proves that the present composition has the obvious suppression effect to cerebral tissue MDA; reduced the NO that raises in the cerebral tissue, neurocyte has also been shown protective effect, Radix Salviae Miltiorrhizae extract-Radix Paeoniae Alba extract wherein (5: 2; or 1: 1) there are the obvious synergistic effect in both, and its reason and mechanism remain further to be inquired into.

2. remove the effect of reactive oxygen free radical

Adopt superoxide anion, the external generation system of hydroxy radical, capture and The Technique of Electron Paramagnetic Resonance compares the present composition, peoniflorin, the extract of TANSHINONES and the vigor of active site removing reactive oxygen free radical thereof of same amount by spin.Experimental result shows, the present composition (TANSHINONES-peoniflorin 3: 1), peoniflorin, TANSHINONES have tangible scavenging action to superoxide anion, and wherein the free radical resisting active function of the present composition obviously is better than peoniflorin or the TANSHINONES used merely.

Five. antiatherogenic pharmacological action

1. to the influence of rabbit experimental atherosclerosis (AS) vascular remodeling

1.1 material

Pharmaceutical composition of the present invention: peoniflorin+TANSHINONES 1: 1,50mg/kg irritates stomach;

Normal control group: normal saline;

Model group: normal saline;

Positive control drug: Radix Salviae Miltiorrhizae extract (50mg/kg), Radix Paeoniae Alba extract (50mg/kg), probucol (25mg/kg), QIONGSHAO JIAONANG (25mg/kg);

1.2 experimental technique

With purebred male new zealand rabbit, random packet, raised for 1 week after, adopt the continue method of feeding high lipid food of balloon injured endothelium to duplicate rabbit experiment AS model.Observed for 12 weeks.

1.3 mensuration project and result

Histopathology: under the optical microscope, the complete no abnormality seen of normal control group endotheliocyte changes; The model group arterial endothelial cell is damaged, neointimal hyperplasia, and neointimal hyperplasia is serious during 6 weeks, tube chamber obvious stenosis and size are irregular, and the cell cytoplasm acidophilia is not obvious, a large amount of big or small irregular foam cells occur, the visible fat necrosis center that has, the visible a large amount of fusiformis proliferative cells of subintima; Damaged minimizing of each administration group endothelium thickens obviously and alleviates, and foam cell reduces, and is optimum with present composition group especially.

Tectology: maximum inner film thickness (MIT), minimum lumen diameter (MLD), tube chamber area (LA), interior elastic force film center on area (EELa) around area (IELa), outer elastic force film, and draw inner membrance area (IA), media area (MA), luminal stenosis percentage ratio (LS), wherein, IA=IELa-LA; MA=EELa-IELa; LS=IA/IELa.See the following form:

Project	Normal control	Model group	Probucol	Radix Paeoniae	Radix Salviae Miltiorrhizae	Compositions
							MIT(mm) IA(mm 2) MLD(mm) LA(mm 2) IELa(mm 2)	0 0 1.32±0.16 2.08±0.29 2.08±0.31	0.37±0.13 1.30±0.66 1.09±0.20 1.69±0.50 2.99±0.89	0.11±0.10 ** 0.45±0.27 ** 1.55±0.31 ** 3.14±1.22 ** 3.59±1.21	0.18±0.07 * 0.33±0.30 ** 1.55±0.32 ** 3.05±1.10 ** 3.38±1.12	0.21±0.13 * 1.1±0.64 1.53±0.53 ** 3.09±0.99 ** 4.19±0.78	0.07±0.07 **△ 0.20±0.29 **△ 1.52±0.33 ** 3.10±0.87 ** 3.30±1.11

EELa(mm 2) MA(mm 2) Ls(％)

2.58±0.41 0.50±0.07 0

4.26±1.99 1.27±1.10 43.33±12.8

5.00±1.72 1.41±0.98 12.5±7.31 **

4.45±1.31 1.07±0.33 9.86±7.63 **

5.41±1.01 1.22±0.34 26.2±11.5 *

4.03±1.09 0.73±0.46 △ 6.01±7.65 **△

Compare with model group ^*P＜0.05, ^*P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with Radix Paeoniae

Reducing aspect MIT, IA and LS, the increase LA, each administration group shows effect in various degree.Aspect the inhibition intimal proliferation, particularly evident with the present composition and the effect of probucol group, significantly be better than Radix Paeoniae group (P＜0.05).

1.4 discuss

Known Radix Paeoniae and Radix Salviae Miltiorrhizae all have certain therapeutical effect to AS, but the emphasis difference of its anti-AS, the effective ingredient of Radix Salviae Miltiorrhizae mainly shows as has an inhibitory action to cholesterol is synthetic, generation has certain inhibitory action to malonaldehyde, and these can be confirmed by the effect result of study of Radix Salviae Miltiorrhizae extract to blood fat and the formation of AS speckle.The Radix Paeoniae Alba extract that with the peoniflorin is main active helps preventing platelet adhesion, gathering, and can significantly reduce serum total cholesterol low-density lipoprotein cholesterol and triglyceride levels, and HDL-C is raise, improve lipoprotein component ratio, so more tangible anti-AS effect is also arranged.Share of Radix Paeoniae and Radix Salviae Miltiorrhizae, its main active is that the merging of glycoside and ketone is used, compatibility is relatively stable, can not produce chemical reaction and lost efficacy or the drug effect that detracts, on the contrary, since treatment mechanism stress the direction difference, can produce more significant synergism, be better than the effect that Radix Paeoniae and other active component (for example Rhizoma Chuanxiong) share.

Six. the pharmacological action of anti-inflammatory aspect

1. xylol causes the influence of mouse skin capillary permeability

1.1 material

Pharmaceutical composition of the present invention: peoniflorin+danshensu 10: 1,20mg/kg, 40mg/kg irritate stomach;

Normal control group: normal saline;

Positive control drug: Radix Salviae Miltiorrhizae extract (50mg/kg); Radix Paeoniae Alba extract (50mg/kg); FUFANG DANSHEN PIAN (30mg/kg); DANSHAO KELI (30mg/kg contains 9 flavor medicines such as Cornu Bubali, the Radix Rehmanniae, Radix Salviae Miltiorrhizae, Radix Paeoniae Rubra, Caulis Spatholobi);

1.2 experimental technique

" herbal pharmacology research methodology " with reference to the Qi Chen chief editor makes the animal inflammatory model, the results are shown in following table:

Group	The OD value
		Normal control group FUFANG DANSHEN PIAN DANSHAO KELI	0.067±0.022 0.051±0.023 * 0.038±0.021 **

The Radix Paeoniae Alba extract Radix Salviae Miltiorrhizae extract present composition (low) present composition (height)

0.039±0.018 ** 0.034±0.023 ** 0.031±0.025 ** 0.023±0.017 **△

Compare with matched group ^*P＜0.05, ^*P＜0.01; Compare △ P＜0.05 with Radix Paeoniae/Radix Salviae Miltiorrhizae group

1.3 result

No matter be Radix Paeoniae, Radix Salviae Miltiorrhizae or contain Radix Paeoniae and/or the compound medicine of Radix Salviae Miltiorrhizae, and the present composition, can alleviate mice caused by dimethylbenzene xylene capillary of skin permeability, have the effect that the early stage capillary permeability of inflammation-inhibiting increases, compare with matched group and have significant difference.Compare with the one pack system extract group of Isodose, high dose composition group of the present invention also has significant difference (P＜0.05), proves Radix Paeoniae and Radix Salviae Miltiorrhizae under the prerequisite that all has antiinflammatory action, and two medicines share, and effect strengthens, and demonstrates synergism.

Seven. the pharmacological action of others

1. treat the observation of curative effect of rat fat liver

1.1 materials and methods

The present composition (Radix Paeoniae Alba extract+Radix Salviae Miltiorrhizae extract 2: 1,60mg/kg, 20mg/kg); Radix Salviae Miltiorrhizae extract (contains salvianolic acid, 40mg/kg); Radix Paeoniae Alba extract (contains peoniflorin, 20mg/kg).

50 of male SD rats, body weight 150g ± 10g.After normal 1 week of nursing, be divided into 2 groups at random: experimental group (40), raise with high fat high cholesterol diet (10.0% Adeps Sus domestica, 2.0% cholesterol, 0.5% sodium cholate, 87.5% normal feedstuff); With normal control group (10), give normal feedstuff, two groups of rats are all freely intake.

After 12 weeks, randomly draw 8 from experimental group, the normal control group is randomly drawed 2, and the execution animal is got liver and does pathological section, checking fatty liver modeling success.Remaining experimental group rat is divided into compositions high-dose therapy group, compositions low dose therapy group, Treated with Radix Salviae Miltiorrhizae group and peoniflorin treatment group more at random by the body weight level.The normal control group is to irritate stomach with the isometric(al) distilled water, and each group is all given normal feedstuff and raised, and blood and hepatic tissue are got in administration after 4 weeks, detect every index.

1.2 observation index

When (1) experiment finishes to put to death animal, weigh and the liver weight;

(2) biochemical index: content, the empty stomach serum insulin (FINS) of measuring fasting glucose (FBG) T-CHOL (TC), triglyceride (TG) and highdensity lipoprotein-cholesterol (HDL-C);

(3) insulin resistance index: insulin resistance index HOMA-IR=(FBG * FINS)/22.5; With

(4) histopathological examination: the content of spectrophotometry TG.

1.3 result

Each group did not all have animal dead during experiment was carried out.

When experiment finished, body weight, the liver index (liver weight in wet base/body weight * 100%) of Radix Salviae Miltiorrhizae, peoniflorin treatment treated animal significantly increased (P＜0.05 than normal control group; P＜0.01); Compare with Radix Salviae Miltiorrhizae, peoniflorin treatment group, body weight, the liver index of high and low dose combination treatment group significantly reduce (P＜0.01); Compare with the normal control group, high and low dose combination treatment group body weight, liver index differential not statistically significant see the following form 8.

The variation of serum and liver tissue homogenate's lipid: Radix Salviae Miltiorrhizae, peoniflorin treatment group serum TG, TC and hepatic tissue TG are normal, and matched group raises; Compare with Radix Salviae Miltiorrhizae, peoniflorin treatment group, These parameters is all obviously improved in the high and low dose combination treatment group, sees the following form 9.

Variation such as FBG and FINS: Treated with Radix Salviae Miltiorrhizae group FBG and FINS and HOMA-IR are and increase trend; Peoniflorin treatment group FBG and FINS and HOMA-IR are on a declining curve; Compare with the Treated with Radix Salviae Miltiorrhizae group, the FINS and the HOMA-IR of high and low dose combination treatment group significantly descend, and the equal not statistically significant of all the other comparing differences sees the following form 10.

Pathological change: (1) perusal: Radix Salviae Miltiorrhizae, Radix Paeoniae treatment group rats'liver outward appearance are butter yellow, and volume obviously increases, the edge rust, and the quality deliquescing, tangent plane is greasy feeling slightly; High and low dose combination treatment group liver outward appearance is near the normal control group; (2) om observation: the fat drop that occurs differing in size in Radix Salviae Miltiorrhizae, the peoniflorin treatment group lobules of liver center band hepatocyte, part of hepatocytes nuclear is then pushed by fat drop and obvious off normal, reach the focal inflammatory cell infiltration in portal area in the lobule, with some lamellar necrosis to a certain degree; High and low dose combination treatment group lobules of liver and hepatic sinusoid clear in structure are seen a little vesicle fat drop, accidental hepatic necrosis in the cell.

1.4 conclusion

Above-mentioned experiment prompting, the present composition is used for the intervention of rat fat liver model can significantly improve the fatty live lesions degree, improves lipid metabolism, is better than using separately Radix Salviae Miltiorrhizae or Radix Paeoniae and intervenes, and has significant difference.

Because the generation and the insulin resistant of non-alcoholic fatty liver disease are closely related, and the patient often merges obesity, hyperglycemia, hyperinsulinemia.We think that the present composition is by reducing patients with insulin resistance, improve lipid metabolism, aspects such as anti-cell inflammatory produce the effect improve fatty live lesions, and all do not present under this situation that acts on independent use Radix Salviae Miltiorrhizae and Radix Paeoniae, and its synergism mechanism is worth further inquiring into.

Table 8 rat body weight, liver index variation (X ± S, n=8)

Grouping	Body weight (g)	The liver index
			Normal control group Treated with Radix Salviae Miltiorrhizae group	380.5±48.21 456.0±57.46 *	2.53±0.33 3.34±0.13 #

Radix Paeoniae treatment group compositions high-dose therapy group compositions low dose therapy group

440.6±36.53 * 372.56±29.86 △▲ 385.38±30.76 △▲

3.02±0.29 # 2.21±0.10 △▲ 2.43±0.12 △▲

Compare with the normal control group: ^*P＜0.05; #P＜0.01;

Compare with the normal control group: P＞0.05; Compare with Radix Salviae Miltiorrhizae, Radix Paeoniae treatment group: ▲ P＜0.01

The variation of table 9 rat blood serum and liver homogenate lipid (X ± S)

Grouping	TG(mmol/L)	TC(mmol/L)	HDL-C(mmol/L)	Hepatic tissue TG (mg/g)
					Normal control Radix Salviae Miltiorrhizae Radix Paeoniae compositions (height) compositions (low)	0.74±0.33 1.20±0.48 * 1.19±0.67 * 0.83±0.28 △▲ 0.88±0.32 △▲	1.37±0.31 2.21±0.38 # 2.22±0.31 # 1.51±0.25 △▲ 1.63±0.27 △▲	0.88±0.23 0.43±0.19 # 0.48±0.11 # 0.80±0.09 △▲ 0.89±0.12 △▲	16.41±6.78 26.45±6.63 # 25.96±6.87 # 18.16±6.17 △▲ 18.32±6.34 △▲

Compare with the normal control group: ^*P＜0.05; #p＜0.01;

Compare with model control group: P＞0.05; Compare with Radix Salviae Miltiorrhizae, Radix Paeoniae treatment group: ▲ p＜0.05

The variation of table 10 rat fasting blood-glucose, serum insulin and insulin resistance index level (X ± S)

Grouping	Fasting glucose (mmol/L)	Serum insulin (mu/L)	Insulin resistance index
				Normal control Treated with Radix Salviae Miltiorrhizae Radix Paeoniae therapeutic combination (height) compositions (low)	5.65±0.72 6.21±1.61 5.55±0.34 5.12±0.48 5.33±0.52	27.20±3.79 29.82±6.47 25.98±8.57 25.88±4.87 * 26.01±5.11 *	6.76±2.02 8.32±2.67 5.15±2.38 5.21±0.65 * 5.61±0.74 *

Compare with the Treated with Radix Salviae Miltiorrhizae group: ^*P＜0.05

2. treat the experimentation of the rabbit retinal vein occlusion

2.1 material and method

36 of purebred male New Zealand rabbits, body weight 2.1-2.4kg causes retinal vein occlusion model.

Be divided into 6 groups, every group 6, that is: blank group, present composition treatment group (peoniflorin+danshensu 1: 15, high, medium and low three the dosage groups of branch), Radix Salviae Miltiorrhizae (danshensu) treatment group, peoniflorin treatment group, the 3rd day began successive administration 10 days after the modeling, and the blank group waits the capacity drinking water.

2.2 result

The optical fundus situation: the 2nd day visible retinal hemorrhage of modeling, the 6th day present composition high dose group retinal hemorrhage obviously begins to absorb, and blank group retinal hemorrhage just obviously begins after 20 days to absorb, difference that there was a significant difference.Treated with Radix Salviae Miltiorrhizae group and peoniflorin treatment group obviously begin to absorb with the 11st, 18 day beginning retinal hemorrhage respectively, and this compares there was no significant difference with the blank group.After blood absorbs fully, the optical fundus blood vessel of blank group and peoniflorin treatment group is thin and tortuous, and the optical fundus blood vessel of 3 dosage groups of the present composition is all near normal condition, and the optical fundus blood vessel of Treated with Radix Salviae Miltiorrhizae group changes between blank group and present composition low dose group.The results are shown in Table 11.

Fundus photography and fundus fluorescein angiography inspection: 3 dosage groups of the present composition, Treated with Radix Salviae Miltiorrhizae group optical fundus blood vessel form are near normal, do not see the fluorescein seepage, also do not see new vessels, though and blank group, peoniflorin group retinal hemorrhage have absorbed, but still the plain seepage of visible fluorescence, and visible new vessels.6 hemorrhage all absorptions fully of group are seen in fundus photography, but the vascular morphology difference, situation is consistent with the inspection of direct ophthalmoscope.

2.3 conclusion

Experiment shows that the present composition has the therapeutical effect of highly significant to the experimental central retinal vein occlusion of rabbit.Especially it should be noted that the therapeutic effect that the Radix Salviae Miltiorrhizae used separately or Radix Paeoniae all can't reach the present composition.We think, this with compositions in Radix Salviae Miltiorrhizae and peoniflorin to produce obvious synergism in following mechanism of action relevant: blood vessel dilating, reduce vascular resistance; Microcirculation improvement improves hypoxia-bearing capability; It is synthetic to suppress fibrin, anticoagulation and hamartoplasia; Suppressed the release of sensitive media, antianaphylaxis.

The influence of hemorrhage complete soak time at the bottom of the table 11 pair lagophthalmos (x ± s, n=6)

Group	Dosage/(mgkg -1)	Soak time/d
			The blank group Treated with Radix Salviae Miltiorrhizae group peoniflorin treatment group present composition, (high dose) present composition, (middle dosage) present composition, (low dosage)	-- 20 20 30 20 10	36.34±4.23 29.89±5.23 33.64±6.14 19.85±4.64 ** 22.53±4.27 ** 24.09±5.33 *

Compare with the normal saline group, ^*P＜0.05 ^*P＜0.01

Toxicology

1. chmice acute toxicity

Behind the disposable oral compositions 50g/kg of the present invention of mice, observe continuously, do not see the animal toxicity reaction, more do not have dead the generation.The mice LD of pharmaceutical composition of the present invention ₅₀＞50g/kg.

2. rat long term toxicity

Compositions 1.00,0.75 of the present invention, three dosage continuous orals of 0.35g/kg, 12 weeks of administration, 26 weeks and 4 weeks of drug withdrawal, each administration group male and female rat general signs and matched group no significant difference; In the routine urianlysis, every index and matched group do not have marked difference; All other biochemical indicators are all in normal range; During 26 weeks, each organ coefficient of administration group is compared with matched group does not all have significant difference to compositions of the present invention in administration; PATHOMORPHOLOGICAL OBSERVATION OF PULLORUM, rat main organs there is no and be subjected to the relevant pathological change of reagent thing toxicity.

Clinical observation

1. the clinical trial for the treatment of cardiac and cerebral vascular diseases

Adopt the method for randomized controlled to investigate its curative effect and untoward reaction, observe coronary heart disease patient 170 examples altogether, wherein 100 examples are organized in treatment, curative effect cure-remarkable-effectiveness rate 39.87%, total effective rate 88.33%; Matched group 70 examples, cure-remarkable-effectiveness rate 26.46%, 74.93%, two group of coronary heart disease curative effect of total effective rate is learned processing by statistics, and there is significant difference P＜0.05, and the treatment group is better than matched group.The treatment group is not seen tangible untoward reaction.

2. the clinical observation of treatment hyperlipemia

2.1 material and method

Case selected condition: (1) fasting plasma TC 〉=5.8mmol/L, TG 〉=1.8mmol/L; (2) no liver, kidney, abnormal thyroid function; (3) non-diabetic medical history can be with hypertension.

The first people of curing the disease that blood lipid level reaches inclusion criteria is totally 93 examples, wherein: hypercholesterolemia 60 examples (male 18 examples, women 42 examples, 57.9 ± 11.4 years old), hypertriglyceridemia 64 examples (male 36 examples, women 48 examples, 56.1 ± 9.5 years old), patient is equally divided into three groups more at random.The Xuezhikang treatment same period is matched group totally 37 examples (male 21 examples, women 16 examples, 52 ± 9 years old age), and four groups of case ages and sex are learned by statistics and handled no marked difference.

Medicine: (1) positive control drug: XUEZHIKANG JIAONANG (oral, 1.2g/ day); (2) the present invention's combination (contained peoniflorin+salvianolic acid B 1: 2, oral, 60mg/ day); (3) Radix Salviae Miltiorrhizae Tabellae (oral, as to be equivalent to salvianolic acid B 66mg/ day); (4) Radix Paeoniae Alba extract (oral, as to be equivalent to peoniflorin 30mg/ day).

2.2 observation index and result

Serum TC, TG and GDL-C measure with Enzymology method.Serum LDL-C calculates acquisition by Friedwald formula: LDL-C=TC-HDL-C-TG/2.2, the results are shown in Table 12.

The result shows, after 8 weeks of taking medicine, significantly reduces before combination of the present invention and Xuezhikang group patient's serum TC, TG level are all taken medicine, and Radix Salviae Miltiorrhizae and Radix Paeoniae group be index there are no significant difference before and after the treatment then.This shows that behind combined therapy of the present invention, hyperlipemia serum TC, TG all can reduce, and effect is with to obey the 1.2g XUEZHIKANG JIAONANG every day identical, and obviously is better than using separately the therapeutic scheme of Radix Salviae Miltiorrhizae and Radix Paeoniae.

Table 12 clinical observation result x ± s (n), mmol/L

Group	TC	TG	LDL-C	HDL-C
							Before taking medicine
The present invention's combination	7.05±1.26(20)	2.98±1.43(28)	3.65±1.17(31)	1.34±0.52(31)

Radix Salviae Miltiorrhizae Radix Paeoniae Xuezhikang	6.95±1.21(20) 7.15±1.31(20) 6.63±0.82(37)	2.68±1.33(28) 2.48±0.93(28) 1.69±0.54(37)	3.25±1.13(31) 3.73±1.07(31) 3.98±0.62(37)	1.39±0.48(31) 1.36±0.55(31) 1.42±0.21(37)
							Take medicine after 8 weeks
The present invention makes up Radix Salviae Miltiorrhizae Radix Paeoniae Xuezhikang	5.75±0.62(20) * 6.65±1.11(20) 6.73±1.25(20) 5.19±0.45(37) *	2.31±1.37(28) * 2.55±1.21(28) 2.31±0.86(28) 1.35±0.19(37) *	3.28±0.81(31) 3.01±1.03(31) 3.55±1.00(31) 2.59±0.34(37) *	1.37±0.35(31) 1.37±0.43(31) 1.34±0.46(31) 1.44±0.18(37)
							Difference (%) before and after the administration
The present invention makes up Radix Salviae Miltiorrhizae Radix Paeoniae Xuezhikang	-18.4 -4.3 -5.9 -21.7	-22.5 -4.8 -6.8 -20.1	-10.2 -7.4 -4.8 -34.9	+2.2 -0.04 -1.8 +1.4

^*P＜0.01 with take medicine before compare on the same group

3. the clinical observation of cerebral infarction secondary prevention

3.1 object

Inclusion criteria: age＜75 year old; Cerebral infarction; Run initially or the secondary recurrent cases; After March acute stage; The CT/MRI diagnosis is arranged, and be consistent with clinical manifestation.

Exclusion standard: various hemorrhagic apoplexies; Three times and above cerebral seizure; Imaging examination is a cerebral infarction, and does not have the patient of clinical symptoms or sign; The patients with cerebral apoplexy that no CT/MRI makes a definite diagnosis; Cerebral infarction is in 3 months acute stages; The tumor apoplexy; Hematopathy; Serious hepatic and renal function damage; The tranquillization apoplexy.

3.2 method and result

The present invention's combination: Radix Salviae Miltiorrhizae extract is (with Tanshinone I I _AMeter), oral 2mg/ days, and Radix Paeoniae Alba extract (containing peoniflorin) oral 15mg/ days, 400 examples;

Medicine contrast: aspirin, oral 75mg/ days, 480 examples;

Blank: do not provide aspirin or the present invention combination, 470 examples.

In the 30th, 60,90,120 day of the experiment beginning, observe whether the apoplexy recurrence is arranged, side reaction symptoms such as (gastrointestinal upset, stomachache occur, feel sick) belch and seriously side reaction (melena to occur, fecal occult blood is checked positive, melena, occult blood disappear for judging upper gastrointestinal hemorrhage side reaction foundation after the antiacid treatment of drug withdrawal), the evaluation recurrence must have CT/MRI to make a definite diagnosis.The results are shown in Table 13.

3.3 conclusion

Combination of the present invention and aspirin all can reduce the relapse rate of cerebral infarction, and both effects are suitable.Compare with the blank group, combination of the present invention and medicine matched group all have significant difference.

Take in 480 examples of aspirin, 37 routine side effect and the serious side reaction of 11 examples occur; And take in 400 examples of the present invention's combination, have only 8 routine side reactions, the serious side reaction of 1 example produces, and two groups of contrasts have significant difference.

The clinical observation result of table 13 secondary prevention

	30 days	60 days	90 days	120 days	The accumulation recurrence
								The apoplexy relapse rate
Composition of medicine contrast blank of the present invention	11 11 16	15 15 25	17 21 42	22 28 53	5.5％ 5.8％ 11.3％
								Side reaction
Composition of medicine contrast blank of the present invention	1 11 2	3 21 2	5 28 5	8 37 8	2.00％ 7.71％ 1.70％
								Serious side reaction
Composition of medicine contrast blank of the present invention	0 3 0	0 5 0	1 6 1	1 11 1	0.25％ 2.29％ 0.43％

Embodiment

Embodiment 1 tablet

Get Radix Salviae Miltiorrhizae 2000g, add 95% alcohol reflux 1.5 hours, filter, filtrate recycling ethanol is to thick paste; Medicinal residues decoct with water 1 hour, filter, and filtrate and above-mentioned thick paste merge, and are evaporated in right amount, add right amount of auxiliary materials, mixing.Get Radix Paeoniae Rubra 1000g, be ground into coarse powder, add 75% alcohol reflux three times, first and second time each 2 hours, 1 hour for the third time, merge extractive liquid, was evaporated to about 400ml, with n-butanol extraction three times, each 300ml merges n-butanol extracting liquid, be evaporated to no n-butyl alcohol flavor, add water 200ml, heating for dissolving, filter, the filtrate spray drying is with above-mentioned Radix Salviae Miltiorrhizae extract uniform mixing, conventional tabletting makes 1000, and coating promptly.After testing, contain Radix Salviae Miltiorrhizae (with salvianolic acid B (C in every ₃₆H ₃₀O ₁₆)) count 40mg and Radix Paeoniae (in peoniflorin) 20mg.

Embodiment 2 capsules

Get Radix Salviae Miltiorrhizae 5000g, add 90% alcohol reflux 1.5 hours, extracting solution filters, and filtrate recycling ethanol also is concentrated into an amount of, standby; Medicinal residues add 50% alcohol heating reflux 1.5 hours, and extracting solution filters, and filtrate recycling ethanol also is concentrated into an amount of, standby.Other gets peoniflorin 5g and above-mentioned Radix Salviae Miltiorrhizae extract uniform mixing, adds starch, magnesium stearate again, and mixing in the hard capsule of packing into, is pressed into 1000 soft capsules.After testing, contain Radix Salviae Miltiorrhizae in every capsule (with salvianolic acid B (C ₃₆H ₃₀O ₁₆) meter) be 100mg and peoniflorin 5mg.

Embodiment 3 soft capsules

Get Radix Salviae Miltiorrhizae 2000g, add 90% alcohol reflux 1.5 hours, extracting solution filters, and filtrate recycling ethanol also is concentrated into an amount of, standby; Medicinal residues add 50% alcohol heating reflux 1.5 hours, and extracting solution filters, and filtrate recycling ethanol also is concentrated into an amount of, standby.Other gets peoniflorin 20g and above-mentioned Radix Salviae Miltiorrhizae extract uniform mixing, adds the vegetable oil mixing again, makes capsule casing material with gelatin, is pressed into 1000 soft capsules.After testing, contain Radix Salviae Miltiorrhizae in every capsule (with Tanshinone I I _A(C ₁₉H ₁₈O ₃) meter) be 2mg and peoniflorin 20mg.

Embodiment 4 slow releasing tablets

Get Radix Salviae Miltiorrhizae 4000g, decoct with water, decocting liquid filters, and filtrate concentrates, and adds ethanol, leaves standstill and makes precipitation, gets supernatant, reclaims ethanol, is condensed into thick paste, and is standby.Other gets peoniflorin 5g and above-mentioned Radix Salviae Miltiorrhizae extract uniform mixing, adds lactose, microcrystalline Cellulose, hydroxypropyl methyl base cellulose, polyethylene pyrroles, hard magnesium, prepares 1000 according to standard granulation and tablet forming technique.After testing, every contains Radix Salviae Miltiorrhizae (with danshensu (C ₉H ₁₀O ₅) meter) be 20mg and peoniflorin 5mg.

Embodiment 5 lyophilized injections

Get 25g Tanshinone I I _ASodium sulfonate, 2g polyvidon add water for injection 800ml and make dissolving, behind the adjusting pH value, through 0.45 μ m filtering with microporous membrane; Filtrate was placed 48 hours down at 5 ℃, was diluted to 1000ml with water for injection, 0.1 μ m filtering with microporous membrane, and ultrafiltration (molecular cut off is 5000), filtrate adds peoniflorin 25g to dissolving, and mix homogeneously, filtering with microporous membrane add the injection water to 2000ml.Then, 0.02% active carbon that adds amount of preparation stirs 5-10min, filter with aseptic suction funnel, and reuse sterilization sintered filter funnel fine straining or ultrafiltration, 1000 of filtrate packing embeddings after the assay was approved, lyophilization, radiation sterilization, packing gets final product.After testing, every contains Radix Salviae Miltiorrhizae (Tanshinone I I _A(C ₁₉H ₁₈O ₃) meter) be 25mg and peoniflorin 25mg.

Claims (9)

1. a pharmaceutical composition comprises active component and pharmaceutic adjuvant, and described active component is:

A. the Radix Salviae Miltiorrhizae extract that contains salvianolic acid, TANSHINONES; Or contain the water-soluble extract of red sage root of salvianolic acid, danshensu; Or salvianolic acid monomer or its pharmaceutical salts; Or the monomeric mixture of salvianolic acid; Or contain the Radix Salviae Miltiorrhizae liposoluble extract of TANSHINONES; Or TANSHINONES monomer or its pharmaceutical salts, or the monomeric mixture of TANSHINONES; With

B. the dry root powder of Radix Paeoniae, or contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae, Hydroxy peoniflorin, oxypaeoniflorin, benzoylpaeoniflorin, lacdtlorin, or the peoniflorin monomer,

Wherein among the component a in salvianolic acid or TANSHINONES and the components b part by weight of peoniflorin be 0.01-20: 1.

2. pharmaceutical composition as claimed in claim 1 comprises following component:

A. the water-soluble extract of red sage root that contains salvianolic acid, danshensu; Contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae with b., wherein the part by weight of salvianolic acid and peoniflorin is 0.05-10: 1.

3. pharmaceutical composition as claimed in claim 1 comprises following component:

A. salvianolic acid monomer or its pharmaceutical salts; Or the monomeric mixture of salvianolic acid; Contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae with b., wherein the part by weight of salvianolic acid and peoniflorin is 0.05-10: 1.

4. pharmaceutical composition as claimed in claim 1 comprises following component:

A. the Radix Salviae Miltiorrhizae liposoluble extract that contains TANSHINONES; With b. peoniflorin monomer, wherein the part by weight of TANSHINONES and peoniflorin is 0.05-10: 1.

5. pharmaceutical composition as claimed in claim 1 comprises following component:

A. TANSHINONES monomer or its pharmaceutical salts, or the monomeric mixture of TANSHINONES; With b. peoniflorin monomer, wherein the part by weight of TANSHINONES and peoniflorin is 0.05-10: 1.

6. as claim 1, one of 3 or 5 pharmaceutical composition, wherein the part by weight of salvianolic acid or TANSHINONES and peoniflorin is 0.05-1: 1.

7. as the pharmaceutical composition of one of claim 1-6, be oral or non-intestinal drug delivery agent form.

The pharmaceutical composition of one of claim 1-7 preparation be used for the treatment of and/or the medicine of prevent diabetes and complication thereof, senile dementia, cardiovascular and cerebrovascular disease, central retinal vein occlusion, hyperlipemia, fatty liver in application.

9. the pharmaceutical composition of one of claim 1-8 is used for preventing the application of the medicine of cardiovascular and cerebrovascular disease recurrence in preparation.