CN105434417A - Application of salvianolic acid A in preparation of medicine for resisting tunica intima thickening, post-angioplasty restenosis and/or in-stent restenosis - Google Patents

Abstract

The invention discloses the application of salvianolic acid A in the preparation of anti-vascular intimal thickening and/or anti-restenosis after angioplasty and/or in-stent restenosis drugs. Experimental studies have found that salvianolic acid A can inhibit the proliferation of human umbilical artery vascular smooth muscle cells, and can reduce the vascular intimal thickening and vascular lumen restenosis rate in animal models of vascular intimal thickening after balloon injury, and has significant anti-inflammatory effects. The effect of vascular intimal thickening and restenosis after angioplasty and/or restenosis in the stent can be used for preparing medicines for inhibiting intimal thickening and restenosis after angioplasty and/or restenosis in the stent, especially It is used to prepare drugs for preventing restenosis and in-stent restenosis after percutaneous transluminal coronary angioplasty, or to prepare drug-coated stents, so as to be used after angioplasty, especially after percutaneous transluminal coronary angioplasty and stent It provides an efficient, safe and economical drug and solution for the prevention and treatment of internal restenosis.

Description

Application of salvianolic acid A in the preparation of anti-intima thickening, anti-angioplasty and/or in-stent restenosis drugs

technical field

The present invention relates to a new application of salvianolic acid A, a chemical component extracted from Salvia miltiorrhiza, in the preparation of medicines, and mainly relates to the preparation of salvianolic acid A in the preparation of anti-intima thickening and/or anti-restenosis after angioplasty and/or The application in stent restenosis drugs, particularly relates to the application of salvianolic acid A in the preparation of anti-restenosis after percutaneous transluminal coronary angioplasty and the application of in-stent restenosis drugs, which belongs to the technical field of medicine.

Background technique

The vascular wall is composed of vascular intima, media and adventitia, and is a physiological structure for the maintenance of important functions such as metabolism, nutrient supply, and blood pressure regulation of tissues and organs. The tunica intima is the innermost layer of the vessel wall, composed of endothelium and subendothelium, and is the thinnest of the three layers; the tunicamedia is located between the intima and adventitia and is mainly composed of smooth muscle cells . Generally speaking, when the vessel wall is damaged, the intracellular signal transduction can cause the expression of many proto-oncogenes and the production of cytokines, thus breaking the balance between the proliferation and apoptosis of vascular smooth muscle cells and causing the vascular smooth muscle cells to migrate to the intima. Migrate and proliferate abnormally, eventually causing thickening of the vascular intima.

The thickening of vascular intima leads to insufficient blood perfusion of organs, which is the common pathological basis of cardiovascular and cerebrovascular diseases such as hypertensive vascular disease, end-stage renal disease, diabetic vascular disease, ischemic stroke, pulmonary hypertension and coronary heart disease. Therefore, the anti-smooth muscle cell migration and proliferation to achieve the effect of inhibiting vascular intimal thickening is the best way to relieve hypertensive vascular disease, delay end-stage renal disease, improve diabetic vascular disease, prevent ischemic stroke and coronary heart disease, and treat pulmonary hypertension. Important means, and the direction of drug development.

On the other hand, for blood vessels that have been stenotic or occluded (such as carotid arteries, coronary arteries, etc.), percutaneous transluminal angioplasty (PTA) is generally used to recanalize blood vessels to improve organ blood perfusion.

PTA has been widely used clinically, and has become an effective method for the diagnosis and treatment of coronary heart disease and other arteriovenous stenosis, and has achieved good curative effect, but the incidence of restenosis after dilatation is high. Restenosis mostly occurs within a few months to a year after PTA. Studies have found that after PTA, the vascular intima is damaged, local thrombus forms, the vascular smooth muscle cells in the media layer migrate and proliferate to the subintima, and the extracellular matrix accumulates, leading to pathological remodeling of the blood vessels, and finally the intima Thickening, vascular lumen significantly narrowed, or even completely occluded. Although the combination of intracoronary or other intravascular stent implantation can effectively inhibit the elastic recoil and negative remodeling of blood vessels after PTA, the formation of neointima due to the proliferation of vascular smooth muscle and protein and carbohydrate matrix still occurs. The leading cause of in-stent restenosis.

At present, oral drugs and drug-coated stents are mainly used in the prevention and treatment of anti-intimal thickening and post-PTA intimal thickening and restenosis, but the effect is not ideal. Anti-proliferation and immunosuppressant coating stents such as rapamycin and paclitaxel have a clear effect on inhibiting restenosis. Preliminary clinical trials have shown that they can significantly reduce the rate of restenosis, but coated stents are expensive and inhibit vascular re-endothelialization. There is still the possibility of recurrent restenosis. Drugs used to prevent restenosis mainly include antiplatelet drugs, anticoagulant drugs, anti-inflammatory drugs, anti-cell proliferation drugs, antioxidants, and HMG-CoA reductase inhibitors; but the effects are not ideal.

Salvia miltiorrhiza (SalviamiltiorrhizaBge.) is the dry root of Lamiaceae Salvia. It has the effects of dispelling blood stasis and relieving pain, promoting blood circulation and promoting menstrual flow, clearing away heart-fire and relieving restlessness. Salvia miltiorrhiza is an important traditional Chinese medicine. Traditional medicine believes that danshen has the effects of dispelling blood stasis and relieving pain, promoting blood circulation and stimulating menstruation, clearing heart and eliminating troubles. Recent studies on the role of Danshen mainly focus on improving the ischemia-reperfusion injury of the heart, liver, lung, brain and other organs; damage to liver cells; liver fibrosis, cirrhosis, and liver cancer; regulation of immune response; Infection and anti-tumor, etc., but there is no report on the anti-intimal thickening of blood vessels and the restenosis of blood vessel lumen in angioplasty or stents. As a traditional medicine commonly used in clinical practice, Danshen’s active ingredients have attracted more and more attention from medical researchers. The Institute of Materia Medica, Chinese Academy of Medical Sciences first discovered a variety of salvianolic acids from Danshen, among which salvianolic acid A is important. A water-soluble ingredient whose chemical structure is as follows:

In recent years, studies have found that salvianolic acid components in Danshen have stronger anti-myocardial ischemia and hypoxia activity than danshensu and protocatechualdehyde, among which salvianolic acid A is one of the strongest antioxidant compounds currently known. So far, there is no report on the application of salvianolic acid A in the preparation of anti-intimal thickening and restenosis drugs after angioplasty or in-stent.

Contents of the invention

The purpose of the present invention is to provide salvianolic acid A in the preparation of anti-intimal thickening and angioplasty restenosis and/or in-stent restenosis medicine, especially for the preparation of anti-percutaneous transluminal coronary angioplasty (PTCA) ) and in-stent restenosis drugs or further preparation of drug-coated stents, so as to provide an efficient, safe, economical solution.

Therefore, the present invention provides the application of salvianolic acid A in the preparation of anti-intimal thickening and/or restenosis after angioplasty and/or restenosis in stent.

One aspect of the present invention provides the application of salvianolic acid A in the preparation of anti-vascular intimal thickening drugs, wherein the vascular intimal thickening is the thickening of the vascular intimal caused by the proliferation and/or migration of vascular smooth muscle Pathological factors of insufficient blood supply to the lungs, brain, and heart.

Further, the thickening of the vascular intima refers to the thickening of the vascular intima in the states of hypertensive vascular disease, end-stage renal disease, diabetic vascular disease, ischemic stroke, pulmonary hypertension and coronary heart disease.

Another aspect of the present invention also provides the use of salvianolic acid A in the preparation of anti-restenosis drugs after angioplasty. The restenosis is the restenosis of the vessel lumen caused by the proliferation of involved vascular smooth muscle cells after angioplasty.

Further, the angioplasty is percutaneous intraluminal coronary, carotid and other arterial angioplasty.

Further, the angioplasty is selected from balloon angioplasty, laser angioplasty, atherectomy and intravascular stents.

The invention also provides the application of the salvianolic acid A in the preparation of anti-restenosis drugs in stents. The in-stent restenosis refers to the vascular restenosis caused by the proliferation of vascular smooth muscle cells and the like in the stent after the stent is placed in the narrowed blood vessel.

Further, the salvianolic acid A and a pharmaceutically acceptable carrier are made into various dosage forms of anti-angioplasty lumen restenosis drugs according to conventional preparation methods;

Further, the salvianolic acid A and a pharmaceutically acceptable carrier are made into slow-release dosage forms of anti-restenosis after PTA and intra-stent restenosis drugs according to conventional preparation methods, and then coated on the surface of the stent to make a drug-coated stent .

The present invention therefore also relates to pharmaceutical compositions comprising a compound according to the invention as active ingredient. The pharmaceutical composition can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be prepared by combining the compounds of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention in its pharmaceutical composition is usually 0.1-95% by weight.

The compound of the present invention or the pharmaceutical composition containing it can be administered in the form of a unit dosage, and the route of administration can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.

The dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true solutions and colloid solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including aqueous injections, powder injections and infusion solutions), eye drops Agents, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.

The compound of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

To form the compound of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, iso Propanol, etc.; binders can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, arabic mucilage, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hypromellose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked poly Vinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecylsulfonate, etc.; lubricant and flow aid The agent can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol and the like.

Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

In order to make the administration unit into a capsule, the active ingredient compound of the present invention can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient compound of the present invention can also be made into granules or pellets with diluents, binders, and disintegrants, and then placed in hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrants, and glidants used in the preparation of tablets of the compound of the present invention can also be used in the preparation of capsules of the compound of the present invention.

In order to make the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixtures can be used as solvent and an appropriate amount of commonly used solubilizers, cosolvents, pH regulators and osmotic pressure regulators in this field can be added. The solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be Sodium chloride, mannitol, glucose, phosphate, acetate, etc. For preparation of freeze-dried powder injection, mannitol, glucose, etc. can also be added as proppants.

In addition, coloring agents, preservatives, fragrances, flavoring agents or other additives can also be added to the pharmaceutical preparations, if necessary. In order to achieve the purpose of medication and enhance the therapeutic effect, the medicine or pharmaceutical composition of the present invention can be administered by any known administration method. The dosage of the pharmaceutical composition of the compound of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, individual conditions of the patient or animal, administration route and dosage form, etc. In general, a suitable daily dosage range of the compound of the present invention is 0.001-250 mg/Kg body weight. The above-mentioned dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the doctor and the dosage regimen including the use of other therapeutic means.

The compound or composition of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dose should be adjusted according to the actual situation.

The beneficial effect of the present invention is that: the present invention adopts human umbilical artery smooth muscle cell model and rat common carotid artery balloon-injured restenosis model respectively to salvianolic acid A to resist vascular intimal thickening and lumen restenosis after angioplasty , especially in-stent restenosis was investigated, and the results showed that salvianolic acid A could inhibit PDGF-BB-induced smooth muscle cell proliferation, arrest the cell cycle in G0/G1 phase, and alleviate the symptoms of experimental restenosis in animal models. The degree of intimal hyperplasia can reduce the rate of restenosis, and has significant anti-intimal thickening and lumen restenosis effects, and can be used to prepare anti-intimal thickening and lumen restenosis after angioplasty, especially in-stent Drugs for restenosis or further preparation of drug-coated stents, thereby providing an efficient, safe and economical solution for the prevention and treatment of restenosis after angioplasty and in-stent restenosis.

Description of drawings:

In order to make the object of the present invention, technical scheme and advantage clearer, the present invention will be described in further detail below in conjunction with accompanying drawing, wherein: definition: SAA is salvianolic acid A.

Figure 1. shows the inhibitory effect of SAA on the proliferation of human umbilical artery smooth muscle cells induced by PDGF-BB;

Figure 2 shows the inhibitory effect of SAA on the cell cycle of human umbilical artery smooth muscle cells;

Figure 3. Shows the inhibitory effect of SAA on intimal thickening and lumen stenosis of the common carotid artery in rats after common carotid artery balloon surgery;

Figure 4 shows the inhibitory effect of SAA on the thickening of carotid artery intima-media ratio after common carotid artery balloon surgery in rats;

Figure 5. Shows the protective effect of common carotid artery lumen stenosis after common carotid artery balloon surgery in SAA rats.

detailed description

Example 1. SAA inhibits the proliferation of human umbilical artery smooth muscle cells induced by PDGF-BB

Experimental Materials:

Human umbilical artery smooth muscle cells (hUASMCs) were purchased from ScienCell (Carlsbad, Calif). Smooth muscle cell culture medium: ScienCell (Carlsbad, Calif), fetal bovine serum FBS (Gibco). PDGF-BB was purchased from R&D Company. SAA was dissolved in DMSO into a 20mM stock solution, and the final concentration of DMSO was less than 0.1%, which had no effect on the growth of smooth muscle cells. The stock solution was aliquoted and stored in a -20°C refrigerator in the dark.

Human umbilical artery smooth muscle cells were planted in 96-well plates at a density of 10 ⁴ per well, until 50% confluent, serum was removed and incubated for 48 hours, then according to the experimental design, 0, 0.1, 0.3 and 1 μM SAA were added for pre-incubation for 24 hours, and then respectively Continue to incubate with 20ng/ml PDGF-BB, discard the cell supernatant after 48h, and use crystal violet staining to observe the OD value of each group. Grouping: blank control group (no SAA pre-incubation and no PDGF-BB effect group); model group (no SAA pre-incubation, but PDGF-BB effect group); low-dose group (0.1μMSAA pre-incubation for 24 hours, add PDGF -BB final concentration was 20ng/ml and continued to incubate for 48 hours); middle dose group (after 0.3μMSAA pre-incubation for 24 hours, added PDGF-BB with a final concentration of 20ng/ml and continued to incubate for 48 hours); high-dose group (1μMSAA pre-incubation for 24 hours) Hours later, add PDGF-BB at a final concentration of 20ng/ml and continue to incubate for 48 hours); toxicity control group (after 24 hours of pre-incubation with 1μMSAA, continue to incubate for 48 hours) (Figure 1)

Results: 20ng/mL PDGF-BB significantly induced the proliferation of hUASMCs, and the OD value was 1.9±0.1 times that of the control group. There was no difference in the OD value between the high-dose toxicity control group and the blank control group. It shows that high-dose SAA itself does not affect the growth of hUASMC; the OD values of low-dose, middle-dose and high-dose groups are respectively 1.54±0.21, 1.29±0.12, 1.05±0.07 times of the normal control group (p values are 0.12, <0.05 and < 0.05). SAA dose-dependently inhibited PDGF-BB-induced smooth muscle cell proliferation (results are shown in Table 1).

Table 1. Inhibitory effect of SAA on PDGF-BB-induced proliferation of human umbilical artery smooth muscle cells

Example 2. SAA inhibits the cell cycle of human umbilical artery smooth muscle cells

Cell culture method is the same as embodiment 1. Smooth muscle cells were planted in a 100mm culture dish at a density of 5×10 ⁶ until they reached 50% confluence, and cultured in serum-free DMEM medium for 48 hours. Give different concentrations of SAA for pre-incubation for 24 hours, then give 20ng/ml PDGF-BB stimulation, and continue to incubate for 48 hours; collect the cell supernatant, digest the cells with 0.25% trypsin, collect the cell suspension, centrifuge at 1000r/min×5min, discard supernatant. Fix with 70% cold ethanol pre-cooled at 4°C for 18 hours, then adjust the cell concentration to 10 ⁶ /ml, stain with propidium iodide (PI) and incubate at 37°C for 30 minutes for flow cytometry analysis, and use ModFitLT3.0 software to analyze cell cycle Percentage of cells in each phase to total cells; calculate cell proliferation index (PI), PI=(S+G2/M)/(G0/G1+S+G2/M). The groups were as follows: normal control group: smooth muscle cells without PDGF-BB and SAA; model group: smooth muscle cells with a final concentration of PDGF-BB of 20 ng/mL; each dose group: after pre-incubation with SAA for 24 h, add PDGF-BB to the final The concentration is 20ng/mL.

Flow cytometry technology distinguishes cells in different phases based on the principle that the DNA content of cells is different in different phases. The cell cycle consists of G0/G1 phase, S phase, and G2/M phase. The S phase is the DNA synthesis phase, and the cell composition ratio in the S phase increases, reflecting active cell proliferation. The cell proliferation index refers to the ratio of the sum of cells in S phase and G2/M phase to the total number of cells, which reflects the proliferation speed of the group of cells. The cell proliferation index refers to the ratio of the sum of cells in S phase and G2/M phase to the total number of cells, which reflects the proliferation speed of the group of cells. Proliferation index is the "gold standard" for evaluating cell proliferation ability. Our results showed that compared with normal group cells, the percentage of G0/G1 phase cells in smooth muscle cells induced by PDGF-BB decreased significantly, which was 15.115%, and the normal group was 83.1%; on the contrary, PDGF-BB group G2/M phase and The content of cells in S phase was significantly higher than that in the normal group, which were 79.81% and 4.88%, respectively, and the content of cells in G2/M phase and S phase in the normal control group were 11.8% and 4.08%, respectively; compared with the PDGF-BB group, SAA showed a dose-dependent The content of cells in G0/G1 phase was significantly increased while the content of cells in G2/M and S phase was decreased. The content of G0/G1 phase cells in SAA0.1μM, 0.3μM, and 1μM groups were 20.6%, 27%, and 40%, respectively; G2/M The contents of cells in phase were 79.31%, 72.92%, 64.4% respectively; the contents of cells in S phase were 9.06%, 5.45%, 7.97%, 8.38%. ; Compared with PDGF-BB group, the proliferation index of each SAA treatment group decreased significantly (p<0.01).

The experimental results showed that SAA could significantly inhibit PDGF-BB-induced smooth muscle cell proliferation, the cell proliferation index decreased significantly, and SAA could significantly arrest the cell cycle in G0/G1 phase (see Table 2 for details).

Table 2. The inhibitory effect of SAA on the proliferation cycle of hUASMC cells induced by PDGF-BB

Example 3. Experimental study of SAA against restenosis after balloon-injured common carotid artery in rats

The restenosis model of rat common carotid artery balloon injury is an internationally recognized classic animal model of restenosis after PTA and in-stent restenosis.

Experimental materials: salvianolic acid A (purity ≥ 98%), made into 0.01mg/mL with triple distilled water; male SD rats with a body weight of 300-350g (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) .

Experimental method: the rats were randomly divided into 3 groups, namely the sham operation group, the model group and the salvianolic acid A group; after intraperitoneal anesthesia with 30% chloral hydrate 0.1mL/100g. The skin and subcutaneous tissue were incised in the front of the neck, the common carotid artery and the internal carotid artery were clamped with arterial clips, a wedge-shaped incision was made in the external carotid artery, a 2F (2×20mm) balloon (Medtronic, USA) was inserted, and normal saline was injected Inflate the balloon with 0.2ml, slowly pull back the balloon to the flat incision, draw out the liquid in the balloon, repeat the above process 3-4 times, withdraw the balloon, ligate the external carotid artery, and restore blood flow. The incision was washed with 400,000 U of gentamicin and the subcutaneous tissue and skin were sutured. They were fed with common feed and had free access to water. The sham operation group only incised the skin to separate the subcutaneous tissue without inserting the balloon (n=6); the model group: 3 days after the operation, 1ml/100g body weight of normal saline was administered orally every day (n=10), and the drug intervention group was On the third day after operation, 0.3 mg·kg-1·d-1 of SAA was administered orally (n=11). Materials: All animals were sacrificed by dislocation of the left common carotid artery after anesthesia on the 21st day after operation. Whole blood was centrifuged at 4000r/min for 20min, and the supernatant was stored in a -20°C refrigerator; the common carotid artery was washed with heparin saline and divided into two equal parts, fixed with 40g/L formaldehyde and stored in liquid nitrogen.

health observation

Experimental results: No obvious abnormal changes were observed in the sham operation group during the experiment; the diet and drinking water of the model group and SAA group were normal after operation, and the postoperative wound healed well; after operation, the rats in the model group lost luster and lost weight slightly at the beginning. The activity decreased, but with the increase of feeding time, the body weight increased, and the mental state gradually recovered. The hair, diet and mental state of the rats in the salvianolic acid A group were even better than those in the sham operation group with the prolongation of the administration time, but the body weight decreased slightly at first, and then gradually increased.

Histopathological analysis

Experimental method: Rats were killed on the 21st day after operation, and 0.5 cm of the blood vessel in the lesion area after balloon strain was taken, fixed with 10% neutral formaldehyde solution, dehydrated, embedded in paraffin vertically, routinely sectioned, HE stained, positive Observe under an optical microscope.

Morphological observation of blood vessels

Experimental results: As shown in Figure 3, the structure of the model group was unclear, the intima was irregularly thickened, the lumen was concentric or eccentrically narrow, the internal elastic plate was damaged and broken to varying degrees, and a large number of smooth muscle cells proliferated. Membrane damage was seen, smooth muscle cells deformed, extracellular matrix increased, adventitia thickened, lumen area decreased significantly, most lumens were almost completely blocked, and thrombus formed in some lumens. In the SAA group, the vascular structure was clearer, the inner elastic plate was slightly damaged and broken, the area of intimal hyperplasia was significantly smaller than that of the model group, the proliferation of smooth muscle cells was reduced, the area of the lumen was significantly increased compared with the model group, and the degree of vascular restenosis was greatly reduced .

Semi-quantitative analysis of vascular histomorphology

The semi-quantitative analysis of intima-media ratio (I/M) and lumen area ratio was carried out by image analysis system on the results of HE staining.

The experimental results are shown in Figure 4. The ordinate represents the ratio of intima to media thickness (I/M) after common carotid artery balloon injury. (I/M) was 0.31. In the model group, the intima was damaged and broken, and the media layer extended toward the intima layer and subintima, and was seriously thickened. The I/M was 4.32. The salvianolic acid A group significantly reversed the intima-media The thickening trend, I/M decreased to 1.27, the I/M ratio of each group is summarized in Table 3.

Table 3. The inhibitory effect of SAA on the increase of intima-media ratio (I/M) caused by balloon injury of common carotid artery

Figure 5. The vertical axis represents the ratio of the residual lumen area of the common carotid artery to the cross-sectional area of the vessel after balloon injury. The ratio of the lumen area in the sham operation group was the highest, which was 69.58%. The restenosis of the blood vessels in the model group was obvious. decreased to 11.19%, and the proportion of lumen area increased significantly to 49.27% after SAA treatment. The data of each group are summarized in Table 4;

Table 4. SAA inhibits the decrease in the proportion of vessel lumen area after carotid balloon surgery

In summary, the present invention adopts human umbilical artery vascular smooth muscle cell proliferation model and rat common carotid artery balloon-injured restenosis model on salvianolic acid A anti-vascular intimal thickening and PTA postoperative restenosis and in-stent restenosis. The narrowing effect was investigated, and the results showed: (1) salvianolic acid A can significantly inhibit the proliferation of smooth muscle cells, and the inhibitory effect of salvianolic acid A on the proliferation of smooth muscle cells is related to the inhibition of cell cycle; (2) salvianolic acid A can inhibit the proliferation of smooth muscle cells. Salvianolic acid A has a significant therapeutic effect on rat common carotid artery balloon-injured restenosis, can reduce the area of intimal hyperplasia, increase the area of the lumen, and reduce the rate of restenosis. Therefore, salvianolic acid A has a significant anti-PTA effect. Restenosis and in-stent restenosis. With salvianolic acid A as the active substance, used alone or/with other pharmacologically active compounds and/or extracts to form a compound, according to the conventional preparation methods in the field of pharmacy, various dosage forms of anti-PTA postoperative restenosis and In-stent restenosis drugs, or conventional preparations made into sustained-release dosage forms to make various dosage forms of anti-PTA restenosis and intra-stent restenosis drugs, or made into slow-release dosage forms of anti-PTA restenosis and stents The internal restenosis drug is coated on the surface of the stent to make a drug-coated stent, which can provide an efficient, safe and economical solution for the prevention or treatment of restenosis after PTA and intra-stent restenosis.

Finally, it is noted that the above embodiments are only used to illustrate the technical solutions of the present invention without limitation. Although the present invention has been described with reference to the preferred embodiments of the present invention, those of ordinary skill in the art should understand that it can be reformulated Various changes may be made in matter and details thereof without departing from the spirit and scope of the invention as defined in the appended claims.

Claims (12)

1. such as formula the application of salvianolic acid A (I) Suo Shi in the anti-angiogenic intimal thickening of preparation and/or anti-angiogenic Restenosis After Angioplasty and/or in-stent restenosis medicine

2. application according to claim 1, is characterized in that: described vascellum tunica interna incrassation is the vascellum tunica interna incrassation because vascular smooth muscle cell proliferation and/or migration cause.

3. application according to claim 2, is characterized in that: described vascellum tunica interna incrassation causes kidney, lung, brain, heart organ blood for not enough pathological factor.

4. application according to claim 2, it is characterized in that described vascellum tunica interna incrassation refer to hypertensive vasculopathy, end stagerenaldisease, diabetic angiopathy, Ischemic Stroke, pulmonary hypertension or coronary heart disease state under vascellum tunica interna incrassation.

5. application according to claim 1, is characterized in that: described postangioplasty restenosis is postangioplasty, the vessel lumen restenosis that involved vessels smooth muscle cell proliferation causes.

6. application according to claim 5, is characterized in that, described angioplasty is through transluminal coronary, carotid artery and other artery angioplasties.

7. application according to claim 6, described angioplasty is selected from balloon angioplasty, laser angioplasty, medicated porridge sample speckle excision and Ink vessel transfusing eyelid retractor.

8. application according to claim 1, is characterized in that: the vascular smooth muscle cell that described in-stent restenosis occurs after referring to narrow blood vessel placing rack in support etc. breed the vessel lumen restenosis caused.

9. the application of the pharmaceutical composition containing the salvianolic acid A shown in formula (I) in the anti-angiogenic intimal thickening of preparation and/or anti-angiogenic Restenosis After Angioplasty and/or in-stent restenosis medicine, is characterized in that: described pharmaceutical composition comprises the salvianolic acid A of effective dose and pharmaceutically acceptable carrier

10. application according to claim 9, is characterized in that, described acceptable carrier comprises conventional adjuvant and preparations carrier, and described pharmaceutical composition is selected from oral formulations, injection system form of administration, various dosage forms by the administration such as mucocutaneous; Wherein, oral formulations comprises tablet, slow releasing agent, capsule, controlled release agent, drop pill, liquid preparation, and injection system form of administration comprises intramuscular injection, intravenous injection, intravenous drip.

11. application according to claim 1, is characterized in that: described salvianolic acid A can be coated with the coating stent of medicine being loaded in rack surface and making.

12. application according to claim 11, is characterized in that: when salvianolic acid A be coated be loaded in coating stent of medicine that rack surface makes time, also containing and pharmaceutically acceptable carrier.