KR20090087795A - Pharmaceutical composition and stent for preventing and treating coronary restenosis - Google Patents

Abstract

A pharmaceutical composition for preventing and treating coronary restenosis containing pyrazolopyrimidinone compound or its pharmaceutically acceptable salt is provided to suppress the vascularization and cell proliferation of vascular smooth muscle. A pharmaceutical composition for preventing and treating coronary restenosis comprises pyrrazolopyrimidinone compound of the chemical formula 1 or 2 or its pharmaceutically acceptable salt as an active ingredient. In the chemical formula 2, R1 is hydrogen or C1-C6 alkyl, R2 is hydrogen or C2-C6 alkyl, R3 is C1-C6 alkyl and R4 is heterocycle selected from pyridine, thiazol, pyrimidine, indane, benzothiazole, pyrazole, piperidine, morpholine, imidazole, pyrrolidine, thienyl, triazole, and pyrrole which is substituted or non-substituted with C1-C10 alkyl group. The coronary restenosis is caused by excessive proliferation of vascular smooth muscle cell.

Description

Pharmaceutical compositions for the prevention and treatment of vascular restenosis and stents comprising the same {{ARMARMUTICAL COMPOSITION AND STENT FOR PREVENTING AND TREATING CORONARY RESTENOSIS}

The present invention provides a blood vessel comprising a pyrazolopyrimidinone compound or a pharmaceutically acceptable salt thereof, which can be useful for preventing and treating diseases caused by vascular smooth muscle cell overproliferation by inhibiting vascular smooth muscle cell proliferation. A pharmaceutical composition for preventing and treating restenosis and a stent coated with the composition.

Many patients worldwide suffer from cardiovascular diseases such as angina pectoris, myocardial infarction, heart failure, arrhythmia, and valve disease.In Korea, due to aging and westernization of diet, the mortality rate due to cardiovascular diseases is rapidly increasing. It is occupied above.

In general, in patients with angina pectoris and myocardial infarction, stenosis occurs in blood vessels such as coronary arteries and peripheral blood vessels due to cholesterol deposition, thereby lowering blood flow and causing severe pain or sudden death. Percutaneous coronary angioplasty has been used as a treatment for the treatment of atherosclerosis and ischemic heart disease.

The percutaneous coronary angioplasty is a method of expanding a narrowed coronary artery without surgery, and the procedure includes percutaneous coronary balloon dilation and percutaneous coronary stent insertion.

Among these, percutaneous coronary balloon dilatation is performed by inserting a guide catheter through the femoral or arm arteries, and then placing the catheter at the inlet of the coronary artery with the lesion through the aorta and confirming the location of the guide catheter. Through the catheter attached to the end of the balloon is placed in the stenosis of the coronary artery and then expand the balloon. The expanded balloon is expanded by narrowing the coronary arteries by compressing plaques, resulting in improved blood flow to the coronary arteries, which has a high rate of symptom improvement for angina, and a low risk of myocardial infarction.

However, after coronary angioplasty using balloon catheter, about 20 to 50% of patients develop vascular restenosis within about 6 months. It is known to be more frequent and worse.

In order to improve this problem, percutaneous coronary stent insertion using a stainless steel mesh stent (stent) has been performed. Stent insertion involves placing a wire mesh coated balloon on the stenosis and then expanding the balloon to coat the inner wall of the coronary artery. Such stent implantation has been reported to have a significantly lower restenosis rate than balloon dilation. However, coronary restenosis caused by neointima hyperplasia due to vascular damage of the stent remains a big problem until recently.

In the case of coronary angioplasty, vascular endothelial hyperplasia is a process of vascular endothelial hyperplasia that is induced by injury. Restenosis occurs due to proliferation of cells in neointima, accumulation of extracellular matrix (reendothelialization), apoptosis, and the like. After the procedure, restenosis may occur in about 6.8% of patients, such as thrombosis or vascular spasms.Severe vascular restenosis may occur in 3 to 6 months after vasodilation, and balloon dilatation in about 40% of patients. Findings of restenosis can be found (Herrman J-PR et al ., Drugs , vol. 46 , 18-52, 1993). In addition, secondary vessel changes may occur in 20% of the arterial and venous bypass vessels and endarterectomy of the coronary and femoral vessels (VolteasN et al ., Int. Angiol). , 2: 13 (2) , 143-147, 1994).

Therefore, in order to prevent vascular restenosis, the introduction of new coronary angioplasty equipment such as laser angioplasty, high-speed rotary atherosclerosis, and coronary angioplasty using a cutting balloon, and anti-platelet, antithrombotic, vasodilator, and cytostatic agents Although attempts have been made to prevent restenosis after coronary angioplasty, no method has been established to effectively reduce restenosis.

In order to prevent restenosis by directly administering drugs directly to the site where coronary angioplasty has been performed, a double-balloon catheter, a dispatch, or a microsphere balloon has been developed and used in clinical practice. Attempts have been made to treat sexual microparticles or stents with drugs. Currently used drugs include rapamycin, paclitaxel, silorimus, verapamil, and the like.

However, the aforementioned drug has the disadvantage of inhibiting endothelialization of the surgical site by inhibiting proliferation of vascular endothelial cells as well as neointimal proliferation. Therefore, there is a problem that acute myocardial infarction due to late thrombosis cannot be obtained due to late thrombosis prevention effect due to vascular endothelialization of the site.

In other words, no drug has been reported to significantly reduce the restenosis occurring after coronary angioplasty. Therefore, there is an urgent need for the development of medicines that exhibit excellent effects on the prevention of vascular restenosis after angioplasty in patients with ischemic heart disease.

Pyrazolopyrimidinone compound represented by Formula 1 according to the present invention (Korean Patent Registration No. 353014) has an excellent effect of inhibiting the activity of phosphodiesterase-5, and thus an erectile dysfunction treatment agent (trade name Zidea, ingredient name Udena). Phil, Dong-A Pharmaceutical).

Sildenafil, an inhibitor of phosphodiesterase-5, is known to be used as a therapeutic agent for pulmonary hypertension by inhibiting the proliferation of pulmonary smooth muscle cells (Benedetta Tantini et al ., Basic Res Cardiol 100 : 131 -138, 2005, Wharton, Strange, Moller et al ., A American Journal of Respiratory and Critical Care Medicine 172 , 105-113, 2005)

However, it has not been reported that the pyrazolopyrimidinone compound represented by Formula 1 effectively inhibits vascular restenosis after coronary angioplasty.

Therefore, the present inventors have repeatedly conducted extensive studies to prevent and treat new vascular restenosis, and as a result, the pyrazolopyrimidinone compound represented by Formula 1, which is widely known as an erectile dysfunction treatment agent, suppresses low proliferation of vascular endothelial cells. It has been found that it can be usefully used as a preventive and therapeutic agent for vascular restenosis by inhibiting the growth of vascular smooth muscle cells and proliferating angiogenesis, thereby completing the present invention.

An object of the present invention includes a pyrazolopyrimidinone compound or a pharmaceutically acceptable salt thereof having low proliferation inhibitory effect on vascular endothelial cells and inhibiting vascular smooth muscle cell proliferation and formation of angiogenesis. To provide a pharmaceutical composition for preventing and treating vascular restenosis.

Another object of the present invention is to provide a stent coated with the composition.

In order to achieve the above object, the present invention

It provides a pharmaceutical composition for preventing and treating vascular restenosis comprising a pyrazolopyrimidinone compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

(In Formula 1, R ₁ , R ₂ , R ₃ and R ₄ are as described in the specification.)

In addition, the present invention

It provides a pharmaceutical composition for preventing and treating vascular restenosis comprising a pyrazolopyrimidinone compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 2]

In addition, the present invention provides a stent coated with the pharmaceutical composition.

The pharmaceutical composition according to the present invention may be useful for the prevention and treatment of vascular restenosis caused by vascular smooth muscle cell overproliferation by inhibiting proliferation of vascular smooth muscle cells and neovascularization. In addition, it has a low proliferation inhibitory effect on vascular endothelial cells, which can reduce vascular endothelial inhibition at the site of coronary angioplasty.

Therefore, by administering a high concentration of the drug site-specific using the stent coated with the composition according to the present invention it can prevent and treat coronary artery stenosis.

Hereinafter, the present invention will be described in detail.

The present invention relates to a novel use of a pyrazolopyrimidinone compound having an erectile dysfunction effect as a phosphodiesterase-5 inhibitor as an agent for preventing and treating vascular restenosis.

The pyrazolopyrimidinone compound, which is an active ingredient of the present invention, has a structure of Formula 1 below:

(In Formula 1,

R ₁ is hydrogen or alkyl of C ₁ to C ₆ ,

R ₂ is hydrogen or alkyl of C ₂ to C ₆ ,

R ₃ is C ₁ -C ₆ alkyl,

R ₄ is pyridine, isoxazole, thiazole, pyrimidine, indane, benzthiazole, pyrazole, thiadiazole, oxazole, piperidine, morpholine, unsubstituted or substituted with C ₁ to C ₁₀ alkyl groups, This is a heterocycle selected from midazole, pyrrolidine, thienyl, triazole, pyrrole and furyl.)

More preferably, the compound of Formula 1

R ₁ is C ₁ -C ₆ alkyl, R ₂ is C ₂ -C ₆ alkyl, R ₃ is C ₁ -C ₆ alkyl, and R ₄ is substituted or substituted with C ₁ -C ₁₀ alkyl group It is not pyrrolidine.

Particularly preferred compounds of the formula 1 of the present invention are specifically compounds of the formula

Pyrazolopyrimidinone compounds according to the invention may comprise asymmetric carbons. The present invention therefore encompasses both racemic mixtures and individually isolated isomers.

The pyrazolopyrimidinone compound of the present invention may be prepared by methods known in the art, or may be used by purchasing a commercially available product.

The pharmaceutical composition of the present invention inhibits the vascular narrowing by inhibiting the proliferation of vascular smooth muscle cells and the formation of angiogenesis.

According to Experimental Example 1 of the present invention, the pyrazolopyrimidinone compound having the structure of Formula 2 inhibited the proliferation of human aortic smooth muscle cells at the level of 100 uM to 1 mM in an in vitro experiment.

According to Preferred Experiment 2 of the present invention, the pyrazolopyrimidinone compound having the structure of Formula 2 is significantly lower in human umbilical vein endothelial compared to the inhibition rate of human aortic smooth muscle cell proliferation in Experiment 1 in an in vitro experiment. Cell proliferation inhibition rate was shown.

In addition, according to Experimental Example 3 of the present invention, the pyrazolopyrimidinone compound having the structure of Formula 2 effectively inhibited carotid artery restenosis in an in vivo experiment.

The composition of the present invention can be preferably formulated into a pharmaceutical composition including one or more pharmaceutically acceptable carriers in addition to the active ingredients described above within the scope of not impairing the effects of the present invention.

Acceptable pharmaceutical carriers in compositions formulated as liquid solutions are sterile and physiologically compatible, including saline, sterile water, Ringer's solution, buffered saline, albumin injectable solutions, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary.

In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable formulations, pills, capsules, granules, or tablets such as aqueous solutions, suspensions, emulsions, and the like, and may act specifically on target organs. Target organ specific antibodies or other ligands may be used in combination with the carriers so as to be used. Furthermore, the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA can be formulated according to each disease or component according to the appropriate method in the art.

Pharmaceutical formulation forms of the pharmaceutical compositions of the present invention may be granules, powders, coated tablets, tablets, capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and sustained release formulations of the active compounds, and the like. Can be.

The pharmaceutical composition may be administered in conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intraperitoneal, sternum, transdermal, nasal, inhalation, topical, rectal, oral, intraocular or subcutaneous routes. have. The method of administration is not particularly limited thereto, but parenteral administration is preferred, and more preferably, it is directly applied around the stenosis by coating in a stent.

In the present invention, the effective amount of the drug for inhibiting vascular restenosis includes the type of disease, the severity of the disease, the type and amount of the active ingredient and other ingredients contained in the composition, the type of the dosage form and the age, weight, general state of health of the patient, It can be adjusted according to a variety of factors including sex and diet, time of administration, route of administration and rate of composition, duration of treatment, drugs used concurrently.

Dosage of the composition is a conventional dosage of the anti-vascular restenosis agent, for example, in the case of an adult can be used from 1,000 μg / kg to 10,000 μg / kg, preferably 10 μg / stent to 1,000 μg / stent.

The pharmaceutical composition of the present invention can be used for the purpose of preventing vascular narrowing because it inhibits the proliferation of vascular smooth muscle cells and the formation of angiogenesis. That is, coronary restenosis after percutaneous coronary angioplasty such as balloon surgery or stent implantation, vascular restenosis after percutaneous cerebrovascular and peripheral vessel intervention, vascular restenosis after various vascular surgery, vascular stenosis after bypass surgery and arteriovenous fistula surgery, autovascularization and artificial It can be usefully used for the prevention and treatment of stenosis and atherosclerosis after blood vessel transplantation.

 One preferred use of the pharmaceutical composition according to the invention is to coat the stent. Therefore, the present invention provides a stent coated with a pharmaceutical composition for preventing and treating vascular restenosis, which comprises the composition as an active ingredient.

The method of coating the pharmaceutical composition on the stent may be any method known in the art, and the type is not particularly limited. Typical dip coatings, spin coatings, bar coatings and spray coatings are possible.

At this time, the pharmaceutical composition of the present invention may be attached to the stent together with the biodegradable polymer or directly coated on the stent without using the biodegradable polymer.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

Experimental Example 1: In vitro ( in vitro ) Effect of Human Aortic Smooth Muscle Cell Proliferation Inhibition

1-1. Cell culture

Cell experiments were performed using human artery vascular smooth muscle cells (HASMCs; ATCC, Rockville, MD). Cells were 37 ° C. in culture with 10% fetal bovine serum (FBS; Gibco, Karlsruhe, Germany) and 1% penicillin in DMEM (Dulbecco's modified Eagle's medium-low glucose, DMEM; Gibco, Karlsruhe, Germany). Cultured in a cell incubator containing 5% CO ₂ . The culture used for cell culture was changed every two days. Cells were used from 20 to 22 passages.

1-2. Effect of Eudenafil on HASMCs Growth Inhibition

Eudenafil (trade name Zydena, Dong-A Pharmaceutical) was used by dissolving in 100% ethanol at a concentration of 1 mM, 100 uM, 10 uM, 1 uM. The cultured HASMCs were washed with PBS (phosphate-buffered saline), treated with trypsin (0.25%), and removed from the petri dish. The cell count was measured using a cell counter, and 1 × 10 ⁴ cells were prepared in a 96-well plate. Aliquots and incubated for 24 hours. After 24 hours of incubation in the serum free medium, the control group was added to the culture medium without any substances, and the administration group was 1 mM, 100 uM, 10 uM and 1 uM of udenafil were added to the culture and allowed to react for 24 hours. After washing with PBS again, MTT (50ul, Calbiodhem, Germany) was added and incubated for 3 hours, the treated reagent was removed and then treated with DMSO (150ul, sigma chemical company, Germany) for 5 minutes. Thereafter, the absorbance was measured at a wavelength of 590 nm using an ELISA, and the results are shown in FIG. 1.

Referring to FIG. 1, although the effect of inhibiting the proliferation of vascular smooth muscle cells was less than 10 uM of udenafil, the cell proliferation inhibitory effect was increased with increasing concentration, and the cell proliferation inhibitory effect was remarkably increased at 1mM and 100uM concentration.

Experimental Example 2: In vitro ( in vitro ) Confirmation of Human Umbilical Vein Endothelial Cell Proliferation Effect

2-1. Cell culture

Cell experiments were performed using human umbilical vein endothelial cells (Human Umbilical Vein Endothelial Cells, HUVECs; Bio4you, Seoul, Korea). Cells were 37 ° C. in culture with 10% fetal bovine serum (FBS; Gibco, Karlsruhe, Germany) and 1% penicillin in DMEM (Dulbecco's modified Eagle's medium-low glucose, DMEM; Gibco, Karlsruhe, Germany). Cultured in a cell incubator containing 5% CO ₂ . The culture used for cell culture was changed every two days. Cells were used from three to five passages.

2-2. Eudenafil HUVECs Inhibitory Growth

Eudenafil (trade name Zydena, Dong-A Pharmaceutical) was used by dissolving in 100% ethanol at a concentration of 1 mM, 100 uM, 10 uM, 1 uM. The cultured HUVECs PBS (phosphate-buffered saline), after then removed from the Petri dish by treatment with trypsin (0.25%), cell numbers and measuring 1 × 10 ⁴ cells using a cell counter washed with a 96-well plate Aliquots and incubated for 24 hours. After 24 hours of incubation in a serum free medium, the control group was added to the culture medium without any substance, and the administration group added 1 mM, 100 uM, 10 uM, and 1 uM of udenafil to the culture for 24 hours. I was. After washing with PBS again, MTT (50ul, Calbiodhem, Germany) was added and incubated for 3 hours, the treated reagent was removed and then treated with DMSO (150ul, sigma chemical company, Germany) for 5 minutes. Thereafter, the absorbance was measured at a wavelength of 590 nm using an ELISA, and the results are shown in FIG. 2.

Referring to FIG. 2, the umbilical vein endothelial cell proliferation inhibitory effect increased with increasing udenafil concentration, but showed a significantly lower inhibition rate compared to the vascular smooth muscle cell proliferation inhibition rate of udenafil. It has been shown to have an inhibitory effect. Therefore, the possibility of endothelialization at the site of coronary angioplasty increases, which is expected to prevent problems of vascular restenosis and late thrombosis.

Experimental Example 3: In vivo ( in vivo ) Inhibition of carotid artery stenosis

3-1. Preparation of Eudenafil-Pluronic Gel for Coating

One day before the experiment, the F-127 Pluronic gel (sigma chemical company, Germany) was dissolved in cold PBS to 25%, and left at 4 ° C for at least 12 hours to completely dissolve the powdered F-127 Pluronic gel. On the day of the experiment, powdered udenafil was dissolved in 100% ethanol at the concentrations of 100 uM, 10 uM and 1 uM and then ethanolic udenafil (100 uM / L, 10 uM / L, 1 uM /) in 180ul of 25% F-127 Pluronic gel. L udenafil) was added at a rate of 20ul to prepare 200ul of udenafil-pluronic gel. Pluronic gels for application were colorless and transparent gels with or without eudenafil.

3-2. Animals

Sprague-Dawley male adult white papers weighing 300-350 g were used. Three control subjects who received left total carotid artery balloon injury only, and 13 treatment groups who received Udenafil at each concentration after balloon injury were used as the experimental group.

3-3. Carotid Artery Injury Model and Udenafil Topical Therapy

Ketamine (ketamine (50 mg / kg)) and xylazine (xylazine (6.7 mg / kg) were anesthetized in the abdominal cavity, and the left neck was dissected to separate the carotid, external and internal carotid arteries. A microvascular clamp (Acland, S & T, Switzerland) was applied to the aortic initiation and distal carotid artery of the total carotid artery, and the external carotid artery was dissected with the blood flow temporarily stopped. Balloons were inserted into the total carotid artery, the balloon was inflated larger than the diameter of the total carotid artery, reciprocated three times to remove endothelial cells, and the inside of the carotid artery was washed with physiological saline. The microvascular clamp was then removed to reperfusion the blood flow and suture the incision site. The control group was injured in the total carotid artery and reperfused the blood flow. The Udenafil 100uM, 10uM, and 1uM treatment groups used the same method to remove endothelial cells and remove the microvascular clamp to resume blood flow and suture the incision site. After removing the secretion and blood on the outside of the carotid artery, the pre-prepared Udenafil-Pluronic gel and Pluronic-free Pluronic gel were applied to the control group and the Udenafil treatment group. After applying evenly to the outer wall 200ul by using a syringe sutured to the incision site.

3-4. Carotid Artery Pathology and Analysis

After 21 days of anesthesia, the carotid artery was extracted and fixed in 10% formalin solution. 1cm of the central part of the fixed carotid artery was taken and embedded in paraffin. Then, a continuous section of 4um was made. Hematoxylin-Eosin staining was performed, followed by optical microscopy.

The photographs were scanned and transferred to a computer, followed by quantitative morphometry analysis using Image Analysis Software (Image-Pro Plus version 6.0). Factors used in the analysis were neointima area, media area, and intima / media ratio.

Figure 3 (a) is a control carotid artery cross section of Experimental Example 3, (b) a carotid artery cross section of the udenafil 1uM administration group, (c) a carotid artery cross section of the udenafil 10uM administration group, (d) a carotid artery cross section of the udenafil 100uM administration group Optical micrograph (100 times).

Referring to FIG. 3, it was confirmed that the effect of inhibiting carotid artery restenosis was less than 10 uM of udenafil, but a significant effect of preventing carotid restenosis at 1mM and 100uM concentration was shown.

Figure 4 is a graph showing the comparison of the area of the neointima and the media of the control group, udenafil administration group of Experimental Example 3.

Figure 5 is a graph showing a comparison of the area of the neointima / media of the control group, udenafil-treated group of Experimental Example 3.

Referring to FIGS. 4 and 5, the area ratio of neointima to media was reduced compared to the control group at less than 10 uM of udenafil, and the area ratio of neointima to media was significantly reduced at 1mM and 100 uM concentrations to effectively suppress neointimal formation. Could confirm.

The pharmaceutical composition according to the present invention will be effectively suppressed vascular narrowing, and will be applied in an efficient manner for the treatment of various cardiovascular diseases.

1 is a graph showing a comparison of the results obtained by measuring absorbance at a wavelength of 590 nm using an ELISA of a control group and udenafil administration group of Experimental Example 1. FIG.

Figure 2 is a graph showing the results of measuring the absorbance at a wavelength of 590nm using the ELISA of the control group, the udenafil administration group of Experimental Example 2.

Figure 3 (a) is a control carotid artery cross section of Experimental Example 3, (b) a carotid artery cross section of the udenafil 1uM administration group, (c) a carotid artery cross section of the udenafil 10uM administration group, (d) a carotid artery cross section of the udenafil 100uM administration group Optical micrograph (100 times).

Figure 4 is a graph showing the comparison of the area of the neointima and the media of the control group, udenafil administration group of Experimental Example 3.

Figure 5 is a graph showing a comparison of the area of the neointima / media of the control group, udenafil-treated group of Experimental Example 3.

Claims (6)

A pharmaceutical composition for preventing and treating vascular restenosis comprising a pyrazolopyrimidinone compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: [Formula 1]

(In Formula 1, R ₁ is hydrogen or alkyl of C ₁ to C ₆ , R ₂ is hydrogen or alkyl of C ₂ to C ₆ , R ₃ is C ₁ -C ₆ alkyl, R ₄ is pyridine, isoxazole, thiazole, pyrimidine, indane, benzthiazole, pyrazole, thiadiazole, oxazole, piperidine, morpholine, unsubstituted or substituted with C ₁ to C ₁₀ alkyl groups, Heterocycle selected from imidazole, pyrrolidine, thienyl, triazole, pyrrole and furyl.) The compound of claim 1, wherein R ₁ is C ₁ -C ₆ alkyl, R ₂ is C ₂ -C ₆ alkyl, R ₃ is C ₁ -C ₆ alkyl, and R ₄ is C ₁ -C ₆ Pharmaceutical composition, characterized in that the pyrrolidine substituted or unsubstituted with an alkyl group of ₁₀ . A pharmaceutical composition for preventing and treating vascular restenosis comprising a pyrazolopyrimidinone compound represented by Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient: [Formula 2]

4. The pharmaceutical composition of claim 1 or 3, wherein the vascular restenosis is due to vascular smooth muscle cell hyperproliferation. 5. The method of claim 4, wherein the vascular smooth muscle cell hyperplasia comprises percutaneous coronary angioplasty, balloon angioplasty, percutaneous cerebrovascular and peripheral vascular intervention, autovascular and artificial vascular grafts, stent insertion, coronary artery bypass graft, arterial-vein anastomosis and arteriosclerosis. Pharmaceutical composition, characterized in that caused by one selected from the group consisting of. A stent coated with a pharmaceutical composition for preventing and treating vascular restenosis according to claim 1.

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