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WO2006115279A1 - Composition pour la preservation de l'endothelium vasculaire - Google Patents

Composition pour la preservation de l'endothelium vasculaire Download PDF

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Publication number
WO2006115279A1
WO2006115279A1 PCT/JP2006/308788 JP2006308788W WO2006115279A1 WO 2006115279 A1 WO2006115279 A1 WO 2006115279A1 JP 2006308788 W JP2006308788 W JP 2006308788W WO 2006115279 A1 WO2006115279 A1 WO 2006115279A1
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WIPO (PCT)
Prior art keywords
stent
composition
chain
derivative
preserving
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PCT/JP2006/308788
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English (en)
Japanese (ja)
Inventor
Noboru Fukuda
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Nihon University
Gentier Biosystems, Inc.
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Application filed by Nihon University, Gentier Biosystems, Inc. filed Critical Nihon University
Publication of WO2006115279A1 publication Critical patent/WO2006115279A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1136—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against growth factors, growth regulators, cytokines, lymphokines or hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/258—Genetic materials, DNA, RNA, genes, vectors, e.g. plasmids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense

Definitions

  • Vascular endothelial preservation composition
  • the present invention relates to a vascular endothelial preserving composition capable of preventing coronary restenosis and preserving endothelium in blood vessels. More specifically, the present invention relates to a vascular endothelial preservation composition comprising an antisense oligonucleotide for platelet-derived growth factor-A chain (hereinafter simply referred to as PDGF-A chain) or a derivative thereof as an active ingredient.
  • PDGF-A chain platelet-derived growth factor-A chain
  • the present invention also relates to a method for preventing or treating coronary restenosis by using this vascular endothelial preserving composition in a stent coating agent or the like.
  • ischemic heart diseases such as angina pectoris and myocardial infarction
  • a method of expanding a coronary artery with a balloon or a stent in percutaneous coronary angioplasty has been performed.
  • this method is highly effective, there is a problem that coronary artery restenosis is likely to occur due to damage to the vascular endothelium caused by insertion of a balloon or stent, and abnormal proliferation of vascular smooth muscle cells at the damaged site. .
  • sirolimus-coated drug-eluting stent (registered trademark, CYPHER) strongly suppresses the proliferation of cells in the blood vessel, and coronary artery Effective in preventing restenosis.
  • CYPHER registered trademark
  • the rate of coronary restenosis 6 months after stent placement has drastically decreased to less than a quarter of the restenosis rate compared to the conventional stent (for example, (See Non-Patent Documents 1 and 2).
  • sirolimus is a drug that stops the cell cycle, only vascular smooth muscle cells It also suppresses the proliferation of vascular endothelial cells, but even though coronary restenosis can be prevented, the endothelium of the stent lumen cannot be preserved, and the metal surface of the stent is exposed. .
  • SAT subacute thrombosis
  • FDA United States Food and Drug Administration
  • SAT subacute thrombosis
  • FDA United States Food and Drug Administration
  • ticlovidin hydrochloride has serious side effects such as severe liver damage and decreased white blood cells and platelets, and there are concerns about the risk of side effects from long-term use.
  • composition that prevents coronary restenosis, maintains the proliferation of endothelial cells in blood vessels, preserves the endothelium, and has a low risk of side effects.
  • Patent Document 1 Japanese Patent Publication No. 5-502179
  • Patent Document 2 JP-A-6-9390
  • Non-specific S 1 Regar E, Serruys PW, Bode C, Holubarsch C, Guermonprez JL, Wijns s W, Bartorelli A, Constantini C, Degertekin, Tanabe K, Disco C, Wuelfert E, perennial MC; RAVEL Study Group. Circulation 106: 1949-1956, 2002.
  • Non-Patent Document 2 Cohen DJ, Bakhai A, Shi C, Githiora L, Lavelle T, Berezin RH, Leon MB, Moses JW, Carrozza JP Jr, Zidar JP, Kuntz RE; SIRIUS Investigators. Circulati on. 110: 508-514 , 2004.
  • Non-Patent Document 3 FDA public health web notification: Food and Drug Administration. 2 003. Available at: 1113809079625— 0.% 20Accessed March 12, 2004.
  • the present invention prevents coronary restenosis, further maintains the proliferation of endothelial cells in blood vessels, It is an object of the present invention to provide a vascular endothelial preserving composition capable of preserving blood. Another object of the present invention is to provide a method for preventing or treating coronary restenosis by using this vascular endothelial preservation composition.
  • this composition for preserving vascular endothelium as a stent coating agent or the like, it was found that the composition was effective for the prevention or treatment of coronary restenosis, and the present invention was completed.
  • the present invention relates to the following (1) to (9).
  • composition for preserving vascular endothelium comprising as an active ingredient an antisense oligonucleotide for platelet-derived growth factor-A chain or its derivative.
  • composition according to (1) further having an inhibitory effect on proliferation of vascular smooth muscle cells.
  • composition according to (1) or (2) above, wherein the derivative is chemically modified to a phosphorotype is chemically modified to a phosphorotype.
  • a stent coating agent comprising a composition for preserving vascular endothelium, comprising an antisense oligonucleotide for platelet-derived growth factor-A chain or its derivative as an active ingredient.
  • a drug-eluting stent coated with a vascular endothelial preserving composition containing a conductor as an active ingredient or a stent coating agent containing the composition is provided.
  • a method for preventing or treating coronary restenosis comprising preserving the endothelium in a blood vessel, comprising administering an antisense oligonucleotide for platelet-derived growth factor-A chain or a derivative thereof to an affected area.
  • the coronary restenosis is after coronary artery restenosis as described in (7) above. Prevention or treatment method.
  • composition for preserving vascular endothelium of the present invention can specifically inhibit the proliferation of vascular smooth muscle cells, maintain the proliferation of the vascular endothelial cells, and preserve the endothelium in the blood vessel.
  • preserving the endothelium in the blood vessel it is possible to prevent or treat coronary restenosis in angina pectoris, myocardial infarction, etc., and to recover the underlying disease.
  • FIG. 1 is a diagram showing the base sequences of antisense ODN and non-sense ODN (Example 1)
  • FIG. 2 shows that antisense ODN has flowed out of a stent and has been distributed to endothelial cells of coronary arteries (Example 5).
  • FIG. 3 is a graph showing the presence or absence of a coronary artery lumen (Example 5).
  • FIG. 4 is a view showing the volume ratio of restenosis portion in a coronary stent (Example 5).
  • FIG. 5 shows the results of IVUS (Example 5).
  • FIG. 6 shows coronary artery pathological findings (Example 5).
  • FIG. 7 is a graph showing the area ratio of restenosis in a coronary stent (Example 5).
  • FIG. 8 shows the results of coronary artery hematoxin staining (Example 5).
  • “preservation of endothelium in blood vessels” refers to the suppression of excessive proliferation of vascular smooth muscle cells accompanying damage of vascular endothelium in blood vessels, thereby maintaining the proliferation of vascular endothelial cells, To preserve the endothelium in blood vessels.
  • treatment of diseases in organs such as the heart and brain particularly all diseases related to vascular stenosis and restenosis, mainly caused by excessive proliferation of vascular smooth muscle cells. And can be used for prevention.
  • diseases mainly caused by excessive proliferation of vascular smooth muscle cells include treatment of ischemic heart diseases such as angina pectoris and myocardial infarction. Coronary restenosis in medical treatment.
  • Coronary restenosis which is one of the targets for prevention or treatment of the present invention, refers to platelet aggregation caused by damage to the vascular endothelium, and platelet-derived growth factor (hereinafter sometimes simply referred to as PDGF).
  • PDGF platelet-derived growth factor
  • it refers to the blockage of blood vessels due to abnormal proliferation of vascular smooth muscle cells. Therefore, in order to prevent or treat this coronary restenosis, the abnormal proliferation of vascular smooth muscle cells is specifically suppressed, and the proliferation of vascular endothelial cells is maintained to preserve the endothelium in the blood vessel. Is required.
  • the “inhibition of proliferation of vascular smooth muscle cells” in the present invention refers to specifically inhibiting the proliferation of vascular smooth muscle cells by interfering with the action of PDGF involved in the proliferation of vascular smooth muscle cells. As a result, the proliferation of vascular endothelial cells is maintained, and the endothelium in the blood vessel can be preserved.
  • the “antisense oligonucleotide against PDGF-A chain” of the present invention refers to an oligonucleotide complementary to the base sequence of PDGF-A chain for suppressing the expression of PDGF-A chain.
  • the oligonucleotide contains a nucleotide sequence that is complementary to the base sequence of the PDGF-A chain.
  • any fragment may be used.
  • fragments having a length of about 15 to 17 bases are preferable because they are easy to handle.
  • an antisense oligonucleotide for example, the oligonucleotide of SEQ ID NO: 1 in the Sequence Listing can be mentioned.
  • antisense oligonucleotides for example, those synthesized by a consignment contractor such as Qiagen or Proligo can be used.
  • the base of the oligonucleotide may be either DNA or RNA.
  • the "derivative of an antisense oligonucleotide for PDGF-A chain” of the present invention is an oligonucleotide containing a base sequence complementary to the base sequence of PD GF-A chain. In order to enhance stability, it is a chemical modification of one or more base atoms contained in an oligonucleotide. For example, phosphorothioate, morpholino, and the like. Such thiogonucleotide derivatives are resistant to nucleolytic enzymes and are resistant to nucleolytic enzymes in tissues and living organisms with high stability. The dose will be lower as the patient improves.
  • the antisense oligonucleotide or derivative thereof for the PDGF-A chain of the present invention can be used as it is as long as it suppresses vascular smooth muscle cell proliferation and preserves endothelial cells in blood vessels. It can also be used as a composition together with pharmaceutically acceptable additives such as agents.
  • the present inventors have confirmed that the "antisense oligonucleotide for PDGF-A chain or a derivative thereof" of the present invention has an inhibitory action on proliferation of vascular smooth muscle cells in vitro using vascular smooth muscle cells. Confirm with this experiment.
  • Fukuda N, Kubo A, Watanabe Y, Nakayama T, Soma M, Izumi Y, Kanmatsuse K Antisense oligodeoxynucleotide com plementary to platelet-derived growth factor A-chain messenger RNA inhibits the ar terial proliferation in spontaneously hypertensive rats without alterating their blood pressure.J Hypertens 15: 1123-1136, 1997.
  • the "vascular endothelial-preserving thread and composition" of the present invention refers to a composition comprising an antisense oligonucleotide for PDGF-A chain or a derivative thereof as an active ingredient. It means a composition to which an additive such as a stabilizer acceptable in the above is added.
  • lipofectin, lipofectamine, polyethylenemine, HVJ-envelope and the like can be used, and it is particularly preferable to use polyethylenemine for stably storing an antisense oligonucleotide or a derivative thereof.
  • vascular endothelial preserving composition of the present invention can be used for any pharmaceutical composition, pharmaceutical, and medical device as long as it suppresses the proliferation of vascular smooth muscle cells and preserves endothelial cells in the blood vessels. .
  • an effective pharmaceutical composition such as a catheter or injection It can also be used as a component.
  • the "stent coating agent" of the present invention is a combination of an endothelium preserving composition containing an antisense oligonucleotide for PDGF-A chain or a derivative thereof as an active ingredient, and a pharmaceutically acceptable carrier. It refers to a drug prepared so that it can be applied to a stent.
  • Pharmaceutically acceptable carriers can be used in solid or liquid form.
  • a solid carrier additives such as calcium phosphate, magnesium stearate, talc, glucose, sucrose, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, carboxymethyl cellulose-sodium and polyvinylpyrrolidone are used.
  • a liquid carrier water, a solution partially containing an additive, alcohols and derivatives thereof, fats and oils, organic solvents, and the like can be used.
  • vascular endothelial preserving composition are combined, and further mixed with excipients such as cell mouth, glycerin fatty acid ester, calcium phosphate, etc. as necessary, and compressed into tablets, powders, granules, capsules It may be in the form of chewable, cream, ointment, paste, gel, viscous liquid.
  • excipients such as cell mouth, glycerin fatty acid ester, calcium phosphate, etc.
  • the stent coating agent formed in a solid state can be prepared in a liquid form or a cream form for easy application when applied to the stent.
  • the "drug-eluting stent" of the present invention means that the drug applied to the stent dissolves into the inner wall of the blood vessel and suppresses abnormal growth of vascular smooth muscle cells, whereby the proliferation of vascular endothelial cells is maintained.
  • a stent coating agent containing an antisense oligonucleotide for PDGF-A chain or a derivative thereof as an active ingredient for example, a 3.5 mm ⁇ 20 mm stent.
  • the stent to which the stent coating agent of the present invention is applied is a stent that is inserted into a blood vessel and held in a place to be treated or prevented, and is capable of eluting the drug with blood vessel expansion. You can also use a good stent. Furthermore, in the case of a metal stent, it is preferable to use a stent capable of carrying a drug-supporting coating covering at least the metal portion.
  • a Hyde mouth gel coating is used as a method of applying the stent coating agent of the present invention to a stent.
  • a Hyde mouth gel coating is used as a method of applying the stent coating agent of the present invention.
  • it can be applied by hide-mouth gel coating.
  • the insertion site can be placed at a site where coronary restenosis can be prevented or treated by force that varies depending on the degree of symptoms of the patient, for example, intravenous administration.
  • this drug-eluting stent has an inhibitory effect on abnormal proliferation of vascular smooth muscle cells for 1 to 60 days after insertion, depending on the amount of drug applied.
  • coronary arteries in the treatment of ischemic heart diseases such as angina pectoris and myocardial infarction by using the vascular endothelial preserving composition of the present invention and suppressing the excessive proliferation of vascular smooth muscle cells.
  • ischemic heart diseases such as angina pectoris and myocardial infarction
  • the proliferation of vascular endothelial cells is maintained and the endothelium within the blood vessels can be preserved.
  • a stent coating agent containing the vascular endothelial preserving composition of the present invention as an active ingredient and using a drug-eluting stent to which this is applied, coronary artery restenosis can be prevented or treated.
  • Example 1 Examples of the present invention are shown below, but the present invention is not limited by these.
  • Example 1 Examples of the present invention are shown below, but the present invention is not limited by these.
  • Antisense oligodeoxynucleotides (hereinafter referred to as "antisense oligodeoxynucleotides”), which include the complementary base sequence of the start codon from the human and rat PDGF—A chain sequences, and the total length of the front and rear IJs is 15 bases.
  • nonsense oligonucleotides (nons ense oligodeoxynucleotides) were designed and synthesized and purified in the same manner as antisense oligonucleotides.
  • the base sequence of the purified non-sense oligonucleotide is shown in SEQ ID NO: 2 in the Sequence Listing. These base sequences are shown in FIG.
  • the resulting ODN was modified as a phosphorothioate by oxidation of the phosphate bond of 3H-1,2-benzodithiol-3-one 1,1-dioxide.
  • Vascular endothelium-preserving, anomaly was prepared by the following method.
  • An antisense oligonucleotide solution (1 ug / ⁇ ⁇ ) prepared by dissolving the antisense oligonucleotide prepared above in physiological saline is used as a stock solution and diluted with physiological saline to obtain an antisense oligonucleotide solution ( 50 g / 1.25 inl) was prepared and used as solution A.
  • Solution B was added to solution A, vortexed for 10 seconds, and incubated at room temperature for 10 minutes.
  • a stent coating agent prepared by the same method as in Examples 1 and 2 was applied to a stent (diameter 3.5 mm, length 20 mm, manufactured by Interventional Radiology) to prepare a drug eluting stent.
  • a stent coating agent prepared using an antisense oligonucleotide solution (20 g / ml) as solution A and a polyethylenelenine solution (100 ⁇ 1 / ml) as a liquid solution was used.
  • the stent coating agent was applied to the stent in the same manner as in Example 3.
  • a stent containing non-sense ODN was prepared as a control, and a physiological stent was applied as a control to a conventional stent.
  • a drug eluting stent was created.
  • the stent coating agent was applied to the stent by the following method. All operations were performed under aseptic conditions.
  • each pig was given aspirin (325 mg) one day before implantation and fasted for 1 kg, followed by intramuscular injection of 25 mg / kg pentovanolebital sodium as a premedication, followed by lm g Anesthesia was performed by intravenous injection of / kg / h ketamine chloride. Henoline was injected intravenously as a 5000 IU bolus.
  • controlled mechanical aeration was performed by cyclic aeration of 10-15 ml / kg in a volumetric cycle ventilator (Servo 900-E, Siemems—Elema Inc.).
  • the stent was inserted into the right carotid artery with a 6F sheath.
  • Nonsense OD is an ODN with the same number of bases in antisense ODN and ACGT, but in a completely different order.
  • the base sequence described in SEQ ID NO: 2 was used.
  • FIG. 2 is a view showing a coronary artery including a stent before and after confirming luminescence.
  • FIG. 3 shows the presence or absence of lumens in groups 1 and 3.
  • the arrows in Fig. 3 indicate the stent, and * indicates the neointima.
  • FIGS. 3C and D in group 1, the neointima due to occlusion crammed the lumen and surrounded the ultrasound catheter.
  • FIGS. 3A and 3B the three groups had very clear lumens.
  • the volume ratios of restenosis in coronary stents were 63.7 ⁇ 11.9, 4 4.4 ⁇ 3.4, and 25.5 ⁇ 3 : 8% in groups 1, 2, and 3, respectively. As shown in Fig. 4, the volume ratio of restenosis in the stent was significantly lower in group 3 compared to groups 1 and 2.
  • the IVUS image recorded on the SVHS tape was analyzed by a computer-based contour detection program (registered trademark, NetralVUS software package for Windows NT, Sclmage Corporation. USA) for three-dimensional reconstruction and volume measurement.
  • the cross grid recorded in the IVUS image was used as a scale.
  • the interface between the neointima and lumen was manually tracked, and outside the outer elastic membrane boundary.
  • the measurement parameters were determined by computer software as follows.
  • LV Lumen volume
  • W Vessel volume
  • the volume ratio of the restenosis portion in the stent was determined by (W—LV) / W.
  • IEL internal elastic lamina
  • the lumen area was defined as the area limited by the neointima-luminal border, and the neointima area was defined as the area between the lumen door IELs.
  • Restenosis in the stent was evaluated as neointima region / IEL region.
  • Results The results of IVUS are shown in FIG. As shown in Figs. 5A to 5C, in each of the 1 to 3 groups, there was no stenosis in the coronary artery where the stent was placed, and the lumen surface was slippery. Met.
  • Fig. 5C it was observed that the metal surface of the stent coated with 3 groups of antisense ODN was embedded in the neointima. It was not observed in the other stents, and it was confirmed that neointima formation was reduced by antisense ODN.
  • Fig. 5D when using a sirolimus-coated drug-eluting stent, exposure of the metal surface of the stent was observed in the lumen, and several red thrombi were observed on the surface of the lumen. It was shown to be attached.
  • Fig. 6 shows the pathological findings of the coronary artery in which groups 2 or 3 were placed. Compared to using two groups of non-sense ODN-coated stents as shown in Fig. 6A, the three-group anti-sense ODN-coated stents were used in the middle, as shown in Fig. 6B. The formation of restenosis was suppressed even if the tip or the proximal part was shifted or distorted.
  • FIG. 7 shows the area ratio of the restenosis portion in the stent in the central and distal portions and the proximal portion of the stent in the groups 1-3. It was confirmed that group 3 reduced restenosis in the stent at all of proximal, central and distal compared to group 1. Therefore, it was shown that restenosis is prevented by using a stent coated with phosphorotype anti-sense ODN.
  • FIG. 8 shows the results of hematoxin staining of the site where the stents coated with antisense QDN of 3 groups or sirolimus-coated drug eluting stents were placed.
  • FIG. 8A it was observed that the endothelial cells were completely and continuously aligned when using three groups of stents.
  • FIG. 8B when the sirolimus-coated drug-eluting stent was used, suspended endothelial cells were observed along the surface of the coronary artery.
  • the vascular endothelial preserving composition of the present invention specifically suppresses the proliferation of vascular smooth muscle cells, The proliferation of vascular endothelial cells is maintained and the endothelium within the blood vessels can be preserved. Furthermore, by using a stent coating agent containing the vascular endothelial preserving composition of the present invention as an active ingredient and a drug-eluting stent, coronary arteries in angina or myocardial infarction due to preservation of the endothelium in the blood vessel is used. It is possible to prevent or treat restenosis and to restore the underlying disease.
  • the drug-eluting stent containing this vascular endothelial preserving composition does not require the use of ticlovidin hydrochloride or the like, and therefore eliminates the risk of side effects caused by the combined drug.

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Abstract

L'invention concerne une composition pour la préservation de l'endothélium vasculaire qui permet de prévenir la resténose coronaire et de préserver l'endothélium vasculaire. La composition comprend un oligonucléotide antisens à chaîne A PDGF ou un dérivé de ce dernier en tant que principe actif. La composition selon l'invention permet d'inhiber la croissance anormale des cellules du muscle lisse de la paroi vasculaire et de préserver l'endothélium vasculaire.
PCT/JP2006/308788 2005-04-21 2006-04-20 Composition pour la preservation de l'endothelium vasculaire WO2006115279A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
JP2008125964A (ja) * 2006-11-24 2008-06-05 Univ Kinki 被覆ステント
WO2008109372A2 (fr) * 2007-03-02 2008-09-12 Mdrna, Inc. Composés d'acide nucléique permettant d'inhiber l'expression de gène pdgf et utilisations de ceux-ci

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WO2004050140A2 (fr) * 2002-12-03 2004-06-17 Scimed Life Systems, Inc. Dispositifs medicaux conçus pour administrer des agents therapeutiques

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Publication number Priority date Publication date Assignee Title
WO2004050140A2 (fr) * 2002-12-03 2004-06-17 Scimed Life Systems, Inc. Dispositifs medicaux conçus pour administrer des agents therapeutiques

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008125964A (ja) * 2006-11-24 2008-06-05 Univ Kinki 被覆ステント
WO2008109372A2 (fr) * 2007-03-02 2008-09-12 Mdrna, Inc. Composés d'acide nucléique permettant d'inhiber l'expression de gène pdgf et utilisations de ceux-ci
WO2008109372A3 (fr) * 2007-03-02 2009-02-26 Mdrna Inc Composés d'acide nucléique permettant d'inhiber l'expression de gène pdgf et utilisations de ceux-ci

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