EP1383447A4 - Freisetzung von statinen mithilfe eines stents zur verhinderung von restenose - Google Patents

Freisetzung von statinen mithilfe eines stents zur verhinderung von restenose

Info

Publication number
EP1383447A4
EP1383447A4 EP02728802A EP02728802A EP1383447A4 EP 1383447 A4 EP1383447 A4 EP 1383447A4 EP 02728802 A EP02728802 A EP 02728802A EP 02728802 A EP02728802 A EP 02728802A EP 1383447 A4 EP1383447 A4 EP 1383447A4
Authority
EP
European Patent Office
Prior art keywords
stent
statin
statin compound
struts
restenosis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02728802A
Other languages
English (en)
French (fr)
Other versions
EP1383447A1 (de
Inventor
Stephen E Epstein
Shmuel Fuchs
Eugenio Stabile
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MedStar Research Institute
Original Assignee
MedStar Research Institute
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by MedStar Research Institute filed Critical MedStar Research Institute
Publication of EP1383447A1 publication Critical patent/EP1383447A1/de
Publication of EP1383447A4 publication Critical patent/EP1383447A4/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheets or tubes, e.g. perforated by laser cuts or etched holes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheets or tubes, e.g. perforated by laser cuts or etched holes
    • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheets or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheets or tubes, e.g. perforated by laser cuts or etched holes
    • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheets or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
    • A61F2002/91533—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheets or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other characterised by the phase between adjacent bands
    • A61F2002/91541—Adjacent bands are arranged out of phase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheets or tubes, e.g. perforated by laser cuts or etched holes
    • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheets or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
    • A61F2002/9155—Adjacent bands being connected to each other
    • A61F2002/91558—Adjacent bands being connected to each other connected peak to peak
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2230/00—Geometry of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2230/0002—Two-dimensional shapes, e.g. cross-sections
    • A61F2230/0028—Shapes in the form of latin or greek characters
    • A61F2230/0054—V-shaped
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body

Definitions

  • This invention relates to the prevention of restenosis of arteries after angioplasty and more particularly to the use of a stent platform which is coated with a composition including a statin compound, the effect of which is to prevent such restenosis .
  • Coronary angioplasty has become an important method of treating narrowed (stenotic) arteries supplying the heart or the legs. Although the initial success rate of coronary angioplasty for opening obstructed coronary arteries exceeds 95%, restenosis occurs at the site of angioplasty in 25-50% of patients within six months, regardless of the type of angioplasty procedure used. Although the use of stents has appreciably reduced the ' rate of stenosis, even with this treatment strategy restenosis occurs in 5 to 20% of patients. Importantly, when restenosis occurs within a stent, the chance that restenosis will recur is very high. Thus, the problem of restenosis is still daunting, despite recent advances in reducing its incidence.
  • Proteins controlling progress of cells through the cell- cycle SMCs within the vessel wall are normally in a quiescent state. Immediately after injury, however, early response genes are expressed and the cells enter the cell cycle, wherein their replication is tightly regulated by an array of cell cycle regulatory proteins acting conjointly and in sequence at various points of the cycle. These regulatory proteins include cyclin-dependent kinases (cdc2 and cdk2) , which phosphorylate critical regulatory proteins, and which interact with cyclin- dependent kinase inhibitors, such as pi6, p21, and p27 ⁇ pl .
  • cdc2 and cdk2 cyclin-dependent kinases
  • Rb tumor suppressor protein retinoblastoma protein
  • E2F DNA binding and gene activating proteins
  • the Rb/E2F complex dissociates, freeing E2F to bind to its DNA binding sites and consequently stimulate the transcription of genes inducing progression to the S phase of the cell cycle.
  • Rapamycin a macrolide antibiotic, is a potent inhibitor of cell proliferation. It has recently been shown in a pig coronary artery injury model to significantly reduce the neointimal response to injury.
  • rapamycin The mechanism of action of rapamycin almost certainly largely derives from its ability to interfere with cell cycling. Thus, down-regulation of p27 k ⁇ pl by mitogens is blocked by rapamycin. Consistent with this activity, in the porcine injury model, rapamycin administration was associated with increased p27 levels and inhibition of Rb phosphorylation within the vessel wall. The most likely relevant molecular mechanisms are as follows : After binding to its cytosolic receptor, FKBP12, rapamycin increases p27, reduces cdc2 and cdk2 activity, and inhibits Rb phosphorylation, thereby inhibiting release of E2F. Eliminating E2F activity blocks the E2F-mediated transcription of the broad array of genes that contribute to cell cycle progression.
  • Microtubular modulation of the response of cells to mitogens and cytokines The microtubular system has been shown to modulate the response of cells to various mitogens and cytokines through activation of transmembrane signaling cascades. Targets of these pathways include activation of kinases, including mitogen-activated protein kinase activity, changes associated with microtubular depolymerization. The microtubules have also shown to play a part in the changes in SMCs that lead to their contributing to the restenosis lesion.
  • Paclitaxel favors stabilization of microtubule assembly, forming numerous disorganized microtubules within the cytoplasm, and thereby inhibiting many of the microtubular mediated cell signaling cascades cited above, including inhibition of cell division, predominantly in the G 0 /G ⁇ and G 2 /M phases of the cell cycle. Importantly, paclitaxel in biologically relevant concentrations does not appear to induce apoptosis. Taxol ® inhibited, in vitro, both platelet-derived growth factor-stimulated SMC migration and SMC proliferation, and in vivo, inhibited neointimal accumulation in the rat carotid artery injury model.
  • That application disclosed a method of preventing restenosis using a stent coated with DNA coding for gene products with anti-restenosis activity or cells containing such DNA.
  • that application did not disclose using a stent coated with particular small molecules capable of exercising anti- restenosis activity on SMCs.
  • a need has continued to exist for additional methods of preventing restenosis using a stent coated with a substance having anti-restenosis activity on the cells of a blood vessel that has been treated by an angioplastic procedure .
  • a stent implanted in the treated artery is coated with a composition incorporating a statin compound (or DNA or other vector containing DNA encoding a molecule with statin-like activity) .
  • the statin may be incorporated into a matrix which is supported by the coating on the stent structure.
  • a further object is to provide a stent for implantation into an artery after angioplasty that is coated with a composition comprising a a source of a statin compound capable of delivering high local concentrations of the statin.
  • a further object is to provide a stent for implantation into an artery after angioplasty that is coated with a composition comprising a very high percentage by weight of a statin compound.
  • Figure 1 illustrates an uncoated or bare stent of the type implanted in an artery after angioplasty to inhibit restenosis.
  • Figure 2 is a schematic illustration of the stent of Figure 1 coated with a composition containing a statin.
  • Figure 3 is a schematic illustration of an enlarged cross- section of a strut of the coated stent of Figure 2, taken along the line 3-3 in Figure 2.
  • Figure 4 is a schematic illustration of the stent of Figure 1 coated with a collagen gel that fills the areas between the struts and releasably contains a statin compound.
  • the invention comprises 1) a delivery system comprising a stent and a stent coating that is impregnated with a selected statin (or DNA or other vector containing DNA encoding a molecule with statin-like activity) , and, correspondingly, 2) contacting the arterial wall adjacent the stent with a high dosage of a statin (or DNA or other vector containing DNA encoding a molecule with statin-like activity) , thus inhibiting restenosis of the stent-treated artery.
  • the strategy described herein has the benefits of substantially reducing the incidence of restenosis with minimal incidence of untoward complications, a result that has not been achieved by other anti-restenosis strategies whose results have been limited or, as with radiation therapy, carry unknown future risks.
  • statin compounds useful in the method of the invention are natural and/or synthetic compounds that are known to have the physiological effect of lowering serum cholesterol levels in human patients.
  • the class of statin compounds is well-known to those skilled in the art. Such compounds are typically mevalonate derivatives that limit cholesterol biosynthesis by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) .
  • Statins useful in the method of the invention include, but are not limited to, lovastatin, pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, and the like. Other molecules having statin-like activity may also be used in the method and coated stent of the invention.
  • the invention includes a method of preventing restenosis using a stent coated with a source of a statin compund that provides a dose of a statin compund to the SMCs of the blood vessel wall, either directly, by releasing a statin to act on the SMCs, or indirectly, by causing cells of the vessel wall adjacent to the stent to produce a statin compound.
  • the delivery systems utilized in contacting the arterial wall with a composition including a statin may take several forms.
  • the delivery system comprises a stent covered by a composition including the selected statin, which adheres to the surface of the stent, thereby facilitating the delivery of the statin within the injured vessel wall, or to cells that are migrating from the media and/or adventitia to form the neointima.
  • the coating can be formed from any material that can cover the surface of the stent and that has the above characteristics.
  • One such candidate coating has been created by the Photolink process of the SurModics Company (Eden Prairie, MN) .
  • a statin is incorporated into the stent coating, which covers the stent struts but not intervening spaces.
  • the stent coating acts as a support scaffolding for the binding of collagen, or a similarly appropriate polymer, to the stent.
  • the collagen or polymer will provide a matrix for the statin that will allow complete coverage of the vessel wall. This interation of the invention would be particularly appropriate for vein grafts, which have no side branches. Hence, the complete coverage for the vessel wall will not result in side branch occlusion.
  • the completely covered stent will facilitate two important features of the invention. a. It will provide efficient contact between the statin and all of that part of the vessel in which the stent is deployed so that a greater percentage of the cells within the vessel wall will be in tight apposition to the statin. b. It will provide a collagen or polymer barrier to cells migrating from the media or adventitia on their way to form the expanding neointima.
  • Figure 1 illustrates the bare stent 100 without coating.
  • the stent comprises struts 102 having interstices or openings 104 between them.
  • Figure 2 illustrates the stent 100 with a coating 106 releasably incorporating a statin compound.
  • the coating 106 covers the metal struts 102 but not the intervening spaces 104.
  • Figure 3 is a greatly enlarged view of a cross-section of a portion of the stent 100 of Figure 2, taken along the line 3-3 in Figure 2, showing the coated strut 102 and coating 106.
  • Figure 4 illustrates the stent 100 of Figure 1 provided with a coating of collagen 110 releasably containing a statin compound.
  • the stent 100 serves as a scaffold for supporting the collagen gel 110 and statin compound incorporated into it.
  • the coating of the collagen gel 110 supported by the stent 100 covers not only the metal struts 102 (which cover only 15-20% of the arterial wall over which the stent extends) , but also the intervening spaces or interstices 104, providing total coverage of the arterial wall.
  • a statin (or DNA or other vector containing DNA encoding a molecule with statin-like activity) will be incorporated into a stent coating.
  • the stent coating will consist of a substance that adheres to the stent, and which will incorporate the statin molecule without damaging it . It is expected that the platform system will facilitate delivery of the molecule to the cells within the injured vessel wall (or to the cells that are migrating from the media and/or adventitia to form the neointima) , and is applied to the injured vessel wall at the time of angioplasty and stent implantation.
  • the invention can be performed in any artery or interposed vein (such as, but not limited to, a saphenous vein graft to a coronary artery) that is obstructed and thereby impairs blood flow to the target tissue (whether it be heart or leg) .
  • the invention will employ any coating that can be attached to a stent and that has the above characteristics, and any molecule related chemically or functionally to a statin or DNA or other vector containing DNA encoding a molecule with statin-like activity.
  • One such candidate coating has been created by the Photolink ® process of SurModics.
  • Oral formulations of many different statin molecules have been clinically tested; any of these, or those still being developed or that will be developed, are candidate molecules for this invention.
  • statin or DNA or other vector containing DNA encoding a molecule with statin-like activity
  • This will exert the desired therapeutic effects on the cells contained within the vessel wall, such as, but not limited to, inhibition of smooth muscle cell (SMC) proliferation or migration and induction of SMC apoptosis.
  • SMC smooth muscle cell
  • statins have antiproliferative effects on SMCs in acute vascular injury in nonatherosclerotic, normocholesterolemic rats and rabbits, and when administered orally to rats significantly reduce neointimal formation both after simple arterial injury and, importantly, after arterial stenting. This activity is completely reversed by simultaneous local administration of mevalonate which, as indicated above, supports a role of protein prenylation inhibition in these statin-induced actions.
  • statin therapy was associated with a significant reduction in repeat target vessel revascularization procedures during 6-month follow-up.
  • Minimal lumen diameter was significantly larger, late lumen loss was significantly less, and net gain significantly increased in patients receiving statin therapy.
  • Dichotomous angiographic restenosis (> 50%) rates were significantly lower, with 25% in the statin group compared with 38% in the no-statin group .
  • the replication of SMC replication is tightly regulated by cell cycle regulatory proteins including cyclin-dependent kinases (cdc2 and cdk2) , which move cells through the cell cycle, and cyclin-dependent kinase inhibitors (such as pl6, p21, and p27 lpl ) , which inhibit progression of cells through the cell cycle.
  • cyclin-dependent kinases cdc2 and cdk2
  • cyclin-dependent kinase inhibitors such as pl6, p21, and p27 lpl
  • the small GTPases The statins also exert molecular effects on cell-cycling proteins, but their effects are targeted to the small GTPases (ras, rho, etc) , which are upstream effectors of the cell cycle regulatory proteins .
  • Rho mediates cell cycle progression by down-regulating the expression of the cdk inhibitor p27 ⁇ pl / thereby leading to increased activity of cdk2 and hyperphosphorylation of Rb, which consequently causes release of E2F and E2F-mediated cell cycle progression.
  • Post translational isoprenylation of these small GTPases is critical to their function by leading to their translocation to the cell membrane.
  • statins competitively inhibit HMG-CoA reductase and thereby reduce cellular levels of mevalonate, precursor of the isoprenoids. Isoprenoids cause the prenylation of the small GTPases noted above. HMG-CoA reductase inhibitors decrease rho geranylgeranylation and membrane translocalization, thereby preventing down-regulation of p27 kxpl expression, which leads to increased activity of cdk2 and hyperphosphorylation of Rb. This consequently inhibits release of E2F and E2F-mediated cell cycle progression, thereby inhibiting SMC proliferation.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Optics & Photonics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Vascular Medicine (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Physics & Mathematics (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Materials For Medical Uses (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Prostheses (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Media Introduction/Drainage Providing Device (AREA)
EP02728802A 2001-04-27 2002-04-18 Freisetzung von statinen mithilfe eines stents zur verhinderung von restenose Withdrawn EP1383447A4 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US28651901P 2001-04-27 2001-04-27
US286519P 2001-04-27
PCT/US2002/012120 WO2002087472A1 (en) 2001-04-27 2002-04-18 Stent-based delivery of statins to prevent restenosis

Publications (2)

Publication Number Publication Date
EP1383447A1 EP1383447A1 (de) 2004-01-28
EP1383447A4 true EP1383447A4 (de) 2007-04-04

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EP (1) EP1383447A4 (de)
JP (1) JP2004533293A (de)
CA (1) CA2445524A1 (de)
WO (1) WO2002087472A1 (de)

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US8236048B2 (en) * 2000-05-12 2012-08-07 Cordis Corporation Drug/drug delivery systems for the prevention and treatment of vascular disease
US7572288B2 (en) 2001-07-20 2009-08-11 Microvention, Inc. Aneurysm treatment device and method of use
US8715312B2 (en) 2001-07-20 2014-05-06 Microvention, Inc. Aneurysm treatment device and method of use
US8252040B2 (en) 2001-07-20 2012-08-28 Microvention, Inc. Aneurysm treatment device and method of use
ES2207407B1 (es) * 2002-11-05 2005-03-16 Iberhospitex, S.A. Stent recubierto con estatinas para la administracion a un paciente.
WO2005037338A1 (en) * 2003-10-14 2005-04-28 Cook Incorporated Hydrophilic coated medical device
EP1591133A1 (de) * 2004-04-30 2005-11-02 Synthes Biologisch aktive Implantate
EP2162101B1 (de) 2007-06-25 2019-02-20 MicroVention, Inc. Selbstexpandierende prothese
EP2707077B1 (de) 2011-05-11 2017-10-04 Microvention, Inc. Vorrichtung zum verschliessen eines lumens
WO2014154804A1 (en) * 2013-03-27 2014-10-02 Centre Hospitalier Universitaire Vaudois (C.H.U.V) Pharmaceutical formulation for use in the treatment and/or prevention of restenosis

Citations (2)

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CA2445524A1 (en) 2002-11-07
EP1383447A1 (de) 2004-01-28
WO2002087472A8 (en) 2003-02-27
JP2004533293A (ja) 2004-11-04

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