EP1735026A1 - Vegf receptor tyrosine kinase inhibitor coated stent - Google Patents
Vegf receptor tyrosine kinase inhibitor coated stentInfo
- Publication number
- EP1735026A1 EP1735026A1 EP05716501A EP05716501A EP1735026A1 EP 1735026 A1 EP1735026 A1 EP 1735026A1 EP 05716501 A EP05716501 A EP 05716501A EP 05716501 A EP05716501 A EP 05716501A EP 1735026 A1 EP1735026 A1 EP 1735026A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- stent
- tyrosine kinase
- receptor tyrosine
- kinase inhibitor
- delivery
- 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- Withdrawn
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
-
- 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
- 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
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
- A61L29/16—Biologically active materials, e.g. therapeutic substances
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/432—Inhibitors, antagonists
- A61L2300/434—Inhibitors, antagonists of enzymes
Definitions
- the present invention relates to drug delivery systems for the prevention and treatment of proliferative diseases, particularly vascular diseases.
- Re-narrowing (restenosis) of an artherosclerotic coronary artery after various revascularization procedures occurs in 10-80% of patients undergoing this treatment, depending on the procedure used and the aterial site.
- revascularization also injures endothelial cells and smooth muscle cells within the vessel wall, thus initiating a thrombotic and inflammatory response.
- Cell derived growth factors such as platelet derived growth factor, infiltrating macrophages, leukocytes or the smooth muscle cells themselves provoke proliferative and migratory responses in the smooth muscle cells.
- inflammatory cells also invade the site of vascular injury and may migrate to the deeper layers of the vessel wall. Proliferation/migration usually begins within one to two days post-injury and, depending on the revascularization procedure used, continues for days and weeks.
- the newly formed tissue is called neointima, intimal thickening or restenotic lesion and usually results in narrowing of the vessel lumen. Further lumen narrowing may take place due to constructive remodeling, e.g. vascular remodeling, leading to further intimal thickening or hyperplasia.
- vascular injury including e.g. surgical injury, e.g. revascularization-induced injury, e.g. also in heart or other grafts.
- VEGF vascular endothelial growth factor receptor tyrosine kinase
- VEGF receptor tyrosine kinase inhibitors especially the compounds of formula I as defined herein and, in particular, PTK787, optionally in conjunction with other active compounds, e.g. antiproliferative compounds, have beneficial effects when locally applied to the lesions sites.
- the invention relates to a method of treating for preventing and treating intimal thickening or restenosis that occurs after injury, e.g. vascular injury, including e.g. surgical injury, e.g. revascularization-induced injury, e.g. also in heart or other grafts, comprising administering a therapeutically effective amount of a VEGF receptor tyrosine kinase inhibitor to a warm-blooded animal in need thereof.
- injury e.g. vascular injury
- surgical injury e.g. revascularization-induced injury
- a warm-blooded animal e.g. also in heart or other grafts
- the VEGF receptor tyrosine kinase inhibitor employed in the present invention can, in particular, be selected from a compound or antibody which inhibits the VEGF receptor tyrosine kinase or a VEGF receptor or a compound which binds to VEGF, e.g. proteins, small molecules or monoclonal antibodies generically and specifically disclosed in WO 98/35958, e.g.
- the invention relates to a method of treating for preventing and treating intimal thickening or restenosis that occurs after injury, e.g. vascular injury, including e.g. surgical injury, e.g. revascularization-induced injury, e.g. also in heart or other grafts, comprising administering a therapeutically effective amount of a compound of formula I
- Ri and R 2 are lower alkyl or (ii) together form a bridge in subformula I * the binding being achieved via the two terminal carbon atoms, or (iii) together form a bridge in subformula I* *
- ⁇ ⁇ 2 (I-) ⁇ 4 ⁇ s
- one or two of the ring members T ⁇ T 2 , T 3 and T are nitrogen, and the others are in each case CH, and the binding is achieved via Ti and T 4 ;
- A, B, D, and E are, independently of one another, N or CH, with the stipulation that not more than 2 of these radicals are N;
- G is lower alkylene, lower alkylene substituted by acyloxy or hydroxy, -CH 2 -O-, -CH 2 -S-, -CH 2 -NH-, oxa (-O-), thia (-S-), or imino (-NH-);
- Q is lower alkyl;
- R is H or lower alkyl;
- X is imino, oxa, or thia;
- Y is unsubstituted or substituted aryl, pyridyl, or unsubstituted or substituted cycloalky
- a preferred compound of formula I is PTK787.
- PTK787 means a compound of formula I wherein r, n and m are each 0, R 1 and R 2 together form a bridge of subformula I * , A, B, D and E are each CH, G is methylene, X is imino, Y is 4-chlorophenyl, and the bonds characterized by a wavy line are double bonds.
- the VEGF receptor tyrosine kinase inhibitor may be applied as the sole active ingredient or in conjunction with an immunosuppressive agent, e.g. a calcineurin inhibitor, e.g. a cyclosporin, for example cyclosporin A, or FK506, an EDG- Receptor agonist, e.g. FTY720, an anti-inflammatory agent, e.g. a steroid, e.g. a corticosteroid, e.g. dexamethasone or prednisone, a NSAID, e.g. a cyclooxygenase inhibitor, e.g. a COX-2 inhibitor, e.g.
- an immunosuppressive agent e.g. a calcineurin inhibitor, e.g. a cyclosporin, for example cyclosporin A, or FK506, an EDG- Receptor agonist, e.g. FTY720, an anti-
- vinblastine especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine
- discodermolides or epothilones or a derivative thereof e.g. epothilone B or a derivative thereof, a tyrosine kinase inhibitor which is not an nhibito of VEGF, e.g. staurosporin and related small molecules, e.g.
- HMG-CoA reductase inhibition activity e.g. fluva- statin, lovastatin, simvastatin, pravastatin, atorvastatin, cerivastatin, pitavastatin, rosuvastatin or nivastatin, a compound, protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium, e.g. FGF, IGF, a matrix metalloproteinase inhibitor, e.g. batimistat, marimistat, trocade, CGS 27023, RS 130830 or AG3340, a modulator (i.e. antagonists or agonists) of kinases, e.g.
- a modulator i.e. antagonists or agonists
- JNK, ERK1/2, MAPK or STAT or a compound stimulating the release of (NO) or a NO donor, e.g. diazeniumdiolates, S-nitrosothiols, mesoionic oxatriazoles, a combination of isosorbide.
- NO NO
- a NO donor e.g. diazeniumdiolates, S-nitrosothiols, mesoionic oxatriazoles, a combination of isosorbide.
- the present invention also provides the local administration or delivery of a VEGF receptor tyrosine kinase inhibitor in conjunction with a calcineurin inhibitor, e.g. as disclosed above, an EDG-Receptor agonist, e.g. as disclosed above, a microtubule stabilizing or destabilizing agent, e.g. as disclosed above, a compound or antibody which inhibits the PDGF receptor tyrosine kinase or a compound which binds to PDGF or reduces expression of the PDGF receptor, e.g.
- a compound or antibody which inhibits the EGF receptor tyrosine kinase or a compound which binds to EGF or reduces expression of the EGF receptor e.g. as disclosed above
- a statin e.g. as disclosed above
- a compound, protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium e.g. as disclosed above
- a matrix rnetalloproteinase inhibitor e.g. as disclosed above
- an inhibitor of a modulator (i.e. antagonists or agonists) of kinases e.g. as disclosed above
- a compound stimulating the release of (NO) or a NO donor e.g. as disclosed above.
- a method for preventing or treating smooth muscle cell proliferation and migration in hollow tubes, or increased cell proliferation or decreased apoptosis or increased matrix deposition in a mammal in need thereof comprising local administration of a therapeutically effective amount of a VEGF receptor tyrosine kinase inhibitor, optionally in conjunction with one or more other active ingredients, e.g. as disclosed above.
- a method for the treatment of intimal thickening in vessel walls comprising the controlled delivery from any catheter-based device or intraluminal medical device of a therapeutically effective amount of a VEGF receptor tyrosine kinase inhibitor, optionally in conjunction with one or more other active ingredients, e.g. as disclosed above.
- the disease to be treated is stenosis, restenosis, e.g. following revascularization or neovascularization, and/or inflammation and/or thrombosis.
- a drug delivery device or system comprising a) a medical device adapted for local application or administration in hollow tubes, e.g. a catheter-based delivery device or intraluminal medical device, and b) a therapeutic dosage of a VEGF receptor tyrosine kinase inhibitor, optionally in conjunction with a therapeutic dosage of one or more other active ingredients, e.g. as disclosed above, each being releasably affixed to the catheter- based delivery device or medical device.
- a medical device adapted for local application or administration in hollow tubes, e.g. a catheter-based delivery device or intraluminal medical device
- a therapeutic dosage of a VEGF receptor tyrosine kinase inhibitor optionally in conjunction with a therapeutic dosage of one or more other active ingredients, e.g. as disclosed above, each being releasably affixed to the catheter- based delivery device or medical device.
- Such a local delivery device or system can be used to reduce stenosis or restenosis as an adjunct to revascularization, bypass or grafting procedures performed in any vascular location including coronary arteries, carotid arteries, renal arteries, peripheral arteries, cerebral arteries or any other arterial or venous location, to reduce anastomic stenosis such as in the case of arterial-venous dialysis access with or without polytetrafluoro- ethylene grafting and with or without stenting, or in in conjunction with any other heart or transplantation procedures, or congenital vascular interventions.
- a VEGF receptor tyrosine kinase inhibitor will be referred to hereinafter as "drug”.
- drug The other active ingredients which may be used in conjunction with the VEGF receptor tyrosine kinase inhibitor, e.g. as disclosed above, will be referred to hereinafter collectively as "adjunct”.
- Drug(s) shall mean drug or drug plus adjunct.
- the local administration preferably takes place at or near the vascular lesions sites.
- the administration may be by one or more of the following routes: via catheter or other intravascular delivery system, intranasally, intrabronchially, interperitoneally or eosophagal.
- Hollow tubes include circulatory system vessels such as blood vessels (arteries or veins), tissue lumen, lymphatic pathways, digestive tract including alimentary canal, respiratory tract, excretory system tubes, reproductive system tubes and ducts, body cavity tubes, etc.
- Local administration or application of the drug(s) affords concentrated delivery of said drug(s), achieving tissue levels in target tissues not otherwise obtainable through other administration route.
- Means for local drug(s) delivery to hollow tubes can be by physical delivery of the drug(s) either internally or externally to the hollow tube.
- Local drug(s) delivery includes catheter delivery systems, local injection devices or systems or indwelling devices. Such devices or systems would include, but not be limited to, stents, coated stents, endolumenal sleeves, stent-grafts, liposomes, controlled release matrices, polymeric endoluminal paving, or other endovascular devices, embolic delivery particles, cell targeting such as affinity based delivery, internal patches around the hollow tube, external patches around the hollow tube, hollow tube cuff, external paving, external stent sleeves, and the like. See, Eccleston et al.
- biocompatible a material which elicits no or minimal negative tissue reaction including e.g. thrombus formation and/or inflammation. Delivery or application of the drug(s) can occur using stents or sleeves or sheathes.
- An intraluminal stent composed of or coated with a polymer or other biocompatible materials, e.g. porous ceramic, e.g. nanoporous ceramic, into which the drug(s) has been impregnated or incorporated can be used.
- Such stents can be biodegradable or can be made of metal or alloy, e.g. Ni and Ti, or another stable substance when intented for permanent use.
- the drug(s) may also be entrapped into the metal of the stent or graft body which has been modified to contain micropores or channels. Also lumenal and/or ablumenal coating or external sleeve made of polymer or other biocompatible materials, e.g. as disclosed above, that contain the drug(s) can also be used for local delivery.
- Stents are commonly used as a tubular structure left inside the lumen of a duct to relieve an obstruction. They may be inserted into the duct lumen in a non-expanded form and are then expanded autonomously (self-expanding stents) or with the aid of a second device in situ, e.g. a catheter-mounted angioplasty balloon which is inflated within the stenose vessel or body passageway in order to shear and disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen.
- a catheter-mounted angioplasty balloon which is inflated within the stenose vessel or body passageway in order to shear and disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen.
- the drug(s) may be incorporated into or affixed to the stent in a number of ways and utilizing any biocompatible materials; it may be incorporated into e.g. a polymer or a polymeric matrix and sprayed onto the outer surface of the stent.
- a mixture of the drug(s) and the polymeric material may be prepared in a solvent or a mixture of solvents and applied to the surfaces of the stents also by dip-coating, brush coating and/or dip/spin coating, the solvent (s) being allowed to evaporate to leave a film with entrapped drug(s).
- a solution of a polymer may additionally be applied as an outlayer to control the drug(s) release; alternatively, the drug may be comprised in the micropores, struts or channels and the adjunct may be incorporated in the outlayer, or vice versa.
- the drug may also be affixed in an inner layer of the stent and the adjunct in an outer layer, or vice versa.
- the drug(s) may also be attached by a covalent bond, e.g. esters, amides or anhydrides, to the stent surface, involving chemical derivatization.
- the drug(s) may also be incorporated into a biocompatible porous ceramic coating, e.g. a nanoporous ceramic coating.
- polymeric materials include biocompatible degradable materials, e.g. lactone- based polyesters or copolyesters, e.g. polylactide; polylactide-glycolide; polycaprolactone- glycolide; polyorthoesters; polyanhydrides; polyaminoacids; polysaccharides; polyphospha- zenes; poly(ether-ester) copolymers, e.g. PEO-PLLA, or mixtures thereof; and biocompatible non-degrading materials, e.g. polydimethylsiloxane; poly(ethylene-vinylacetate); acrylate based polymers or coplymers, e.g. polybutylmethacrylate, poly(hydroxyethyl methyl- methacrylate); polyvinyl pyrrolidinone; fluorinated polymers such as polytetrafluoethylene; cellulose esters.
- biocompatible degradable materials e.g. lactone- based polyesters or copo
- a polymeric matrix When a polymeric matrix is used, it may comprise 2 layers, e.g. a base layer in which the drug(s) is/are incorporated, e.g. ethylene-co-vinylacetate and polybutylmethacrylate, and a top coat, e.g. polybutylmethacrylate, which is drug(s)-free and acts as a diffusion-control of the drug(s).
- the drug may be comprised in the base layer and the adjunct may be incorporated in the outlayer, or vice versa.
- Total thickness of the polymeric matrix may be from about 1 to 20 ⁇ or greater.
- the drug(s) may elute passively, actively or under activation, e.g. light-activation.
- the drug(s) elutes from the polymeric material or the stent over time and enters the surrounding tissue, e.g. up to ca. 1 month to 1 year.
- the local delivery according to the present invention allows for high concentration of the drug(s) at the disease site with low concentration of circulating compound.
- the amount of drug(s) used for local delivery applications will vary depending on the compounds used, the condition to be treated and the desired effect.
- a therapeutically effective amount will be administered.
- therapeutically effective amount is intended an amount sufficient to inhi it cellular proliferation and resulting in the prevention and treatment of the disease state.
- local delivery may require less compound than systemic administration.
- Rats are dosed orally with placebo or a VEGF receptor tyrosine kinase inhibitor, e.g. a compound of formula I, e.g. PTK787.
- Daily dosing starts 3 days prior to surgery and continues for 31 days.
- Rat carotid arteries are balloon injured using a method described by Clowes et al. Lab. Invest. 1983;49; 208-215.
- carotid arteries are removed and processed for histologic and morphometric evaluation. In this assay the ability of the compounds of formula I can be demonstrated to significantly reduce neointimal lesion formation following balloon injury.
- a combined angioplasty and stenting procedure is performed in New Zealand White rabbit iliac arteries.
- Iliac artery balloon injury is performed by inflating a 3.0 x 9.0 mm angioplasty balloon in the mid-portion of the artery followed by "pull-back" of the catheter for 1 balloon length.
- Balloon injury is repeated 2 times, and a 3.0 x 12 mm stent is deployed at 6 atm for 30 seconds in the iliac artery. Balloon injury and stent placement is then performed on the contralateral iliac artery in the same manner.
- a post-stent deployment angiogram is performed. All animals receive oral aspirin 40 mg/day daily as anti-platelet therapy and are fed standard low-cholesterol rabbit chow.
- mice Twenty-eight days after stenting, animals are anesthetized and euthanized and the arterial tree is perfused at 100 mmHg with lactated Ringer's for several minutes, then perfused with 10% formalin at 100 mmHg for 15 minutes.
- the vascular section between the distal aorta and the proximal femoral arteries is excised and cleaned of periadventitial tissue.
- the stented section of artery is embedded in plastic and sections are taken from the proximal, middle, and distal portions of each stent. All sections are stained with hematoxylin-eosin and Movat pentachrome stains.
- Computerized planimetry is performed to determine the area of the internal elastic lamina (IEL), external elastic lamina (EEL) and lumen.
- the neointima and neointimal thickness is measured both at and between the stent struts.
- the vessel area is measured as the area within the EEL.
- Data are expressed as mean + SEM.
- Statistical analysis of the histologic data is accomplished using analysis of variance (ANOVA) due to the fact that two stented arteries are measured per animal with a mean generated per animal. A P ⁇ 0.05 is considered statistically significant.
- PTK787 is administered orally by gavage at an initial dose one day prior to stenting, then dosed at 50 % of the initial dose from the day of stenting until day 27 post-stenting.
- this model a marked reduction in the extent of restenotic lesion formation in the presence of PTK787 can be shown, whereas there is extensive neointimal formation in placebo-treated animals at 28 days, with the lesions consisting of abundant smooth muscle cells in proteoglycan/collagen matrix and apparent full endothelial healing.
- a stent is weighed and then mounted for coating. While the stent is rotating, a solution of polylactide glycolide, 0.75 mg/ml of PTK787 and 0.0015 mg/ml 2,6-di-tert.-butyl-4- methylphenol dissolved in a mixture of methanol and tetrahydrofuran, is sprayed onto it. The coated stent is removed from the spray and allowed to air-dry. After a final weighing the amount of coating on the stent is determined.
- PBS phosphate buffer solution
- PEG polyethylene glycol
- the stent pieces are incubated at 37° C. in a shaker.
- the buffer and PEG solutions are changed daily and different assays are performed on the solution to determine the released PTK787 concentrations.
- stable PTK787 release means that less than 10% of variation of the drug release rate is observed.
- PTK787 in plasma can also be studied. 1 cm pieces of a coated stent are put into 1 mL of citrated human plasma (from Helena Labs.) in lyophilized form and reconstituted by adding 1 mL of sterile deionized water. Three sets of stent plasma solutions are incubated at 37° C and the plasma is changed daily. Different assays are performed on the solution to determine the released PTK787 concentrations. By such method a stable PTK787 release from coated stents in plasma can be demonstrated. The term "stable PTK787 release” means that less than 10% of variation of the drug release rate is observed.
- PDGF-stimulated receptor tyrosine kinase assay can be performed on the last piece of each sample to determine the PTK787 activity. A similar test can be performed with free PTK787.
- the inhibition of PDGF-stimulated receptor tyrosine kinase activity in vitro can be measured in PDGF receptor immunocomplexes of BALB/c 3T3 cells, analogously to the method described by E. Andrejauskas-Buchdunger and U. Regenass in Cancer Research 52, 5353- 5358 (1992). By such approach the stability of free PTK787 and PTK787 in polymer coatings can be compared.
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US55915004P | 2004-04-02 | 2004-04-02 | |
PCT/EP2005/003459 WO2005094916A1 (en) | 2004-04-02 | 2005-04-01 | Vegf receptor tyrosine kinase inhibitor coated stent |
Publications (1)
Publication Number | Publication Date |
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EP1735026A1 true EP1735026A1 (en) | 2006-12-27 |
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ID=34962708
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP05716501A Withdrawn EP1735026A1 (en) | 2004-04-02 | 2005-04-01 | Vegf receptor tyrosine kinase inhibitor coated stent |
Country Status (8)
Country | Link |
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EP (1) | EP1735026A1 (ja) |
JP (1) | JP2007530633A (ja) |
KR (1) | KR20070004795A (ja) |
CN (1) | CN1929882A (ja) |
AU (1) | AU2005229566A1 (ja) |
BR (1) | BRPI0509566A (ja) |
CA (1) | CA2559756A1 (ja) |
WO (1) | WO2005094916A1 (ja) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
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US8057815B2 (en) * | 2004-04-19 | 2011-11-15 | Portola Pharmaceuticals, Inc. | Methods of treatment with Syk inhibitors |
CA2662383C (en) * | 2006-09-26 | 2017-02-21 | Novartis Ag | Coated pharmaceutical compositions comprising an s1p modulator |
EP2234798B1 (en) * | 2008-01-23 | 2012-03-28 | Novartis AG | Method for coating silicone hydrogels |
US20110150862A1 (en) * | 2008-04-09 | 2011-06-23 | Hulot Jean-Sebastien | Inhibitors of stim1 for the treatment of cardiovascular disorders |
EP2525806B1 (en) | 2010-01-20 | 2014-06-04 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Angiopoietin-like-protein-4 (ANGPTL4) for the preservation of vascular endothelial-cell barrier integrity |
WO2012110843A1 (en) | 2011-02-18 | 2012-08-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for promoting fibrinolysis and thrombolysis |
EP2741777B1 (en) | 2011-08-12 | 2017-01-18 | INSERM - Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical compositions for treatment of pulmonary hypertension |
WO2013050441A1 (en) | 2011-10-05 | 2013-04-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical composition for inhibiting or preventing platelet aggregation |
US20140328893A1 (en) | 2011-10-11 | 2014-11-06 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Nutlin compounds for use in the treatment of pulmonary hypertension |
EP2830643A1 (en) | 2012-03-26 | 2015-02-04 | INSERM - Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical compositions for prevention or treatment of ischemia related organ damage |
ES2667814T3 (es) | 2013-01-14 | 2018-05-14 | Institut National De La Santé Et De La Recherche Médicale (Inserm) | Composiciones farmacéuticas para la cardioprotección |
TWI482757B (zh) * | 2013-10-07 | 2015-05-01 | Luminescence Technology Corp | Vegf-2/3受體及蛋白質酪胺酸激酶抑制劑及其醫藥用途 |
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US20050125054A1 (en) * | 2000-12-22 | 2005-06-09 | Avantec Vascular Corporation | Devices delivering therapeutic agents and methods regarding the same |
EP1471853B1 (en) * | 2002-02-06 | 2017-03-22 | OrbusNeich Medical, Inc. | Medical device with coating that promotes endothelial cell adherence and differentiation |
AU2003261100A1 (en) * | 2002-07-25 | 2004-02-16 | Avantec Vascular Corporation | Devices delivering therapeutic agents and methods regarding the same |
MXPA06003164A (es) * | 2003-09-23 | 2006-06-05 | Novartis Ag | Combinaciones de un inhibidor del receptor de vegf con otros agentes terapeuticos. |
-
2005
- 2005-04-01 JP JP2007505513A patent/JP2007530633A/ja active Pending
- 2005-04-01 WO PCT/EP2005/003459 patent/WO2005094916A1/en not_active Application Discontinuation
- 2005-04-01 EP EP05716501A patent/EP1735026A1/en not_active Withdrawn
- 2005-04-01 BR BRPI0509566-2A patent/BRPI0509566A/pt not_active Application Discontinuation
- 2005-04-01 KR KR1020067020310A patent/KR20070004795A/ko not_active Application Discontinuation
- 2005-04-01 CN CNA2005800075100A patent/CN1929882A/zh active Pending
- 2005-04-01 CA CA002559756A patent/CA2559756A1/en not_active Abandoned
- 2005-04-01 AU AU2005229566A patent/AU2005229566A1/en not_active Abandoned
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See also references of WO2005094916A1 * |
Also Published As
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AU2005229566A1 (en) | 2005-10-13 |
KR20070004795A (ko) | 2007-01-09 |
CN1929882A (zh) | 2007-03-14 |
WO2005094916A1 (en) | 2005-10-13 |
CA2559756A1 (en) | 2005-10-13 |
BRPI0509566A (pt) | 2007-09-25 |
JP2007530633A (ja) | 2007-11-01 |
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