WO1998030255A2 - Localized intravascular delivery of antioxidant substances for inhibition of restenosis in recanalized blood vessels - Google Patents
Localized intravascular delivery of antioxidant substances for inhibition of restenosis in recanalized blood vessels Download PDFInfo
- Publication number
- WO1998030255A2 WO1998030255A2 PCT/US1998/000491 US9800491W WO9830255A2 WO 1998030255 A2 WO1998030255 A2 WO 1998030255A2 US 9800491 W US9800491 W US 9800491W WO 9830255 A2 WO9830255 A2 WO 9830255A2
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- WO
- WIPO (PCT)
- Prior art keywords
- catheter
- antioxidant
- blood vessel
- distal end
- infusion
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
- A61K38/063—Glutathione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
- A61K38/446—Superoxide dismutase (1.15)
-
- 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
- A61M25/10—Balloon catheters
- A61M25/104—Balloon catheters used for angioplasty
Definitions
- the present invention relates generally to methods for inhibiting restenosis in a blood vessel which may occur after an initial treatment for opening a stenotic region in the blood vessel. More particularly, the present invention relates to methods for the localized delivery of antioxidant substances for inhibition of localized intimal hyperplasia following balloon angioplasty and other interventional treatments.
- Percutaneous transluminal angioplasty (PTA) procedures are widely used for treating stenotic atherosclerotic regions of a patient ' s vasculature to restore adequate blood flow.
- the catheter having an expansible distal end usually in the form of an inflatable balloon, is positioned in the blood vessel at the stenotic site. The expansible end is expanded to dilate the vessel to restore adequate blood flow beyond the diseased region.
- the present invention is particularly concerned with methods for inhibiting restenosis which occurs as a result of intimal hyperplasia (excessive proliferation of the vessel intima) following balloon angioplasty and other anti-stenotic treatment protocols, such as atherectomy, laser angioplasty, stent placement, and the like.
- Restenosis refers to the re- narrowing of an artery within weeks or months following an initially successful angioplasty or other primary treatment. Restenosis afflicts approximately up to 50% of all angioplasty patients and results at least in part from smooth muscle cell proliferation and migration. The biologic events initiating this smooth muscle cell activity are believed to be in part due to thrombin directly as well as indirectly through release products from platelets which have been recruited by thrombin. Patients suffering from restenosis will typically require further treatment .
- Pharmacologic treatment can be achieved either systemically or via localized intramural drug delivery. While systemic delivery is particularly easy to administer to the patient, it suffers from a number of disadvantages, including: 1) serious complications due to the activity of the agent at sites distant to the site of interest, 2) a large amount of agent is required to achieve therapeutic concentrations throughout the agent's volume of distribution, and 3) exposure of the agent to degradation and elimination by distant organ system.
- the localized delivery of drugs limits the total drug dosage required and provides site-specific activity where the drug has a much higher local concentration than is possible with systemic delivery.
- Systemic and localized intravascular delivery of a variety of drugs have been proposed for the inhibition of restenosis following angioplasty and other primary intravascular treatments .
- Probucol is a well-characterized antioxidant drug which has been utilized by the treatment of atherosclerosis. See, for example Jackson et al . , "Probucol and its mechanisms for reducing atherosclerosis," in: Malmendier et al . , eds . Hyperchol es terol emia, Hypochol esterol emia,
- a preferred infusion catheter for delivering antioxidant substance in accordance with the methods of the present invention is described in copending application serial no. 08/473,800, assigned to the assignee of the present invention, filed on June 7, 1995, the full disclosure of which is incorporated herein by reference.
- This copending application teaches that the catheter may be used for the intravascular delivery of anti-restenotic, anti-proliferative, thrombolytic, fibrinolytic, and other agents useful in connection with angioplasty treatment in a patient ' s coronary vasculature .
- the intramural delivery of tissue factor pathway inhibitor for the inhibition of restenosis is described in copending application Serial No. 08/546,873, filed on October 23, 1995, naming Aaron Kaplan as the sole inventor and assigned to the assignee of the present application.
- the intramural delivery of vascular endothelial growth factor and other growth factors is described in copending application Serial No. (Attorney Docket No. 15509-003110) , filed on November 22, 1996, naming Aaron Kaplan as an inventor and assigned to the assignee of the present application.
- SUMMARY OF THE INVENTION The present invention provides methods for inhibiting restenosis which may result from intimal hyperplasia or other mechanisms in recanalized blood vessels.
- the methods comprise intramurally delivering an antioxidant substance to a target site within the blood vessel, either before, after, or during the recanalization procedure.
- restenosis is defined as the recurrence of stenosis weeks or months after a corrective procedure has been performed at a target site within a patient's vasculature. Restenosis occurs in part as a result of intimal hyperplasia including smooth muscle cell proliferation and migration.
- the intramural delivery of antioxidant substances according to the present invention will inhibit restenosis. In particular, it is believed that the intramural delivery of anti-oxidants will reduce oxidative stress which initiates events which lead to restenosis.
- recanalized is defined as the condition of the blood vessel after an initial corrective procedure has been performed to at least partially cure the stenotic condition.
- the "recanalized blood vessel” may be any blood vessel in the patient's vasculature, including veins, arteries, and particularly including coronary arteries, and prior to performing the initial corrective procedure, the blood vessel could have been partially or totally occluded at the target site.
- the corrective procedure will comprise an intravascular procedure, such as balloon angioplasty, atherectomy, stenting laser angioplasty, or the like, where the lumen of the treated blood vessel is enlarged to at least partially reverse a stenotic condition which existed prior to the treatment.
- the corrective procedure could involve coronary artery bypass, vascular graft implantation, endarterectomy, or the like.
- intramural delivery is defined as localized delivery of the antioxidant substance into the blood vessel wall, including the neointimal, intimal, medial, adventitial and perivascular spaces, adjacent to the target site. Such intramural delivery will typically be effected using an intravascular catheter, as described in greater detail below, but could also be achieved by the implantation of vascular implants capable of releasing a the antioxidant substance over time.
- antioxidant substance is defined to include a wide variety of antioxidant drugs which reduce oxidative stress when administered intramurally to a recanalized blood vessel. Preferred antioxidant substances will be small molecule drugs, typically having a molecular weight below 2,000D, usually being below 1500D, and more usually being below 1,000D.
- antioxidant substances according to the present invention include probucol, vitamin C, vitamin E, ⁇ -carotene, super oxide dismutase (SOD) , Mn-SOD, polyethylene glycol-SOD, tirilazad, 1-banduronic acid and other biophosphonates, melatonin, a- tocopherol, thyme oil, procysteine (available from Transcend Pharmaceutical Company) , glutathione, and notrone-related compounds.
- SOD super oxide dismutase
- Mn-SOD polyethylene glycol-SOD
- tirilazad 1-banduronic acid and other biophosphonates
- melatonin melatonin
- a- tocopherol thyme oil
- procysteine available from Transcend Pharmaceutical Company
- glutathione glutathione-related compounds.
- probucol Presently preferred is the use of probucol.
- the antioxidant substances can be formulated in a variety of conventional ways, including solutions, suspensions, gels, and the like. In some cases, it will be desirable to incorporate the antioxidants in time release compositions or structures. Usually, the antioxidant substances will be in a form suitable for delivery through a catheter. Alternatively, they may be incorporated into stents or other implantable, often erodible, structures.
- the method for inhibiting restenosis in a recanalized blood vessel comprises advancing a distal end of the catheter to the target site within the recanalized blood vessel.
- An amount of the antioxidant substance sufficient to inhibit intimal hyperplasia at said site is then delivered through the distal end of the catheter, either before, during, or after the recanalization procedure.
- the catheter is introduced percutaneously to the patient's vasculature and advanced transluminally to the target site.
- the antioxidant substance is then delivered from a proximal end of the catheter, through a lumen in the catheter body, and to the distal end from where it is released into the blood vessel wall.
- the distal end of the catheter is expanded to engage infusion ports therein against the blood vessel wall to enhance intraluminal penetration.
- the method for inhibiting restenosis in a recanalized blood vessel comprises advancing the distal end of an infusion catheter to a target site within the blood vessel, either before, during or after recanalization.
- the distal end of the infusion catheter is expanded to engage infusion ports therein against the luminal wall of the blood vessel, preferably by positioning a balloon within the distal end of the infusion catheter and inflating the balloon to a predetermined inflation pressure.
- a method for recanalizing a blood vessel comprises enlarging the blood vessel lumen at the target stenotic site. The distal end of an infusion catheter is advanced to the target site either before or closely following the enlarging step and an amount of the antioxidant substance sufficient to inhibit intimal hyperplasia or other cause of restenosis is then delivered through the distal end of the infusion catheter into the blood vessel wall .
- the enlarging step may comprise any conventional intravascular corrective procedure, such as balloon angioplasty, atherectomy, laser angioplasty, stent placement, endarterectomy and the like.
- the antioxidant substance may be delivered to the target site as a bolus, but will more usually be delivered in a continuous or discontinuous stream over an extended time period.
- the total amount of antioxidant substance delivered to the target site is typically in the range from 0.1 ⁇ g/kg to 10 mg/kg, more typically from 0.1 ⁇ g/kg to 1 mg/kg (body weight) .
- the time period of delivery When delivered continuously, the time period of delivery will usually be in the range from 0.1 minute to 360 minutes, more usually being from 15 seconds to 5 minutes, although delivery times more than three minutes may require a delivery system that provides for blood perfusion to the distal vasculature.
- the time of delivery can be extended to one day to 50 weeks, or longer, when controlled release implanted devices, such as stents, endoluminal paving delivery, or timer release particles are employed.
- FIG. 1 is a side view of a sleeve catheter incorporating drug delivery lumens useful in performing the methods of the present invention.
- Figs. 2-6 are cross-sectional views taken along lines 2-6 in Fig. 1, respectively.
- Figs. 7-9 illustrate the use of a balloon catheter to expand the distal end of the catheter of Figs. 1-6.
- Figs. 10A and 10B are cross-sectional views of the distal region of the catheter of Fig. 1 shown in its non- expanded (Fig. 10A) and expanded (Fig. 10B) configurations.
- Fig. 11 illustrates the use of the catheter of
- Fig. 1 to deliver a antioxidant substance to a coronary artery in combination with an angioplasty balloon catheter in accordance with the method of the present invention.
- Fig. 13 is an alternative cross-sectional view similar to Fig. 12.
- Intramural deliver of antioxidant substances according to the methods of the present invention may be accomplished using any of a variety of known intravascular drug delivery systems. Most commonly, the antioxidant substance will be delivered using intravascular catheter delivery systems as described in greater detail below. In some cases, however, it may be advantageous to employ implanted devices, such as implanted stents capable of delivering the antioxidant substance for prolonged periods of time. See, for example, U.S. Patent No. 5,342,348 and EP 604 022, which describe stent apparatus capable of releasing a variety of drugs over time. Such stent apparatus would be suitable for intramural delivery of antioxidant substances according to the method of the present invention.
- Catheters having spaced-apart or helical balloons for expansion within the lumen of a blood vessel and delivery of a therapeutic agent to the resulting isolated treatment site are described in U.S. Patent Nos. 5,279,546; 5,226,888; 5,181,911; 4,824,436; and 4,636,195.
- a particular drug delivery catheter is commercially available under the trade name DispatchTM from SciMed Life Systems, Inc., Maple Grove, Minnesota.
- Non- balloon drug deliver catheters are described in U.S. Patent Nos. 5,180,366; 5,112,305; and 5,021,044; and PCT Publication WO 92/11890.
- Ultrasonically assisted drug delivery catheters are described in U.S. Patent Nos.
- the antioxidant substances used in the methods of the present invention will be incorporated into conventional pharmaceutical compositions for intramural delivery.
- the antioxidant substances will be incorporated into an acceptable fluid carrier, e.g., being formulated with sterile water, isotonic saline, glucose solution, or the like.
- the formulations may contain pharmaceutically acceptable auxiliary substances as are generally used in pharmaceutical preparations, including buffering agents, tonicity adjusting agents, such as sodium acetate, sodium lactate, sodium chloride, potassium chloride, and calcium chloride, and the like.
- the concentration of the antioxidant substance in the liquid formulation may vary widely, from 0.001% to 20%, typically being from 0.01% to 1% by weight. General methods for preparing such pharmaceutical formulations are described in Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Philadelphia, Pennsylvania, 1985.
- compositions will be delivered for a time sufficient to achieve the desired physiological effect, i.e., the partial or complete inhibition of intimal hyperplasia at the target site in the blood vessel.
- the total amount of the antioxidant substance delivered will be selected to be sufficient to inhibit intimal hyperplasia at the target site.
- Suitable total amounts based on patient body weight will be from 0.1 ⁇ g/kg to 10 mg/kg, usually from 0.1 ⁇ g/kg to 1 mg/kg. These amounts can be delivered as a bolus, i.e., in a single amount released over a very short time period, typically on the order of seconds, but will more usually be delivered as a continuous stream (or discontinuous stream, e.g., a series of short pulses) of a fluid pharmaceutical formulation over time.
- the total amount of time will, of course, depend on the delivery rate and drug concentration in the fluid being delivered, typically being from 0.5 minute to 360 minutes, more usually from 1 minute to 120 minutes.
- the pharmaceutical formulations delivered according to the methods of the present invention may include more than one antioxidant substance and/or other active agents in addition to the antioxidant substances.
- the formulations may include anti-coagulants and anti-thrombotic agents, such as heparin, low molecular weight heparin, and the like.
- the methods of the present invention provide for the direct, intramural delivery of an antioxidant substance into the blood vessel wall.
- the amounts of antioxidant substance released into systemic circulation will be sufficiently small so that there are no undesired systemic side effects.
- Figs. 1-6 a particular drug delivery catheter in the form of a sleeve infusion catheter 110 useful for delivering antioxidant substances according to the methods of the present invention will be described.
- Such infusion catheters are described in greater detail in copending application serial no. 08/473,800, filed on June 7, 1995, assigned to the assignee of the present application, the full disclosure of which has previously been incorporated herein by reference .
- the infusion sleeve catheter 110 comprises a radially expansible infusion sleeve 112, a radially expansible portion 113 within the sleeve 112, a manifold section 114, and a shaft 116.
- a hub 118 is attached to the proximal end of the shaft 116 and may be connected to a source of infusion fluid, such as a syringe, pump, or the like.
- An atraumatic tip 119 is secured to the distal end of the sleeve 112.
- Distal end 120 of the shaft is secured within a proximal tubular extension 122 of the manifold structure 114.
- the shaft 116 is a metal hypo tube having a circular cross-sectional area. The length of the shaft will depend on the length of the other portions of the catheter 110, with the overall length of the catheter typically being about 90 to 150 cm for coronary applications introduced through the femoral artery, as described in more detail below.
- the radially expansible infusion sleeve 112 comprises a central receptacle 114 (Figs. 2 and 3) and four infusion lumens 126.
- Infusion ports 128 are formed over the distal-most 2.5 to 10 cm of the expansible portion 113 of the sleeve 112.
- the expansible portion 113 of the sleeve is axially split along lines 132 (Fig. 2) to permit radial expansion, as illustrated in Fig. 9 described below.
- the distal ends of the lumens 126 will be sealed, typically by the tip 119.
- Other structures for providing radial expansibility are described above .
- the manifold structure 114 comprises an outer sheath or tube 140 coaxially received over an inner tube 142.
- Annular lumen 144 directs infusate into the infusion lumens 126.
- the annular lumen 144 is connected to lumen 150 and shaft 116 (Fig. 6) by a crescent-shaped transition lumen region 152 (Fig. 5) which is formed near the balloon catheter entry port 156.
- the balloon entry port 156 opens into a catheter lumen 158, which in turn leads into the balloon receptacle 124, typically having a cross-sectional area in the range from 0.5 mm 2 to 2 mm 2 , typically about 1.25 mm 2 .
- a balloon catheter BC having an inflatable balloon B may be introduced through entry port 156 so that the balloon B extends outward through the distal tip of the sleeve 112.
- the balloon may then be inflated and deflated while the infusion sleeve 112 remains retracted.
- the sleeve 112 may be advanced distally over the balloon, as illustrated in Fig. 8.
- the expansible portion 113 of the sleeve 112 will be expanded, as illustrated in Fig. 9.
- the infusion sleeve 112 may have an alternative cross-section, as illustrated in Figs. 10A and 10B.
- the sleeve 112' may be formed with lumens 126' formed within the wall of the catheter, rather than on the outer surface of the catheter as illustrated in Figs. 1-9.
- the wall thickness in these constructions will typically be slightly greater, usually being in the range from 0.2 mm to 0.4 mm.
- the wall will be axially split along lines 132 ' in order to allow expansion, as shown in Fig. 10B.
- Infusion catheter 110 may be introduced through conventional guiding catheter GC to position the infusion sleeve 12 within a coronary artery in the patient's heart H, as illustrated in Fig. 11.
- Guiding catheter GC may be any conventional guiding catheter intended for insertion into the femoral artery F, then via the patient's aorta A around the aortic arch AA, to one coronary ostia 0.
- Such guiding catheters are commercially available through a number of suppliers, including Medtronic, Minneapolis, Minnesota, available under the tradename SherpaTM. Specific guiding catheters are available for introducing catheters to either the left main or the right coronary arteries.
- Such guiding catheters are manufactured in different sizes, typically from 7F to 10F when used for coronary interventional procedures.
- the balloon catheter BC is introduced through the balloon entry port 156, as described previously in connection with Figs. 7-9.
- the atraumatic tip 119 of the infusion sleeve 112 will be positioned proximally of the balloon, typically by a distance in the range from 25 cm to 35 cm.
- the combination of the balloon catheter BC, and infusion catheter 110 will be introduced through the guiding catheter GC over a conventional guidewire GW until the balloon is positioned within the target site within the coronary artery.
- the infusion sleeve 112 will remain positioned entirely within the guiding catheter GC while the balloon B of the balloon catheter BC is initially located at the target site.
- the antioxidant substance is then delivered through the hub 118 for desired treatment.
- the antioxidant substance will be delivered at a flow rate from 10 ml/min to 40 ml/min, preferably from 20 ml/min to 30 ml/min.
- Infusion proximal pressures will typically be in the range of 30 psi to 150 psi, preferably from 70 psi to 110 psi.
- Balloon inflation pressures during infusion will typically be in the range from 0.5 atm to 6 atm, preferably from 1 atm to 2 atm.
- Specific treatment pressures, times, and other conditions will depend on the nature of the infusate and condition being treated. Typically, treatment periods will not exceed 5 mins . , usually not exceed 3 mins.
- Treatment protocols can be extended, however, by repetitively administering the infusate, i.e., deflating the balloon to reestablish coronary perfusion and then re-inflating the balloon and delivering infusate after a time sufficient to perfuse the distal coronary tissue. Such delivery steps can be repeated two, three, or more times as necessary to achieve a desired effect .
- the infusion sleeve 112 was used to deliver the antioxidant substance after the balloon catheter BC was used to perform an angioplasty treatment within the blood vessel.
- the infusion sleeve could also be used to deliver the antioxidant substance prior to the angioplasty treatment. Note that the infusion treatment is performed at much lower balloon pressures than the angioplasty procedure.
- the delivery of antioxidant can be performed prior to any substantial injury to the blood vessel wall due to overstretching of the blood vessel wall by the angioplasty treatment. It will be further appreciated that delivery of the antioxidant substance could be performed using a separate catheter, either before or after recanalization by balloon angioplasty or other procedure.
- infusion sleeve 112 presents the additional possibility of delivering the antioxidant compound during a balloon angioplasty procedure.
- the infusion lumens 126 would have to be sufficiently reinforced to withstand the high angioplasty pressures, and the antioxidant solutions would have to be delivered under sufficient pressure in order to penetrate the blood vessel wall.
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- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical & Material Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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Abstract
Description
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Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU59593/98A AU5959398A (en) | 1997-01-09 | 1998-01-07 | Localized intravascular delivery of antioxidant substances for inhibition of restenosis in recanalized blood vessels |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US3469397P | 1997-01-09 | 1997-01-09 | |
US60/034,693 | 1997-01-09 |
Publications (3)
Publication Number | Publication Date |
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WO1998030255A2 true WO1998030255A2 (en) | 1998-07-16 |
WO1998030255A3 WO1998030255A3 (en) | 1998-11-12 |
WO1998030255A9 WO1998030255A9 (en) | 1998-12-23 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/US1998/000491 WO1998030255A2 (en) | 1997-01-09 | 1998-01-07 | Localized intravascular delivery of antioxidant substances for inhibition of restenosis in recanalized blood vessels |
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AU (1) | AU5959398A (en) |
WO (1) | WO1998030255A2 (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000010552A2 (en) * | 1998-08-24 | 2000-03-02 | Global Vascular Concepts, Inc. | Use of anti-angiogenic agents for inhibiting vessel wall injury |
WO2002087610A1 (en) * | 2001-04-30 | 2002-11-07 | Fit Biotech Oy Plc. | Medical device |
US6602914B2 (en) | 1997-05-14 | 2003-08-05 | Atherogenics, Inc. | Compounds and methods for the inhibition of the expression of VCAM-1 |
WO2003092727A1 (en) * | 2002-04-30 | 2003-11-13 | Fit Biotech Oyj Plc | Medical device |
US6670398B2 (en) | 1997-05-14 | 2003-12-30 | Atherogenics, Inc. | Compounds and methods for treating transplant rejection |
US6852878B2 (en) | 1998-05-14 | 2005-02-08 | Atherogenics, Inc. | Thioketals and thioethers for inhibiting the expression of VCAM-1 |
WO2005016400A1 (en) * | 2003-08-14 | 2005-02-24 | Blue Medical Devices B.V. | Endoluminal prosthesis comprising a therapeutic agent |
US6881860B2 (en) | 2000-04-11 | 2005-04-19 | Atherogenics, Inc. | Compounds and methods to increase plasma HDL cholesterol levels and improve HDL functionality |
WO2014025526A1 (en) * | 2012-08-06 | 2014-02-13 | South Dakota Board Of Regents | Ascorbic acid-eluting implantable medical devices, systems, and related methods |
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US5573772A (en) * | 1993-03-15 | 1996-11-12 | Gensia, Inc. | Methods for protecting tissues and organs from ischemic damage |
US5584804A (en) * | 1990-10-10 | 1996-12-17 | Life Resuscitation Technologies, Inc. | Brain resuscitation and organ preservation device and method for performing the same |
-
1998
- 1998-01-07 AU AU59593/98A patent/AU5959398A/en not_active Abandoned
- 1998-01-07 WO PCT/US1998/000491 patent/WO1998030255A2/en active Application Filing
Patent Citations (2)
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US5584804A (en) * | 1990-10-10 | 1996-12-17 | Life Resuscitation Technologies, Inc. | Brain resuscitation and organ preservation device and method for performing the same |
US5573772A (en) * | 1993-03-15 | 1996-11-12 | Gensia, Inc. | Methods for protecting tissues and organs from ischemic damage |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6670398B2 (en) | 1997-05-14 | 2003-12-30 | Atherogenics, Inc. | Compounds and methods for treating transplant rejection |
US7375252B2 (en) | 1997-05-14 | 2008-05-20 | Atherogenics, Inc. | Compounds and method for the inhibition of the expression of VCAM-1 |
US7087645B2 (en) | 1997-05-14 | 2006-08-08 | Atherogenics, Inc. | Compounds and methods for treating transplant rejection |
US6602914B2 (en) | 1997-05-14 | 2003-08-05 | Atherogenics, Inc. | Compounds and methods for the inhibition of the expression of VCAM-1 |
US6617352B2 (en) | 1997-05-14 | 2003-09-09 | Atherogenics, Inc. | Compounds and methods for the inhibition of the expression of VCAM-1 |
US6828447B2 (en) | 1997-05-14 | 2004-12-07 | Atherogenics, Inc. | Compounds and methods for the inhibition of the expression of VCAM-1 |
US6852878B2 (en) | 1998-05-14 | 2005-02-08 | Atherogenics, Inc. | Thioketals and thioethers for inhibiting the expression of VCAM-1 |
WO2000010552A2 (en) * | 1998-08-24 | 2000-03-02 | Global Vascular Concepts, Inc. | Use of anti-angiogenic agents for inhibiting vessel wall injury |
WO2000010552A3 (en) * | 1998-08-24 | 2000-11-23 | Global Vascular Concepts Inc | Use of anti-angiogenic agents for inhibiting vessel wall injury |
US6881860B2 (en) | 2000-04-11 | 2005-04-19 | Atherogenics, Inc. | Compounds and methods to increase plasma HDL cholesterol levels and improve HDL functionality |
US7183317B2 (en) | 2000-04-11 | 2007-02-27 | Atherogenics, Inc. | Compounds and methods to increase plasma HDL cholesterol levels and improve HDL functionality |
WO2002087610A1 (en) * | 2001-04-30 | 2002-11-07 | Fit Biotech Oy Plc. | Medical device |
WO2003092727A1 (en) * | 2002-04-30 | 2003-11-13 | Fit Biotech Oyj Plc | Medical device |
WO2005016400A1 (en) * | 2003-08-14 | 2005-02-24 | Blue Medical Devices B.V. | Endoluminal prosthesis comprising a therapeutic agent |
JP2007502135A (en) * | 2003-08-14 | 2007-02-08 | ブルー・メディカル・デバイシーズ・ベスローテン・フェンノートシャップ | Intraluminal prosthesis comprising a therapeutic agent |
CN100400116C (en) * | 2003-08-14 | 2008-07-09 | 兰色医药设备有限公司 | Endoluminal prosthesis comprising a therapeutic agent |
WO2014025526A1 (en) * | 2012-08-06 | 2014-02-13 | South Dakota Board Of Regents | Ascorbic acid-eluting implantable medical devices, systems, and related methods |
US20150182675A1 (en) * | 2012-08-06 | 2015-07-02 | South Dakota Board Of Regents | Ascorbic Acid-Eluting Implantable Medical Devices, Systems, and Related Methods |
Also Published As
Publication number | Publication date |
---|---|
WO1998030255A3 (en) | 1998-11-12 |
AU5959398A (en) | 1998-08-03 |
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