WO2000002501A1 - Stent containing copper - Google Patents

Stent containing copper Download PDF

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Publication number
WO2000002501A1
WO2000002501A1 PCT/GB1999/002238 GB9902238W WO0002501A1 WO 2000002501 A1 WO2000002501 A1 WO 2000002501A1 GB 9902238 W GB9902238 W GB 9902238W WO 0002501 A1 WO0002501 A1 WO 0002501A1
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WO
WIPO (PCT)
Prior art keywords
stent
copper
stent according
present
restenosis
Prior art date
Application number
PCT/GB1999/002238
Other languages
French (fr)
Inventor
Nigel Benjamin
Gail Richardson
Original Assignee
William Harvey Research Limited
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 William Harvey Research Limited filed Critical William Harvey Research Limited
Priority to AU49199/99A priority Critical patent/AU4919999A/en
Publication of WO2000002501A1 publication Critical patent/WO2000002501A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2/00Filters 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
    • A61F2/82Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials 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
    • A61L31/02Inorganic materials
    • A61L31/022Metals or alloys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials 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
    • A61L31/08Materials for coatings
    • A61L31/082Inorganic materials
    • A61L31/088Other specific inorganic materials not covered by A61L31/084 or A61L31/086
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2250/00Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067Means for introducing or releasing pharmaceutical products into the body

Definitions

  • the present invention relates to intravascular stents, stent assemblies, methods of manufacturing intravascular stents and uses thereof.
  • Intravascular stents are increasingly being used to maintain patency and to prevent restenosis of blood vessels occluded by, for example, atheromatous arterial disease. Restenosis is the closure of a blood vessel, particularly an artery, following trauma to the vessel caused by efforts to open an occluded portion of a vessel, by for example, dilation, ablation, atherectomy or laser treatment. A particular use of stents is to prevent restenosis in the coronary circulation following transcutaneous balloon angioplasty. Stents may also be used to repair aneurysms.
  • a stent is inserted into the relevant vessel, generally by a catheter, and expanded so that the stent makes contact with the walls of the affected vessel.
  • a stent comprising fibrin which is said to reduce the incidence of restenosis at the site of vascular injury.
  • a stent which has a polymer formed thereon in which a therapeutic substance is dispersed.
  • stents are described elsewhere with other various coatings.
  • stents are described coated with biocompatible polymeric material.
  • an intravascular stent comprising copper.
  • the present invention overcomes a number of problems associated with prior art stents and provides an efficient method to prevent the re-occlusion of stented vessels and eliminates or reduces the need for the use of systemic anticoagulant and antiplatelet agents.
  • Nitric oxide is normally generated by endothelial cells which line all blood vessels and is thought to be important in preventing platelet activation in healthy vessels. Nitric oxide is also generated by nitrosothiol compounds such as S-nitrosoglutathione (GSNO) which have been detected circulating in the bloodstream.
  • GSNO S-nitrosoglutathione
  • copper (I) ions must be present (see Gordge et al, (1995), British Journal of Pharmacology, 114, pp 1083-1089). It is believed that copper (I) ions are present in trace amounts in the circulation and intravascular tissue leading to the innate generation of nitric oxide.
  • copper present in the stent when exposed to an aqueous solution such as blood plasma, produces copper (I) ions on its surface which enhance the formation of nitric oxide from nitrosothiol compounds in the vicinity of the stent, thereby preventing or reducing platelet activation.
  • the stent of the present invention comprises copper on an exposed surface.
  • stent can be used in the present invention, including the self- expanding type or the balloon-expandable type. Examples of stent designs useful in the present invention are described in US-A-4 733 665, US-A-4 800 882 and US-A-4 886 062.
  • the stent can be made of virtually any material provided the material is biocompatible and has physical properties suitable for its function.
  • the stent may be made from metal such as stainless steel or titanium, biostable polymers such as polyurethanes, silicones and polyesters, or bioabsorbable polymers such as poly(ethylene terephthalate), polyacetal, poly(lactic acid), poly(ethylene oxide)/poly(butylene terephthalate) copolymers.
  • the stent is formed from stainless steel.
  • copper is used to describe metallic copper or any compound (such as copper contaimng chelate or protein, e.g. copper, zinc superoxide dismutase) or alloy comprising copper (such as a copper-steel alloy) which when exposed to an aqueous solution is capable of forming copper (I) ions.
  • the stent of the present invention comprises metallic copper on an exposed surface.
  • an exposed surface is used herein to describe a surface of the stent which when inserted into the lumen of a vessel and expanded, is in contact with an aqueous fluid such as blood plasma.
  • the copper on the exposed surface of the stent of the present invention in use will come into contact with an aqueous fluid and copper (I) ions will be formed.
  • the copper (I) ions allow GSNO to break down and form nitric oxide.
  • the nitric oxide formed will prevent platelet activation and thereby prevent platelet aggregation and thus reduce the tendency of clot formation on the stent surface and in the regions adjacent the stent.
  • the stent of the present invention will therefore be useful in reducing restenosis of the diseased vessel and will reduce the need for the use of systemic anticoagulant and antiplatelet agents.
  • Copper may be provided in a form suitable for incorporation in the material of construction of the stent.
  • the stent may be constructed of a copper alloy (such as a copper-steel alloy).
  • the copper may be provided in a form suitable for attaching to the stent or as a coating on the stent.
  • the copper may be provided as a metal, alloy or copper containing protein for coating the stent.
  • the stent of the present invention has a coating of copper.
  • the copper coating may be applied to the stent using any conventional coating technique, such as plating or painting.
  • a metallic copper coating is applied using electroplating techniques well known to those skilled in the art. Such techniques are described in Practical Electroplating Handbook,
  • the coating may cover all or part of the stent.
  • the stent of the present invention has an external surface which in use, contacts the wall of a vessel, and an internal surface which defines the lumen of the stent.
  • copper is provided on at least a part of the internal surface of the stent.
  • the copper coating formed on the stent of the present invention may be thin, preferably 0.01 to 100 ⁇ m, more preferably 0.1 to 10 ⁇ m thick.
  • the stent of the present invention is made from stainless steel and at least a part of the exposed surface has a copper coating formed thereon.
  • the stent of the present invention comprises sufficient copper on an exposed surface to lead to the generation of sufficient nitric oxide in vivo, to substantially prevent platelet activation in the regions adjacent the stent.
  • the stent of the present invention further comprises a therapeutic substance.
  • a therapeutic substance are described in
  • WO 91/12779 and WO 90/13332 include antiplatelet agents, anticoagulant reagents, antimicrobial agents and antimetabolic agents.
  • Therapeutic substances may be incorporated into the stent of the present invention using the methods described in EP-A-0 566 245, wherein said therapeutic substances are incorporated into the stent in the form of microcapsules, or in EP-A-0 623 354, wherein therapeutic substances are incorporated into the stent by applying a solution which comprises a solvent, a polymer dissolved in the solvent and a therapeutic substance dispersed in the solvent.
  • the stent of the present invention may further comprise a biocompatible coating, which may be present on either or both the internal or external stent surfaces.
  • the copper may be covered with a biocompatible coating such as a membrane which is porous to platelets and GSNO but reduces direct contact of copper with the arterial wall, which may cause inflammation of the arterial wall.
  • a biocompatible coating such as a membrane which is porous to platelets and GSNO but reduces direct contact of copper with the arterial wall, which may cause inflammation of the arterial wall.
  • Suitable membrane materials include phosphoryl choline (Biocompatible Limited, Farnham Surrey). Methods for applying biocompatible coatings are described, for example, in EP-A-0 627 226.
  • the stent of the present invention further comprises a nitrosothiol compound such as GSNO.
  • a stent assembly comprising the stent of the present invention and a catheter.
  • the stent assembly additionally comprises a balloon.
  • the stent assembly is used to insert the assembly into the lumen of a vessel.
  • the stent is a balloon inflatable stent
  • the catheter has the balloon attached at a distal end, and the stent is mounted around the balloon.
  • the stent is delivered to the desired site by the catheter using conventional percutaneoneous techniques well known to those skilled in the art.
  • the balloon is then used to expand the stent so that it makes contact with the walls of the vessel, and the catheter and balloon are then withdrawn leaving the stent in place.
  • a method for making the stent of the present invention comprising attaching copper to an exposed surface of a stent.
  • the copper may be attached using mechanical techniques such as welding, stapling or gluing.
  • the copper is attached to an exposed surface of a stent by electroplate techniques. Electroplate techniques are well known to those skilled in the art and such techniques are described in Practical Electroplating Handbook, N.V. Parthasaradhy, 1989.
  • a fourth aspect of the present invention is the stent of the present invention for use in therapy.
  • the present invention further provides a method of preventing or reducing restenosis comprising the use of a stent according to the present invention.
  • the stent of the present invention is used in conjunction with a composition comprising a nitrosothiol compound such as GSNO.
  • the composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension.
  • compositions may be prepared in a conventional manner using conventional excipients, using standard techniques well known to those skilled in the art of pharmacy.
  • the administration of the composition comprising the nitrosothiol compound will lead to a higher level of the nitrosothiol compound in the body and in turn will lead to a higher level of nitric oxide in the vicinity of the stent, thereby preventing or reducing restenosis.
  • kits for use in the treatment of restenosis comprising the stent of the present invention and a composition comprising a nitrosothiol compound suitable for administration to a patient.
  • the composition is in a form suitable for oral or intravenous administration.
  • kits for use in the treatment of restenosis comprising the stent of the present invention and a catheter.
  • the kit additionally comprises a balloon.
  • a seventh aspect of the present invention is the use of copper in the manufacture of the stent of the present invention for use in the treatment of restenosis.
  • Figure 1 shows the effect of copper metal and copper-containing alloys on nitric oxide generation from 10 ⁇ M GSNO;
  • Figure 2 shows the effect of different surface areas of copper on nitric oxide (NO) release from 1 O ⁇ M GSNO;
  • Nitric oxide was generated by adding 200 ⁇ L samples of lO ⁇ M S- nitrosogluthathione (GSNO) to a reaction flask containing distilled water and different surface areas of copper or copper alloys.
  • the alloys used were NumetalTM (Goodfellow, Cambridge), containing 5% copper and nickel silver, containing 62% copper.
  • the NO generated was detected by a Sievers NOATM 280 analyzer using a chemiluminescence method. Results shown in Figure 1 suggest that the ability of the metal to generate NO from GSNO is related to the amount of copper present.
  • Stainless steel (316L alloy) from which most commercially available stents are manufactured does not generate significant amounts of NO from GSNO (data not shown).
  • Figure 2 shows that by increasing the surface area of copper, the rate of NO production is increased, up to a maximum level.
  • venous blood was collected from fourteen healthy volunteers who were not on drug therapy. Venous blood samples were added to tubes containing 13mM trisodium citrate. Platelet rich plasma was prepared by centrifugation at 150g for 12 minutes at 25°C. Collagen-induced platelet aggregation was measured in 0.5ml aliquots following addition of 1 ⁇ m GSNO and/or copper metal (added as wire with surface area 2 mm ). Whereas the concentration of GSNO alone had no effect on platelet aggregation, the addition of copper caused an impairment of aggregation. See Figure 3.
  • a stainless steel balloon-expandable stent was electroplated with copper over its entire surface using the cyanide bath method.
  • the cyanide bath method is described in Practical Electroplating Handbook, N.V. Parthasaradhy, 1989. However, any conventional method for copper plating stainless steel may be used.
  • the copper coated stent may be used in standard intravascular stent treatments.

Abstract

The present invention relates to intravascular stents, stent assemblies, methods of manufacturing intravascular stents and uses thereof. The intravascular stents of the present invention comprise copper which leads to the generation of sufficient nitric oxide in vivo to substantially prevent platelet activation.

Description

STENT CONTAINING COPPER
The present invention relates to intravascular stents, stent assemblies, methods of manufacturing intravascular stents and uses thereof.
Intravascular stents are increasingly being used to maintain patency and to prevent restenosis of blood vessels occluded by, for example, atheromatous arterial disease. Restenosis is the closure of a blood vessel, particularly an artery, following trauma to the vessel caused by efforts to open an occluded portion of a vessel, by for example, dilation, ablation, atherectomy or laser treatment. A particular use of stents is to prevent restenosis in the coronary circulation following transcutaneous balloon angioplasty. Stents may also be used to repair aneurysms.
In order to prevent restenosis, a stent is inserted into the relevant vessel, generally by a catheter, and expanded so that the stent makes contact with the walls of the affected vessel.
However, a problem with the use of conventional stents is their propensity to cause local blood coagulation and thrombosis formation leading to subsequent occlusion of the stented vessel.
Currently, in order to overcome this problem, patients receiving stents are given systemic therapy using anticoagulants such as heparin and warfarin, and antiplatelet agents such as aspirin. However, the use of systemic therapy in combination with stents can lead to bleeding complications, which may on occasion be severe (see Wong and Leon, (1995),
Current Opinions in Cardiology, 10, pp 404-411).
It has also been proposed in the prior art that stents are seeded with endothelial cells (see Dichek et al, (1989), Circulation, 80, pp 1347-1353). Dichek et al. describe the seeding of endothelial cells onto stainless steel stents until the stents are fully covered. The cells on the stents are then able to be delivered to the vascular wall where they can provide therapeutic proteins. Other methods for providing therapeutic substances to vascular walls by means of stents have also been proposed in, for example, published International Patent Applications WO 91/12779 and WO 90/13332. In these applications it is suggested that antiplatelet agents, anticoagulant agents, antimicrobial agents, antimetabolic agents and other drugs could be supplied in stents to reduce the incidence of restenosis.
In EP-A-0 566 245, a stent is described comprising fibrin which is said to reduce the incidence of restenosis at the site of vascular injury.
In EP-A-0 623 354, a stent is described which has a polymer formed thereon in which a therapeutic substance is dispersed.
Other stents are described elsewhere with other various coatings. For example, in EP-0 627 226, stents are described coated with biocompatible polymeric material.
However, none of the prior art stents efficiently prevent restenosis occurring following vascular injury, such as that following transcutaneous balloon angioplasty, and the prior art stents generally require the need for the use of systemic drugs in order to avoid local blood coagulation and thrombosis formation leading to subsequent occlusion. There remains therefore a need for improved stents capable of resisting and preventing restenosis.
According to the present invention there is provided an intravascular stent comprising copper.
The present invention overcomes a number of problems associated with prior art stents and provides an efficient method to prevent the re-occlusion of stented vessels and eliminates or reduces the need for the use of systemic anticoagulant and antiplatelet agents.
It is believed that the presence of copper on the surface of the stent leads to increased levels of nitric oxide in the vicinity of the stent.
Nitric oxide is normally generated by endothelial cells which line all blood vessels and is thought to be important in preventing platelet activation in healthy vessels. Nitric oxide is also generated by nitrosothiol compounds such as S-nitrosoglutathione (GSNO) which have been detected circulating in the bloodstream. For GSNO to breakdown chemically and form nitric oxide, it has been reported that copper (I) ions must be present (see Gordge et al, (1995), British Journal of Pharmacology, 114, pp 1083-1089). It is believed that copper (I) ions are present in trace amounts in the circulation and intravascular tissue leading to the innate generation of nitric oxide.
Without prejudice to the present invention it is believed that copper present in the stent, when exposed to an aqueous solution such as blood plasma, produces copper (I) ions on its surface which enhance the formation of nitric oxide from nitrosothiol compounds in the vicinity of the stent, thereby preventing or reducing platelet activation.
Preferably, the stent of the present invention comprises copper on an exposed surface.
Any design of stent can be used in the present invention, including the self- expanding type or the balloon-expandable type. Examples of stent designs useful in the present invention are described in US-A-4 733 665, US-A-4 800 882 and US-A-4 886 062. The stent can be made of virtually any material provided the material is biocompatible and has physical properties suitable for its function. The stent may be made from metal such as stainless steel or titanium, biostable polymers such as polyurethanes, silicones and polyesters, or bioabsorbable polymers such as poly(ethylene terephthalate), polyacetal, poly(lactic acid), poly(ethylene oxide)/poly(butylene terephthalate) copolymers. Preferably, the stent is formed from stainless steel.
The term "copper" is used to describe metallic copper or any compound (such as copper contaimng chelate or protein, e.g. copper, zinc superoxide dismutase) or alloy comprising copper (such as a copper-steel alloy) which when exposed to an aqueous solution is capable of forming copper (I) ions. Preferably, the stent of the present invention comprises metallic copper on an exposed surface.
The term "an exposed surface" is used herein to describe a surface of the stent which when inserted into the lumen of a vessel and expanded, is in contact with an aqueous fluid such as blood plasma. The copper on the exposed surface of the stent of the present invention in use, will come into contact with an aqueous fluid and copper (I) ions will be formed. The copper (I) ions allow GSNO to break down and form nitric oxide. The nitric oxide formed will prevent platelet activation and thereby prevent platelet aggregation and thus reduce the tendency of clot formation on the stent surface and in the regions adjacent the stent.
The stent of the present invention will therefore be useful in reducing restenosis of the diseased vessel and will reduce the need for the use of systemic anticoagulant and antiplatelet agents.
Copper may be provided in a form suitable for incorporation in the material of construction of the stent. For example the stent may be constructed of a copper alloy (such as a copper-steel alloy). Alternatively, the copper may be provided in a form suitable for attaching to the stent or as a coating on the stent. For example, the copper may be provided as a metal, alloy or copper containing protein for coating the stent. In a preferred embodiment, the stent of the present invention has a coating of copper.
The copper coating may be applied to the stent using any conventional coating technique, such as plating or painting. Preferably, where the stent is formed from metal, a metallic copper coating is applied using electroplating techniques well known to those skilled in the art. Such techniques are described in Practical Electroplating Handbook,
N.V. Parthasaradhy, 1989.
The coating may cover all or part of the stent. Preferably, the stent of the present invention has an external surface which in use, contacts the wall of a vessel, and an internal surface which defines the lumen of the stent. Preferably, copper is provided on at least a part of the internal surface of the stent.
The copper coating formed on the stent of the present invention may be thin, preferably 0.01 to 100 μm, more preferably 0.1 to 10 μm thick. In a particular preferred embodiment, the stent of the present invention is made from stainless steel and at least a part of the exposed surface has a copper coating formed thereon.
In a preferred embodiment, the stent of the present invention comprises sufficient copper on an exposed surface to lead to the generation of sufficient nitric oxide in vivo, to substantially prevent platelet activation in the regions adjacent the stent.
In a further preferred embodiment, the stent of the present invention further comprises a therapeutic substance. Preferred therapeutic substances are described in
WO 91/12779 and WO 90/13332, and include antiplatelet agents, anticoagulant reagents, antimicrobial agents and antimetabolic agents.
Therapeutic substances may be incorporated into the stent of the present invention using the methods described in EP-A-0 566 245, wherein said therapeutic substances are incorporated into the stent in the form of microcapsules, or in EP-A-0 623 354, wherein therapeutic substances are incorporated into the stent by applying a solution which comprises a solvent, a polymer dissolved in the solvent and a therapeutic substance dispersed in the solvent.
In another preferred embodiment, the stent of the present invention may further comprise a biocompatible coating, which may be present on either or both the internal or external stent surfaces. In particular, the copper may be covered with a biocompatible coating such as a membrane which is porous to platelets and GSNO but reduces direct contact of copper with the arterial wall, which may cause inflammation of the arterial wall. Suitable membrane materials include phosphoryl choline (Biocompatible Limited, Farnham Surrey). Methods for applying biocompatible coatings are described, for example, in EP-A-0 627 226.
In a further preferred embodiment, the stent of the present invention further comprises a nitrosothiol compound such as GSNO. In a second aspect of the present invention there is provided a stent assembly comprising the stent of the present invention and a catheter. Preferably, the stent assembly additionally comprises a balloon.
The stent assembly is used to insert the assembly into the lumen of a vessel. When the stent is a balloon inflatable stent the catheter has the balloon attached at a distal end, and the stent is mounted around the balloon. The stent is delivered to the desired site by the catheter using conventional percutaneoneous techniques well known to those skilled in the art. The balloon is then used to expand the stent so that it makes contact with the walls of the vessel, and the catheter and balloon are then withdrawn leaving the stent in place.
In a third aspect of the present invention there is provided a method for making the stent of the present invention comprising attaching copper to an exposed surface of a stent. The copper may be attached using mechanical techniques such as welding, stapling or gluing. Preferably, the copper is attached to an exposed surface of a stent by electroplate techniques. Electroplate techniques are well known to those skilled in the art and such techniques are described in Practical Electroplating Handbook, N.V. Parthasaradhy, 1989.
A fourth aspect of the present invention is the stent of the present invention for use in therapy.
The present invention further provides a method of preventing or reducing restenosis comprising the use of a stent according to the present invention.
It is particularly preferred that the stent of the present invention is used in conjunction with a composition comprising a nitrosothiol compound such as GSNO. The composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension. In general the above compositions may be prepared in a conventional manner using conventional excipients, using standard techniques well known to those skilled in the art of pharmacy. The administration of the composition comprising the nitrosothiol compound will lead to a higher level of the nitrosothiol compound in the body and in turn will lead to a higher level of nitric oxide in the vicinity of the stent, thereby preventing or reducing restenosis.
In a fifth aspect of the present invention there is provided a kit for use in the treatment of restenosis comprising the stent of the present invention and a composition comprising a nitrosothiol compound suitable for administration to a patient.
Preferably, the composition is in a form suitable for oral or intravenous administration.
In a sixth aspect of the present invention there is provided a kit for use in the treatment of restenosis comprising the stent of the present invention and a catheter.
Preferably, the kit additionally comprises a balloon.
A seventh aspect of the present invention is the use of copper in the manufacture of the stent of the present invention for use in the treatment of restenosis.
The present invention is now described, by way of example only, with reference to the accompanying Figures, in which:
Figure 1 shows the effect of copper metal and copper-containing alloys on nitric oxide generation from 10 μM GSNO;
Figure 2 shows the effect of different surface areas of copper on nitric oxide (NO) release from 1 OμM GSNO; and
Figure 3 shows the effect of the combination of 1 μM GSNO and copper metal on ex-vivo platelet aggregation (*=p<0.05). Effect of Copper Metal and Copper Alloys on Nitric Oxide formation from S- Nitrosoglutathione
Nitric oxide (NO) was generated by adding 200 μL samples of lOμM S- nitrosogluthathione (GSNO) to a reaction flask containing distilled water and different surface areas of copper or copper alloys. The alloys used were Numetal™ (Goodfellow, Cambridge), containing 5% copper and nickel silver, containing 62% copper. The NO generated was detected by a Sievers NOA™ 280 analyzer using a chemiluminescence method. Results shown in Figure 1 suggest that the ability of the metal to generate NO from GSNO is related to the amount of copper present.
Stainless steel (316L alloy) from which most commercially available stents are manufactured does not generate significant amounts of NO from GSNO (data not shown).
Figure 2 shows that by increasing the surface area of copper, the rate of NO production is increased, up to a maximum level.
Effect of Metallic Copper on Platelet Aggregation with S-Nitrosoglutathione
In this experiment, venous blood was collected from fourteen healthy volunteers who were not on drug therapy. Venous blood samples were added to tubes containing 13mM trisodium citrate. Platelet rich plasma was prepared by centrifugation at 150g for 12 minutes at 25°C. Collagen-induced platelet aggregation was measured in 0.5ml aliquots following addition of 1 μm GSNO and/or copper metal (added as wire with surface area 2 mm ). Whereas the concentration of GSNO alone had no effect on platelet aggregation, the addition of copper caused an impairment of aggregation. See Figure 3.
Manufacture of a Copper Coated Stent
A stainless steel balloon-expandable stent was electroplated with copper over its entire surface using the cyanide bath method. The cyanide bath method is described in Practical Electroplating Handbook, N.V. Parthasaradhy, 1989. However, any conventional method for copper plating stainless steel may be used.
The copper coated stent may be used in standard intravascular stent treatments.

Claims

Claims
I . An intravascular stent comprising copper.
2. A stent according to claim 1 comprising copper on an exposed surface.
3. A stent according to claim 1 or 2 which has an external surface which in use contacts the walls of a vessel and an internal surface which defines the lumen of the stent, wherein the copper is on at least a part of the internal surface of the stent.
4. A stent according to any one of claims 1 to 3 having a coating of copper.
5. A stent according to claim 4, wherein the copper coating is 0.01 to 100 ╬╝m thick.
6. A stent according to claim 4 or 5, wherein the stent is made from stainless steel and at least part of the exposed surface has a copper coating.
7. A stent according to any preceding claim wherein the copper is present as copper metal.
8. A stent according to any lone of claims 1 to 6 wherein the copper is present as a copper alloy.
9. A stent according to any one of claims 1 to 6 wherein the copper is present as a copper-containing protein.
10. A stent according to any one of the preceding claims, wherein the stent comprises sufficient copper to lead to the generation of sufficient nitric oxide in vivo to substantially prevent platelet activation in the regions adjacent the stent.
I I. A stent according to any one of the preceding claims wherein the stent further comprises a biocompatible coating.
12. A stent according to any one of the preceding claims further comprising a therapeutic substance.
13. A stent according to claim 12, wherein the therapeutic substance is an anticoagulant agent, an antiplatelet agent, an antimetabolic agent or an antimetabolic agent.
14. A stent according to any one of the preceding claims further comprising a nitrosothiol compound.
15. A stent assembly comprising the stent according to any one of the preceding claims and a catheter.
16. A stent assembly according to claim 15 which additionally comprises a balloon.
17. A method for making the stent according to any one of claims 1 to 14, comprising attaching copper to an exposed surface of a stent.
18. A method according to claim 17 wherein copper metal is attached to the exposed surface of a stent by electroplating.
19. A stent according to any one of claims 1 to 14 for use in therapy.
20. A kit for use in the treatment of restenosis comprising the stent of any one of claims 1 to 14 and a composition comprising a nitrosothiol compound suitable for administration to a patient.
21. A kit according to claim 20 wherein the composition comprising a nitrosothiol compound is suitable for oral or intravenous administration.
22. A kit for use in the treatment of restenosis comprising a stent assembly according to claim 15 or 16.
3. The use of copper in the manufacture of a stent according to any one of claims 1 to 4 for use in the treatment of restenosis.
PCT/GB1999/002238 1998-07-13 1999-07-13 Stent containing copper WO2000002501A1 (en)

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GB9815158.2 1998-07-13

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WO2004012874A1 (en) 2002-08-02 2004-02-12 The Government Of The United States Of America, Represented By The Secretary, Dept. Of Health And Human Services Cross-linked nitric oxide-releasing polyamine coated substrates, compositions comprising same and method of making same
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US9005106B2 (en) 2008-01-31 2015-04-14 Enopace Biomedical Ltd Intra-aortic electrical counterpulsation
US9386991B2 (en) 2012-02-02 2016-07-12 Rainbow Medical Ltd. Pressure-enhanced blood flow treatment
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US9649487B2 (en) 2010-08-05 2017-05-16 Enopace Biomedical Ltd. Enhancing perfusion by contraction
US10779965B2 (en) 2013-11-06 2020-09-22 Enopace Biomedical Ltd. Posts with compliant junctions
US11400299B1 (en) 2021-09-14 2022-08-02 Rainbow Medical Ltd. Flexible antenna for stimulator

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US7128904B2 (en) 2001-01-16 2006-10-31 The Regents Of The University Of Michigan Material containing metal ion ligand complex producing nitric oxide in contact with blood
US8034384B2 (en) 2001-01-16 2011-10-11 The Regents Of The University Of Michigan Method of increasing biocompatibility of medical device by generating nitric oxide
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WO2004012874A1 (en) 2002-08-02 2004-02-12 The Government Of The United States Of America, Represented By The Secretary, Dept. Of Health And Human Services Cross-linked nitric oxide-releasing polyamine coated substrates, compositions comprising same and method of making same
WO2007097875A3 (en) * 2006-02-17 2008-04-17 Advanced Cardiovascular System Nitric oxide generating medical devices
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US10828181B2 (en) 2011-09-09 2020-11-10 Enopace Biomedical Ltd. Annular antenna
US9386991B2 (en) 2012-02-02 2016-07-12 Rainbow Medical Ltd. Pressure-enhanced blood flow treatment
US10779965B2 (en) 2013-11-06 2020-09-22 Enopace Biomedical Ltd. Posts with compliant junctions
US11432949B2 (en) 2013-11-06 2022-09-06 Enopace Biomedical Ltd. Antenna posts
US11400299B1 (en) 2021-09-14 2022-08-02 Rainbow Medical Ltd. Flexible antenna for stimulator

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