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Use of nitric oxide adducts

a technology of nitric oxide and adducts, which is applied in the direction of powder delivery, packaged goods type, peptide/protein ingredients, etc., can solve the problems of limited clinical usefulness of such devices, frequent exposure of blood to artificial surfaces, serious thromboembolic complications, etc., and achieve the effect of modulating the effects of vascular injury and reducing intimal proliferation

Inactive Publication Date: 2007-10-25
NITROMED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016] Toward arriving at the present invention, the inventors hypothesized that local delivery of an EDRF-like species to restore or replace the deficiency in EDRF noted with dysfunctional endothelium will modulate the effects of vascular injury and reduce intimal proliferation following injury. The observations that form the basis of this invention relate to the active deposition of platelets on non-platelet tissue beds rather than platelet-to-platelet aggregation.
[0026] The localized, time-related, presence of nitric oxide adducts administered in a physiologically effective form is efficacious in diminishing, deterring or preventing vascular damage after or as a result of instrumental intervention, such as angioplasty, catheterization or the introduction of a stent (e.g., Palmaz-Schatz stent) or other indwelling medical device.
[0029] Particularly preferred is the localized use of nitroso-proteins, particularly those which do not elicit any significant immune response. An example of such a nitroso-protein which does not elicit any significant immune response is a mono- or polynitrosated albumin. Such nitrosylated albumins, particularly the polynitrosylated albumins, can be present as polymeric chains or three dimensional aggregates where the polynitrosylated albumin is the monomeric unit. The albumin of one monomeric unit can be a functional subunit of full-length native albumin or can be an albumin to which has been attached an additional moiety, such as a polypeptide, which can aid, for example, in localization. The aggregates are multiple inter adherent monomeric units which can optionally be linked by disulfide bridges. Additionally devices which have been substituted or coated with nitroso-protein have the unique property that they can be dried and stored.

Problems solved by technology

However, platelet deposition on artificial surfaces severely limits the clinical usefulness of such devices.
For example, exposure of blood to artificial surfaces frequently leads to serious thromboembolic complications in patients with artificial heart valves, synthetic grafts and other prosthetic devices, and in patients undergoing external circulation, including cardiopulmonary bypass and hemodialysis.
No material has been developed that matches the blood-compatible surface of the endothelium.
This creates problems in the use of artificial materials at the microvascular level, where the ratio of vessel surface area to blood volume is high (Sheppeck et al., supra).
Further, cardiopulmonary support systems used during cardiac surgery are responsible for many of the undesirable hemostatic consequences of such surgery (Bick, Semin. Thromb. Hemost. 3:59-82, 1976).
Thrombosis is also a significant problem in the use of prosthetic blood vessels, arteriovenous shunts, and intravenous or intraarterial catheters.
Conventional methods for preventing thrombus formation on artificial surfaces have a limited effect on the interaction between blood and artificial surfaces.
To further complicate matters, heparin when given systemically, can accelerate hemorrhage, already a frequent complication of cardiac surgery.
While these have some effect in preventing thromboembolism when given with oral anticoagulants, serious adverse effects can result.
In addition, the effect of aspirin and similarly acting drugs is not promptly reversible, which is essential during cardiopulmonary bypass.
Finally, agents such as aspirin, which depress platelet function by inhibiting cyclo-oxygenase, may block platelet aggregation, but they do not prevent the adhesion of platelets to artificial surfaces (Salzman et al., supra, 1981).
Despite considerable efforts to develop non-thrombogenic materials, no synthetic material has been created that is free from this effect.
In addition, the use of anticoagulant and platelet-inhibiting agents has been less than satisfactory in preventing adverse consequences resulting from the interaction between blood and artificial surfaces.
In the same manner as artificial surfaces, damaged arterial surfaces within the vascular system are also highly susceptible to thrombus formation.
Disease states such as atherosclerosis and hyperhomocysteinemia cause damage to the endothelial lining, resulting in vascular obstruction and a reduction in the substances necessary to inhibit blood clotting.
Thus, abnormal platelet deposition resulting in thrombosis is much more likely to occur in vessels in which endothelial damage has occurred.

Method used

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  • Use of nitric oxide adducts
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Examples

Experimental program
Comparison scheme
Effect test

example 1

NO Adducts Make Artificial Surfaces Less Thrombogenic

[0141] One of the best ways to demonstrate that an artificial surface exposed to blood has been made less thrombogenic is to measure or quantitate the number of blood platelets that collect on that surface. This method requires the removal of platelets from an animal or human subject. The platelets are labeled with a radioactive material such as Indium111, which emits gamma rays, detectable by a gamma counter placed 3 to 6 inches away from the source of radioactive platelets. The labeled platelets are either reinjected into the animal or human in vivo, or contacted with the artificial surface in vivo. Platelets will adhere to artificial surfaces or acutely damaged arterial surfaces. Thus, the number of normal platelets and radioactive platelets which stick to the surface is an indication of the thrombogenicity of the surface.

[0142] The inventors have used this methodology in experiments to demonstrate that nitric oxide adducts ...

example 2

Na Nitroprusside Coated Damaged Arterial Surfaces are Less Thrombogenic

[0152] The following experiments demonstrate that nitric oxide-donating compounds, such as sodium nitroprusside and S-nitroso-BSA, can be applied directly to damaged arterial or venous surfaces (blood vessels) to inhibit platelet deposition and thrombus formation.

[0153] The inventors developed an animal model which allows them to mimic a patient with narrowing of the coronary or other arteries and arterial damage caused by atherosclerosis or after angioplasty, atherectomy or other procedure. The model uses anesthetized dogs with open chest and exposed heart. Briefly, an electromagnetic flow probe is placed on the coronary artery to continuously measure blood flow through the artery. Then the arterial wall is damaged (intima and media) by clamping the artery several times with a surgical clamp. In the area of arterial damage, a plastic encircling cylinder is placed around the outside of the coronary artery to p...

example 3

pS-NO-BSA Treats Vascular Injury

[0164] Materials: Sulfanilamide and N-(1-naphthyl) ethylenediamine dihydrochloride were purchased from Aldrich Chemical Co., Milwaukee, Wis. Sodium bicarbonate, sodium chloride, sodium phosphate, sodium nitrite, potassium phosphate-monobasic, 40% formaldehyde solution and sucrose were purchased from Fischer Scientific, Fairlawn, N.J. Sephadex G25 was purchased from Pharmacia, Piscataway, N.J., IODO-BEADS were purchased from Pierce, Rockford, Ill. and Na[125I] from New England Nuclear, Boston, Mass. [111In] oxine was purchased from Amersham, Arlington Heights, Ill. Monoclonal mouse anti-proliferating cell nuclear antigen was purchased from Dako A / S, Denmark. All other chemicals were purchased from Sigma Chemical Co., St. Louis, Mo.

[0165] Citrate-phosphate-dextrose anticoagulant solution (CPD) contained 10 mM citric acid, 90 mM trisodium citrate, 15 mM NaH2PO4H2O, and 142 mM dextrose, pH 7.35. Tris-buffered saline consisted of 10 mM tris[hydroxymethy...

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Abstract

The invention provides a method for preventing adverse effects associated with the use of a medical device in a patient by introducing into the patient a device of which at least a portion includes a prophylactic or therapeutic amount of a nitric oxide adduct. The nitric oxide adduct can be present in a matrix coating on a surface of the medical device; coated per se on a surface of the medical device; directly or indirectly bound to reactive sites on a surface of the medical device; or at least a portion of the medical device can be formed of a material, such as a polymer, which includes the nitric oxide adduct. Also disclosed is a method for preventing adverse effects associated with the use of a medical device in a patient by locally administering a nitric oxide adduct to the site of contact of said device with any internal tissue.

Description

RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 10 / 646,713 filed Aug. 25, 2003, which is a continuation of U.S. application Ser. No. 10 / 253,977 filed Sep. 25, 2002, abandoned, which is a continuation of U.S. application Ser. No. 09 / 621,610 filed Jul. 21, 2000, issued as U.S. Pat. No. 6,471,978, which is a continuation of U.S. application Ser. No. 09 / 433,550 filed Nov. 4, 1999, issued as U.S. Pat. No. 6,174,539, which is a continuation of U.S. application Ser. No. 08 / 460,465 filed Jun. 2, 1995, issued as U.S. Pat. No. 6,087,479, which is a continuation-in-part of U.S. application Ser. No. 08 / 123,331 filed Sep. 17, 1993, abandoned. This application is related to U.S. Pat. No. 6,255,277 and U.S. Pat. No. 6,352,709.FIELD OF THE INVENTION [0002] This invention relates to the use of medical devices and to the treatment of damaged vasculature. More particularly, the invention relates to the use of medical devices which are inserted into a patient...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K33/00A61K31/04A61K31/195A61K38/16A61K39/00A61P7/00A61P9/00A61K9/10A61K38/43A61K33/26A61K31/4245A61L33/10A61K31/00A61K31/095A61K31/21A61K31/275A61K31/295A61K31/35A61K31/405A61K31/41A61K31/415A61K31/495A61K31/535A61K31/54A61K31/60A61K31/715A61K38/00A61K38/17A61K38/38A61K38/49A61K38/55A61K39/395A61K45/00A61K45/06A61K47/48A61L33/00A61P7/02
CPCA61K31/00A61K31/04B82Y30/00A61K31/095A61K31/195A61K31/21A61K31/275A61K31/295A61K31/41A61K31/4245A61K31/535A61K33/00A61K33/26A61K38/1709A61K38/38A61K38/49A61K38/556A61K38/58A61K45/06A61K47/48015A61K47/48238A61K47/48992A61L27/54A61L29/16A61L31/16A61L33/0011A61L33/0082A61L2300/114A61L2300/606A61K2300/00A61K47/52A61K47/62A61K47/6957A61P7/00A61P7/02A61P9/00
Inventor STAMLER, JONATHANLOSCALZO, JOSEPHFOLTS, JOHN D.
Owner NITROMED
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