Drug Combinations Useful for Prevention of Restenosis

Abstract

The current invention comprises an approach to solving the clinical problem of restenosis, which involves the administration of combinations of drugs to patients undergoing PTCA or stent implantation. In one embodiment of the invention, an antiproliferative agent such as rapamycin, vincristine or taxol is administered in combination with the anti-inflammatory agent, dexamethasone, to patients systemically, either subcutaneously or intravenously. In another embodiment of the invention, the antiproliferative and anti-inflammatory agents are bound in a single formulation to the surface of a stent by means of incorporation within either a biodegradeable or biostable polymeric coating. Alternatively, such drug combinations could be incorporated into a stent constructed with a grooved reservoir.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority from application Ser. No. 09 / 575,480 filed May 19, 2000, now U.S. Pat. No. 8,029,561; which claims priority from a Provisional Application of the same title, Application No. 60 / 204,417, filed May 12, 2000.FIELD OF THE INVENTION[0002]This invention describes the delivery of different drug combinations, either systemically or locally, particularly from an intravascular stent, directly from micropores in the stent body or mixed or bound to a polymer coating applied on stent, to inhibit neointimal tissue proliferation and thereby prevent restenosis. This invention given either systemically or locally also facilitates the performance of the stent in inhibiting restenosis.BACKGROUND OF THE INVENTION[0003]Atherosclerotic lesions, which limit or obstruct coronary blood flow, are the major cause of ischemic heart disease related mortality, resulting in 500,000-600,000 deaths annually. Percutaneous transluminal coro...

AI Technical Summary

Benefits of technology

The invention is about a way to treat a condition called restenosis, which occurs when a blood vessel becomes narrow again after a procedure to clear it. The invention suggests using a combination of drugs to reduce the growth of muscle cells in the blood vessel and inflammation. These drugs can be applied either systemically or locally, through a stent. The combination therapy may provide better results than using each drug alone. The invention also mentions using other drugs that work differently to further reduce the growth of muscle cells and prevent the formation of new blood vessels.

Problems solved by technology

Atherosclerotic lesions, which limit or obstruct coronary blood flow, are the major cause of ischemic heart disease related mortality, resulting in 500,000-600,000 deaths annually.

A major limitation of this technique is the problem of post-PTCA closure of the vessel, both immediately after PTCA (acute occlusion) and in the long term (restenosis): 30% of patients with subtotal lesions and 50% of patients with chronic total lesions will go on to restenosis after angioplasty.

Additionally, restenosis is a significant problem in patients undergoing saphenous vein bypass graft.

However, unlike animal models, attempts in human angioplasty patients to prevent restenosis by systemic pharmacologic means have thus far been unsuccessful.

Additionally, the 7E3 humanized monoclonal antibody fragment to the platelet GP IIb / IIIa receptor is still under study but has not shown promising results for the reduction in restenosis following angioplasty and stenting.

These agents must be given systemically, however, and attainments of a therapeutically effective dose may not be possible; antiproliferative (or anti-restenosis) concentrations may exceed the known toxic concentrations of these agents so that levels sufficient to produce smooth muscle inhibition may not be reached (Mak and Topol, 1997; Lang et al., 1991; Popma et al., 1991).

Additional clinical trials in which the effectiveness for preventing restenosis of dietary fish oil supplements or cholesterol lowering agents has been examined have shown either conflicting or negative results so that no pharmacological agents are as yet clinically available to prevent post-angioplasty restenosis (Mak and Topol, 1997; Franklin and Faxon, 1993; Serruys, P. W. et al., 1993).

Currently, however, the most effective treatments for restenosis are repeat angioplasty, atherectomy or coronary artery bypass grafting, because no therapeutic agents currently have US Federal Regulatory Agency (FDA) approval for use for the preventing of post-angioplasty restenosis.

This means that effective prevention of restenosis may not be feasible with agents possessing a single mechanism of action; positive therapeutic results may be best achieved through application of several agents with differing therapeutic targets.

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